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Baralić K, Božović P, Đukić-Ćosić D. Deciphering the molecular landscape of ionising radiation-induced eye damage with the help of genomic data mining. Arh Hig Rada Toksikol 2024; 75:91-101. [PMID: 38963141 PMCID: PMC11223508 DOI: 10.2478/aiht-2024-75-3817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Revised: 01/01/2024] [Accepted: 05/01/2024] [Indexed: 07/05/2024] Open
Abstract
Even at low levels, exposure to ionising radiation can lead to eye damage. However, the underlying molecular mechanisms are not yet fully understood. We aimed to address this gap with a comprehensive in silico approach to the issue. For this purpose we relied on the Comparative Toxicogenomics Database (CTD), ToppGene Suite, Cytoscape, GeneMANIA, and Metascape to identify six key regulator genes associated with radiation-induced eye damage (ATM, CRYAB, SIRT1, TGFB1, TREX1, and YAP1), all of which have physical interactions. Some of the identified molecular functions revolve around DNA repair mechanisms, while others are involved in protein binding, enzymatic activities, metabolic processes, and post-translational protein modifications. The biological processes are mostly centred on response to DNA damage, the p53 signalling pathway in particular. We identified a significant role of several miRNAs, such as hsa-miR-183 and hsamiR-589, in the mechanisms behind ionising radiation-induced eye injuries. Our study offers a valuable method for gaining deeper insights into the adverse effects of radiation exposure.
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Affiliation(s)
- Katarina Baralić
- University of Belgrade, Faculty of Pharmacy, Department of Toxicology “Akademik Danilo Soldatović“, Belgrade, Serbia
| | - Predrag Božović
- University of Belgrade Vinča Institute of Nuclear Sciences, Department of Radiation and Environmental Protection, Belgrade, Serbia
| | - Danijela Đukić-Ćosić
- University of Belgrade, Faculty of Pharmacy, Department of Toxicology “Akademik Danilo Soldatović“, Belgrade, Serbia
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2
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Xu S, Yuan Z, Jiang C, Chen W, Li Q, Chen T. DNMT3A Cooperates with YAP/TAZ to Drive Gallbladder Cancer Metastasis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2308531. [PMID: 38380551 PMCID: PMC11040361 DOI: 10.1002/advs.202308531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 02/07/2024] [Indexed: 02/22/2024]
Abstract
Gallbladder cancer (GBC) is an extremely lethal malignancy with aggressive behaviors, including liver or distant metastasis; however, the underlying mechanisms driving the metastasis of GBC remain poorly understood. In this study, it is found that DNA methyltransferase DNMT3A is highly expressed in GBC tumor tissues compared to matched adjacent normal tissues. Clinicopathological analysis shows that DNMT3A is positively correlated with liver metastasis and poor overall survival outcomes in patients with GBC. Functional analysis confirms that DNMT3A promotes the metastasis of GBC cells in a manner dependent on its DNA methyltransferase activity. Mechanistically, DNMT3A interacts with and is recruited by YAP/TAZ to recognize and access the CpG island within the CDH1 promoter and generates hypermethylation of the CDH1 promoter, which leads to transcriptional silencing of CDH1 and accelerated epithelial-to-mesenchymal transition. Using tissue microarrays, the association between the expression of DNMT3A, YAP/TAZ, and CDH1 is confirmed, which affects the metastatic ability of GBC. These results reveal a novel mechanism through which DNMT3A recruitment by YAP/TAZ guides DNA methylation to drive GBC metastasis and provide insights into the treatment of GBC metastasis by targeting the functional connection between DNMT3A and YAP/TAZ.
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Affiliation(s)
- Sunwang Xu
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200125, China
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
| | - Zhiqing Yuan
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200125, China
| | - Cen Jiang
- Central Laboratory, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Wei Chen
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200125, China
| | - Qiwei Li
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200125, China
| | - Tao Chen
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200125, China
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Apostolo D, Ferreira LL, Vincenzi F, Vercellino N, Minisini R, Latini F, Ferrari B, Burlone ME, Pirisi M, Bellan M. From MASH to HCC: the role of Gas6/TAM receptors. Front Immunol 2024; 15:1332818. [PMID: 38298195 PMCID: PMC10827955 DOI: 10.3389/fimmu.2024.1332818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Accepted: 01/02/2024] [Indexed: 02/02/2024] Open
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is the replacement term for what used to be called nonalcoholic steatohepatitis (NASH). It is characterized by inflammation and injury of the liver in the presence of cardiometabolic risk factors and may eventually result in the development of hepatocellular carcinoma (HCC), the most common form of primary liver cancer. Several pathogenic mechanisms are involved in the transition from MASH to HCC, encompassing metabolic injury, inflammation, immune dysregulation and fibrosis. In this context, Gas6 (Growth Arrest-Specific 6) and TAM (Tyro3, Axl, and MerTK) receptors may play important roles. The Gas6/TAM family is involved in the modulation of inflammation, lipid metabolism, fibrosis, tumor progression and metastasis, processes which play an important role in the pathophysiology of acute and chronic liver diseases. In this review, we discuss MASH-associated HCC and the potential involvement of the Gas6/TAM system in disease development and progression. In addition, since therapeutic strategies for MASH and HCC are limited, we also speculate regarding possible future treatments involving the targeting of Gas6 or TAM receptors.
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Affiliation(s)
- Daria Apostolo
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
| | - Luciana L. Ferreira
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
| | - Federica Vincenzi
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
| | - Nicole Vercellino
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
| | - Rosalba Minisini
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
| | - Federico Latini
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
| | - Barbara Ferrari
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
| | - Michela E. Burlone
- Department of Internal Medicine, Azienda Ospedaliero-Universitaria Maggiore Della Carità, Novara, Italy
| | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
- Department of Internal Medicine, Azienda Ospedaliero-Universitaria Maggiore Della Carità, Novara, Italy
- Center on Autoimmune and Allergic Diseases, Università del Piemonte Orientale, Novara, Italy
| | - Mattia Bellan
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
- Department of Internal Medicine, Azienda Ospedaliero-Universitaria Maggiore Della Carità, Novara, Italy
- Center on Autoimmune and Allergic Diseases, Università del Piemonte Orientale, Novara, Italy
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Tang G, Ding G, Wu G, Wang X, Wang T, Zou Q, Sun K, Wu J. Low expression of PRRG2 in kidney renal clear cell carcinoma: an immune infiltration-associated prognostic biomarker. Discov Oncol 2024; 15:9. [PMID: 38227081 DOI: 10.1007/s12672-024-00864-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 01/11/2024] [Indexed: 01/17/2024] Open
Abstract
OBJECTIVE This study aims to explore the prognostic significance of Proline-rich γ-carboxyglutamic acid protein 2 (PRRG2) in Kidney Renal Clear Cell Carcinoma (KIRC), a prevalent and deadly cancer, and its association with immune cell infiltration, a key strategy in developing effective biomarkers. METHODS The study meticulously elucidated the prognostic significance and potential role of PRRG2 in KIRC, correlating its expression with patient sex, age, metastasis, and pathological stage. Utilizing Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA), the involvement of PRRG2 in immune response was investigated. The association between PRRG2 expression and immune cell infiltration was also scrutinized. Ultimately, cellular and tissue identity were confirmed via immunohistochemical staining and quantitative real-time PCR. RESULTS The study elucidates a notable decrease in PRRG2 expression in KIRC patients, correlating with demographic factors, metastasis, and pathological staging, and portending an unfavorable prognosis. Bioinformatic analyses underscore PRRG2's role in immune response, with its expression significantly tied to immune cell infiltration and marker expression. CONCLUSION PRRG2 may potentially impact prognosis in KIRC patients by regulating immune infiltration, thus rendering PRRG2 a promising candidate prognostic biomarker for KIRC-associated immune infiltration.
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Affiliation(s)
- Gonglin Tang
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20 East Yuhuangding Road, Yantai, 264000, Shandong, China
| | - Guixin Ding
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20 East Yuhuangding Road, Yantai, 264000, Shandong, China
| | - Gang Wu
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20 East Yuhuangding Road, Yantai, 264000, Shandong, China
| | - Xiaofeng Wang
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20 East Yuhuangding Road, Yantai, 264000, Shandong, China
| | - Tianqi Wang
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20 East Yuhuangding Road, Yantai, 264000, Shandong, China
| | - Qingsong Zou
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20 East Yuhuangding Road, Yantai, 264000, Shandong, China
| | - Kai Sun
- Urology Department, Shandong Provincial Hospital, Shandong University, Jinan, 250021, China.
| | - Jitao Wu
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20 East Yuhuangding Road, Yantai, 264000, Shandong, China.
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Ma Q, Zhang Y, Liang H, Zhang F, Liu F, Chen S, Hu Y, Jiang L, Hao Y, Li M, Liu Y. EMP3 as a key downstream target of miR-663a regulation interferes with MAPK/ERK signaling pathway to inhibit gallbladder cancer progression. Cancer Lett 2023; 575:216398. [PMID: 37730106 DOI: 10.1016/j.canlet.2023.216398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 08/31/2023] [Accepted: 09/11/2023] [Indexed: 09/22/2023]
Abstract
Gallbladder carcinoma (GBC) is the most common malignancy of the biliary tract, and its molecular pathogenesis remains unclear. Here we explore the functional roles of epithelial membrane protein 3 (EMP3) in GBC progression, which is aberrantly expressed in various types of cancers. The results showed that the expression level of EMP3 was reduced in human GBC tissues compared with non-malignant tissues. Further, the low expression of EMP3 was associated with the poor prognosis of GBC patients by Kaplan-Meier analysis. The ectopic expression of EMP3 inhibited GBC cell proliferation, migration and invasion in vitro and in vivo. Conversely, the depletion of EMP3 promoted GBC cell growth and metastasis. In addition, we found that EMP3 was a target gene of miR-663a, and the downregulation of EMP3 in GBC was attributed to the overexpression of miR-663a. MiR-663a was also shown to be a tumor-promoting factor mediating GBC development. In this study, we demonstrate that downregulation of EMP3 activates MAPK/ERK signaling, which regulates GBC progression. These data reveal the mechanism by which EMP3 inhibits the progression of GBC, suggesting that the miR-663a/EMP3/MAPK/ERK axis may be a new therapeutic target for GBC treatment.
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Affiliation(s)
- Qiang Ma
- Department of Thyroid Oncology, Shanghai East Hospital Affiliated to Tongji University, School of Medicine, Shanghai 200120, China
| | - Yijian Zhang
- Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University, School of Medicine, Shanghai 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai 200127, China
| | - Haibin Liang
- Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University, School of Medicine, Shanghai 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai 200127, China
| | - Fei Zhang
- Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University, School of Medicine, Shanghai 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai 200127, China
| | - Fatao Liu
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai 200127, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai 200127, China
| | - Shili Chen
- Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University, School of Medicine, Shanghai 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai 200127, China
| | - Yunping Hu
- Institute of Pathology and Southwest Cancer Center, The First Affiliated Hospital, Third Military Medical University, Chongqing 400037,China
| | - Lin Jiang
- Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University, School of Medicine, Shanghai 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai 200127, China
| | - Yajuan Hao
- Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University, School of Medicine, Shanghai 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai 200127, China
| | - Maolan Li
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai 200127, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai 200127, China.
| | - Yingbin Liu
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai 200127, China; Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai 200127, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai 200127, China.
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Julius P, Siyumbwa SN, Maate F, Moonga P, Kang G, Kaile T, West JT, Wood C, Angeletti PC. Yes-associated protein-1 overexpression in ocular surface squamous neoplasia; a potential diagnostic marker and therapeutic target. Front Oncol 2023; 13:1213426. [PMID: 37476371 PMCID: PMC10354641 DOI: 10.3389/fonc.2023.1213426] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 06/20/2023] [Indexed: 07/22/2023] Open
Abstract
Yes-associated protein-1 (YAP-1) is a Hippo system transcription factor, which serves as an oncogene in squamous cell carcinoma, and several solid tumors when the Hippo pathway is dysregulated. Yet, the activity of YAP-1 in ocular surface squamous neoplasia (OSSN) has not been determined. Here, we investigate the relationship between YAP-1 overexpression and OSSN. Using a cross-sectional study design, we recruited 227 OSSN patients from the University Teaching Hospitals in Lusaka, Zambia. Immunohistochemistry was used to assess YAP-1 protein overexpression in tumor tissue relative to surrounding benign squamous epithelium. OSSN patient samples (preinvasive, n = 62, 27% and invasive, n = 165, 73%) were studied. One hundred forty-nine invasive tumors contained adjacent preinvasive tissue, bringing the total number of preinvasive lesions examined to 211 (62 + 149). There was adjacent benign squamous epithelium in 50.2% (114/227) of OSSN samples. Nuclear YAP- 1 was significantly overexpressed in preinvasive (Fisher's (F): p <.0001, Monte Carlo (MC): p <.0001) and invasive (F: p <.0001, MC: p <.0001) OSSN in comparison to adjacent benign squamous epithelium when analyzed for basal keratinocyte positive count, staining intensity, expression pattern, and Immunostaining intensity-distribution index. YAP-1 expression did not differ between preinvasive and invasive OSSN (p >.05), keratinizing and non- keratinizing cancer (p >.05), or between T1/T2 and T3/T4 stages in invasive tumors (p >.05). However, grade 2 and 3 tumors had significantly stronger nucleus YAP-1 overexpression intensity than grade 1 tumors (F: p = .0078, MC: p = .0489). By immunohistochemistry, we identified significant overexpression (upregulation of YAP-1 protein expression) in preinvasive and invasive OSSN lesions compared to neighboring benign squamous epithelium. YAP-1 expression was significantly higher in poorly and moderately differentiated invasive squamous cancer than in well-differentiated carcinomas. Overexpression of YAP-1 within the margin of preinvasive and invasive OSSN, but not in the neighboring normal epithelium, indicates that it plays a role in the development and progression of OSSN.
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Affiliation(s)
- Peter Julius
- Department of Pathology and Microbiology, School of Medicine, University of Zambia, Lusaka, Zambia
| | - Stepfanie N. Siyumbwa
- Department of Pathology and Microbiology, School of Medicine, University of Zambia, Lusaka, Zambia
| | - Fred Maate
- Department of Pathology and Microbiology, School of Medicine, University of Zambia, Lusaka, Zambia
| | - Phyllis Moonga
- University Teaching Hospital, Eye Hospital, Lusaka, Zambia
| | - Guobin Kang
- Department of Interdisciplinary Oncology, Louisiana State University Health Science Center, New Orleans, LA, United States
| | - Trevor Kaile
- Department of Pathology and Microbiology, School of Medicine, University of Zambia, Lusaka, Zambia
| | - John T. West
- Department of Interdisciplinary Oncology, Louisiana State University Health Science Center, New Orleans, LA, United States
| | - Charles Wood
- Department of Interdisciplinary Oncology, Louisiana State University Health Science Center, New Orleans, LA, United States
- Nebraska Center for Virology and the School of Biological Sciences, University of Nebraska-Lincoln, NE, United States
| | - Peter C. Angeletti
- Nebraska Center for Virology and the School of Biological Sciences, University of Nebraska-Lincoln, NE, United States
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Zhang L, Jiang L, Zeng L, Jin Z, Dong X, Zhang Y, Chen L, Shu Y, Liu Y, Huang Y. The oncogenic role of NF1 in gallbladder cancer through regulation of YAP1 stability by direct interaction with YAP1. J Transl Med 2023; 21:306. [PMID: 37147639 PMCID: PMC10163693 DOI: 10.1186/s12967-023-04157-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 04/25/2023] [Indexed: 05/07/2023] Open
Abstract
BACKGROUND Gallbladder cancer (GBC) is the most prevalent and invasive biliary tract malignancy. As a GTPase-activating protein, Neurofibromin 1 (NF1) is a tumor suppressor that negatively regulates the RAS signaling pathway, and its abnormality leads to neurofibromatosis type 1 (NF-1) disease. However, the role of NF1 playing in GBC and the underlying molecular mechanism has not been defined yet. METHODS A combination of NOZ and EH-GB1 cell lines as well as nude mice, were utilized in this study. mRNA expression and protein levels of NF1 and YAP1 were evaluated by quantitative real-time PCR (qRT-PCR), western blot (WB), and immunohistochemistry (IHC). In vitro and in vivo assays were performed to explore the biological effects of NF1 in NOZ and EH-GB1 cells via siRNA or lv-shRNA mediated knockdown. Direct interaction between NF1 and YAP1 was detected by confocal microscopy and co-immunoprecipitation (Co-IP), and further confirmed by GST pull-down assay and isothermal titration calorimetry assay (ITC). The stability of proteins was measured by western blot (WB) in the presence of cycloheximide. RESULTS This study showed that a higher level of NF1 and YAP1 was found in GBC samples than in normal tissues and associated with worse prognoses. The NF1 knockdown impaired the proliferation and migration of NOZ in vivo and in vitro by downregulating YAP1 expression. Moreover, NF1 co-localized with YAP1 in NOZ and EH-GB1 cells, and the WW domains of YAP1 specifically recognized the PPQY motif of NF1. The structural modeling also indicated the hydrophobic interactions between YAP1 and NF1. On the other hand, YAP1 knockdown also impaired the proliferation of NOZ in vitro, phenocopying the effects of NF1 knockdown. Overexpression of YAP1 can partially rescue the impaired proliferation in NF1 stably knockdown cells. In mechanism, NF1 interacted with YAP1 and increased the stability of YAP1 by preventing ubiquitination. CONCLUSIONS Our findings discovered a novel oncogenic function of NF1 by directly interacting with YAP1 protein and stabilizing YAP1 to protect it from proteasome degradation in NOZ cells. NF1 may serve as a potential therapeutic target in GBC.
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Affiliation(s)
- Lingxiao Zhang
- Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital, Shanghai Jiao Tong University, Shanghai, 200092, China
- Department of Biliary-Pancreatic Surgery, State Key Laboratory of Oncogenes and Related Genes, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Lin Jiang
- Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital, Shanghai Jiao Tong University, Shanghai, 200092, China
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, 200093, China
| | - Ling Zeng
- Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital, Shanghai Jiao Tong University, Shanghai, 200092, China
| | - Zhaohui Jin
- Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital, Shanghai Jiao Tong University, Shanghai, 200092, China
| | - Xuanjia Dong
- Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital, Shanghai Jiao Tong University, Shanghai, 200092, China
| | - Yuhan Zhang
- Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital, Shanghai Jiao Tong University, Shanghai, 200092, China
| | - Litian Chen
- Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital, Shanghai Jiao Tong University, Shanghai, 200092, China
| | - Yijun Shu
- Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital, Shanghai Jiao Tong University, Shanghai, 200092, China.
| | - Yingbin Liu
- Department of Biliary-Pancreatic Surgery, State Key Laboratory of Oncogenes and Related Genes, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
| | - Ying Huang
- Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital, Shanghai Jiao Tong University, Shanghai, 200092, China.
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Taurodeoxycholic acid-YAP1 upregulates OTX1 in promoting gallbladder cancer malignancy through IFITM3-dependent AKT activation. Oncogene 2023; 42:1466-1477. [PMID: 36928361 DOI: 10.1038/s41388-023-02660-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 02/24/2023] [Accepted: 03/02/2023] [Indexed: 03/18/2023]
Abstract
Orthodenticle homeobox (OTX1) is reported to be involved in numerous cancers, but the expression level and molecular function of OTX1 in gallbladder cancer (GBC) remain unknown. Here, we found the elevated level of OTX1 associated with poor prognosis in human gallbladder cancer. In vitro and in vivo studies of human gallbladder cancer cell lines demonstrated that overexpression of OTX1 promoted cell proliferation, whereas the downregulation inhibited it. Additionally, we found a tight correlation between the serum level of taurodeoxycholic acid (TDCA) and OTX1 expression. TDCA-induced activation of YAP1 by phosphorylation inhibition contributed to the transcriptional activation of OTX1. Mechanistically, we identified that OTX1 activated AKT signaling pathway by transactivating the expression of IFITM3 and thus promoted the proliferation of GBC cells. Taken together, our results showed that TDCA-YAP1-dependent expression of OTX1 regulated IFITM3 and affected GBC proliferation via the AKT signaling pathway. Our experiments also suggested that OTX1 is a novel therapeutic target for GBC.
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Skouras P, Markouli M, Strepkos D, Piperi C. Advances on Epigenetic Drugs for Pediatric Brain Tumors. Curr Neuropharmacol 2023; 21:1519-1535. [PMID: 36154607 PMCID: PMC10472812 DOI: 10.2174/1570159x20666220922150456] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 08/14/2022] [Accepted: 09/08/2022] [Indexed: 11/22/2022] Open
Abstract
Pediatric malignant brain tumors represent the most frequent cause of cancer-related deaths in childhood. The therapeutic scheme of surgery, radiotherapy and chemotherapy has improved patient management, but with minimal progress in patients' prognosis. Emerging molecular targets and mechanisms have revealed novel approaches for pediatric brain tumor therapy, enabling personalized medical treatment. Advances in the field of epigenetic research and their interplay with genetic changes have enriched our knowledge of the molecular heterogeneity of these neoplasms and have revealed important genes that affect crucial signaling pathways involved in tumor progression. The great potential of epigenetic therapy lies mainly in the widespread location and the reversibility of epigenetic alterations, proposing a wide range of targeting options, including the possible combination of chemoand immunotherapy, significantly increasing their efficacy. Epigenetic drugs, including inhibitors of DNA methyltransferases, histone deacetylases and demethylases, are currently being tested in clinical trials on pediatric brain tumors. Additional novel epigenetic drugs include protein and enzyme inhibitors that modulate epigenetic modification pathways, such as Bromodomain and Extraterminal (BET) proteins, Cyclin-Dependent Kinase 9 (CDK9), AXL, Facilitates Chromatin Transcription (FACT), BMI1, and CREB Binding Protein (CBP) inhibitors, which can be used either as standalone or in combination with current treatment approaches. In this review, we discuss recent progress on epigenetic drugs that could possibly be used against the most common malignant tumors of childhood, such as medulloblastomas, high-grade gliomas and ependymomas.
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Affiliation(s)
- Panagiotis Skouras
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Mariam Markouli
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Dimitrios Strepkos
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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Engelsen AST, Lotsberg ML, Abou Khouzam R, Thiery JP, Lorens JB, Chouaib S, Terry S. Dissecting the Role of AXL in Cancer Immune Escape and Resistance to Immune Checkpoint Inhibition. Front Immunol 2022; 13:869676. [PMID: 35572601 PMCID: PMC9092944 DOI: 10.3389/fimmu.2022.869676] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 03/16/2022] [Indexed: 12/12/2022] Open
Abstract
The development and implementation of Immune Checkpoint Inhibitors (ICI) in clinical oncology have significantly improved the survival of a subset of cancer patients with metastatic disease previously considered uniformly lethal. However, the low response rates and the low number of patients with durable clinical responses remain major concerns and underscore the limited understanding of mechanisms regulating anti-tumor immunity and tumor immune resistance. There is an urgent unmet need for novel approaches to enhance the efficacy of ICI in the clinic, and for predictive tools that can accurately predict ICI responders based on the composition of their tumor microenvironment. The receptor tyrosine kinase (RTK) AXL has been associated with poor prognosis in numerous malignancies and the emergence of therapy resistance. AXL is a member of the TYRO3-AXL-MERTK (TAM) kinase family. Upon binding to its ligand GAS6, AXL regulates cell signaling cascades and cellular communication between various components of the tumor microenvironment, including cancer cells, endothelial cells, and immune cells. Converging evidence points to AXL as an attractive molecular target to overcome therapy resistance and immunosuppression, supported by the potential of AXL inhibitors to improve ICI efficacy. Here, we review the current literature on the prominent role of AXL in regulating cancer progression, with particular attention to its effects on anti-tumor immune response and resistance to ICI. We discuss future directions with the aim to understand better the complex role of AXL and TAM receptors in cancer and the potential value of this knowledge and targeted inhibition for the benefit of cancer patients.
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Affiliation(s)
- Agnete S. T. Engelsen
- Centre for Cancer Biomarkers and Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Maria L. Lotsberg
- Centre for Cancer Biomarkers and Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Raefa Abou Khouzam
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates
| | - Jean-Paul Thiery
- Centre for Cancer Biomarkers and Department of Biomedicine, University of Bergen, Bergen, Norway
- Guangzhou Laboratory, Guangzhou, China
- Inserm, UMR 1186, Integrative Tumor Immunology and Immunotherapy, Villejuif, France
| | - James B. Lorens
- Centre for Cancer Biomarkers and Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Salem Chouaib
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates
- Inserm, UMR 1186, Integrative Tumor Immunology and Immunotherapy, Villejuif, France
- Gustave Roussy, Villejuif, France
- Faculty of Medicine, University Paris Sud, Le Kremlin-Bicêtre, France
| | - Stéphane Terry
- Inserm, UMR 1186, Integrative Tumor Immunology and Immunotherapy, Villejuif, France
- Gustave Roussy, Villejuif, France
- Faculty of Medicine, University Paris Sud, Le Kremlin-Bicêtre, France
- Research Department, Inovarion, Paris, France
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11
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Montico B, Giurato G, Pecoraro G, Salvati A, Covre A, Colizzi F, Steffan A, Weisz A, Maio M, Sigalotti L, Fratta E. The pleiotropic roles of circular and long noncoding RNAs in cutaneous melanoma. Mol Oncol 2022; 16:565-593. [PMID: 34080276 PMCID: PMC8807361 DOI: 10.1002/1878-0261.13034] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/30/2021] [Accepted: 05/17/2021] [Indexed: 12/14/2022] Open
Abstract
Cutaneous melanoma (CM) is a very aggressive disease, often characterized by unresponsiveness to conventional therapies and high mortality rates worldwide. The identification of the activating BRAFV600 mutations in approximately 50% of CM patients has recently fueled the development of novel small-molecule inhibitors that specifically target BRAFV600 -mutant CM. In addition, a major progress in CM treatment has been made by monoclonal antibodies that regulate the immune checkpoint inhibitors. However, although target-based therapies and immunotherapeutic strategies have yielded promising results, CM treatment remains a major challenge. In the last decade, accumulating evidence points to the aberrant expression of different types of noncoding RNAs (ncRNAs) in CM. While studies on microRNAs have grown exponentially leading to significant insights on CM biology, the role of circular RNAs (circRNAs) and long noncoding RNAs (lncRNAs) in this tumor is less understood, and much remains to be discovered. Here, we summarize and critically review the available evidence on the molecular functions of circRNAs and lncRNAs in BRAFV600 -mutant CM and CM immunogenicity, providing recent updates on their functional role in targeted therapy and immunotherapy resistance. In addition, we also include an evaluation of several algorithms and databases for prediction and validation of circRNA and lncRNA functional interactions.
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Affiliation(s)
- Barbara Montico
- Immunopathology and Cancer BiomarkersCentro di Riferimento Oncologico di Aviano (CRO)IRCCSAvianoItaly
| | - Giorgio Giurato
- Laboratory of Molecular Medicine and GenomicsDepartment of Medicine, Surgery and Dentistry 'Scuola Medica Salernitana'University of SalernoBaronissiItaly
- Genome Research Center for Health – CRGSUniversity of Salerno Campus of MedicineBaronissiItaly
| | - Giovanni Pecoraro
- Laboratory of Molecular Medicine and GenomicsDepartment of Medicine, Surgery and Dentistry 'Scuola Medica Salernitana'University of SalernoBaronissiItaly
- Genome Research Center for Health – CRGSUniversity of Salerno Campus of MedicineBaronissiItaly
| | - Annamaria Salvati
- Laboratory of Molecular Medicine and GenomicsDepartment of Medicine, Surgery and Dentistry 'Scuola Medica Salernitana'University of SalernoBaronissiItaly
| | - Alessia Covre
- Center for Immuno‐OncologyUniversity Hospital of SienaItaly
- University of SienaItaly
| | - Francesca Colizzi
- Immunopathology and Cancer BiomarkersCentro di Riferimento Oncologico di Aviano (CRO)IRCCSAvianoItaly
| | - Agostino Steffan
- Immunopathology and Cancer BiomarkersCentro di Riferimento Oncologico di Aviano (CRO)IRCCSAvianoItaly
| | - Alessandro Weisz
- Laboratory of Molecular Medicine and GenomicsDepartment of Medicine, Surgery and Dentistry 'Scuola Medica Salernitana'University of SalernoBaronissiItaly
- Genome Research Center for Health – CRGSUniversity of Salerno Campus of MedicineBaronissiItaly
| | - Michele Maio
- Center for Immuno‐OncologyUniversity Hospital of SienaItaly
- University of SienaItaly
- NIBIT Foundation OnlusSienaItaly
| | - Luca Sigalotti
- Oncogenetics and Functional Oncogenomics UnitCentro di Riferimento Oncologico di Aviano (CRO)IRCCSAvianoItaly
| | - Elisabetta Fratta
- Immunopathology and Cancer BiomarkersCentro di Riferimento Oncologico di Aviano (CRO)IRCCSAvianoItaly
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12
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Lotsberg ML, Davidsen KT, D’Mello Peters S, Haaland GS, Rayford A, Lorens JB, Engelsen AST. The Role of AXL Receptor Tyrosine Kinase in Cancer Cell Plasticity and Therapy Resistance. BIOMARKERS OF THE TUMOR MICROENVIRONMENT 2022:307-327. [DOI: 10.1007/978-3-030-98950-7_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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13
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Casati G, Giunti L, Iorio AL, Marturano A, Galli L, Sardi I. Hippo Pathway in Regulating Drug Resistance of Glioblastoma. Int J Mol Sci 2021; 22:ijms222413431. [PMID: 34948224 PMCID: PMC8705144 DOI: 10.3390/ijms222413431] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 11/30/2021] [Accepted: 12/09/2021] [Indexed: 12/13/2022] Open
Abstract
Glioblastoma (GBM) represents the most common and malignant tumor of the Central Nervous System (CNS), affecting both children and adults. GBM is one of the deadliest tumor types and it shows a strong multidrug resistance (MDR) and an immunosuppressive microenvironment which remain a great challenge to therapy. Due to the high recurrence of GBM after treatment, the understanding of the chemoresistance phenomenon and how to stimulate the antitumor immune response in this pathology is crucial. The deregulation of the Hippo pathway is involved in tumor genesis, chemoresistance and immunosuppressive nature of GBM. This pathway is an evolutionarily conserved signaling pathway with a kinase cascade core, which controls the translocation of YAP (Yes-Associated Protein)/TAZ (Transcriptional Co-activator with PDZ-binding Motif) into the nucleus, leading to regulation of organ size and growth. With this review, we want to highlight how chemoresistance and tumor immunosuppression work in GBM and how the Hippo pathway has a key role in them. We linger on the role of the Hippo pathway evaluating the effect of its de-regulation among different human cancers. Moreover, we consider how different pathways are cross-linked with the Hippo signaling in GBM genesis and the hypothetical mechanisms responsible for the Hippo pathway activation in GBM. Furthermore, we describe various drugs targeting the Hippo pathway. In conclusion, all the evidence described largely support a strong involvement of the Hippo pathway in gliomas progression, in the activation of chemoresistance mechanisms and in the development of an immunosuppressive microenvironment. Therefore, this pathway is a promising target for the treatment of high grade gliomas and in particular of GBM.
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Affiliation(s)
- Giacomo Casati
- Neuro-Oncology Unit, Department of Pediatric Oncology, Meyer Children’s Hospital, 50139 Florence, Italy; (L.G.); (A.L.I.); (A.M.); (I.S.)
- Correspondence:
| | - Laura Giunti
- Neuro-Oncology Unit, Department of Pediatric Oncology, Meyer Children’s Hospital, 50139 Florence, Italy; (L.G.); (A.L.I.); (A.M.); (I.S.)
| | - Anna Lisa Iorio
- Neuro-Oncology Unit, Department of Pediatric Oncology, Meyer Children’s Hospital, 50139 Florence, Italy; (L.G.); (A.L.I.); (A.M.); (I.S.)
| | - Arianna Marturano
- Neuro-Oncology Unit, Department of Pediatric Oncology, Meyer Children’s Hospital, 50139 Florence, Italy; (L.G.); (A.L.I.); (A.M.); (I.S.)
| | - Luisa Galli
- Infectious Disease Unit, Department of Health Sciences, University of Florence, 50139 Florence, Italy;
| | - Iacopo Sardi
- Neuro-Oncology Unit, Department of Pediatric Oncology, Meyer Children’s Hospital, 50139 Florence, Italy; (L.G.); (A.L.I.); (A.M.); (I.S.)
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14
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CircPTK2 (hsa_circ_0003221) Contributes to Laryngeal Squamous Cell Carcinoma by the miR-1278/YAP1 Axis. JOURNAL OF ONCOLOGY 2021; 2021:2408384. [PMID: 34691176 PMCID: PMC8528618 DOI: 10.1155/2021/2408384] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 09/08/2021] [Accepted: 09/15/2021] [Indexed: 11/21/2022]
Abstract
Laryngeal cancer accounts for 20% of all head and neck malignancies. Laryngeal squamous cell carcinoma (LSCC) is the most common type of laryngeal cancer and is characterized by squamous differentiation, a high mortality rate, and poor prognosis. Accumulating studies have indicated that circular RNAs (circRNAs) are critical regulators in many cancers. CircPTK2 exerts an important regulatory role in several cancers. In this study, we aimed to elucidate the function of circPTK2 (hsa_circ_0003221) in LSCC. Through a series of investigations, we discovered that circPTK2 was significantly upregulated in LSCC tissues cells. Functionally, cell counting kit-8 (CCK-8) and flow cytometry analyses revealed that knockdown of circPTK2 suppressed LSCC cell viability and the cell cycle while promoting cell apoptosis. Notably, silencing circPTK2 inhibited tumor growth in vivo. Mechanistically, circPTK2 functioned as a molecular sponge of miR-1278 to upregulate YAP1 expression in LSCC cells. Moreover, YAP1 knockdown inhibited malignant phenotypes of LSCC cells. The rescue experiments showed that YAP1 overexpression reversed the effects of circPTK2 on LSCC cells. Therefore, we concluded that circPTK2 facilitates LSCC progression through the miR-1278/YAP1 axis.
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15
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Gu JF, Fu W, Qian HX, Gu WX, Zong Y, Chen Q, Lu L. TBL1XR1 induces cell proliferation and inhibit cell apoptosis by the PI3K/AKT pathway in pancreatic ductal adenocarcinoma. World J Gastroenterol 2020; 26:3586-3602. [PMID: 32742128 PMCID: PMC7366057 DOI: 10.3748/wjg.v26.i25.3586] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 05/09/2020] [Accepted: 05/26/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest solid tumors. Identification of diagnostic and therapeutic biomarkers for PDAC is urgently needed. Transducin (β)-like 1 X-linked receptor 1 (TBL1XR1) has been linked to the progression of various human cancers. Nevertheless, the function and role of TBL1XR1 in pancreatic cancers are unclear.
AIM To elucidate the function and potential mechanism of TBL1XR1 in the development of PDAC.
METHODS Ninety patients with histologically-confirmed PDAC were included in this study. PDAC tumor samples and cell lines were used to determine the expression of TBL1XR1. CCK-8 assays and colony formation assays were carried out to assess PDAC cell viability. Flow cytometry was performed to measure the changes in the cell cycle and cell apoptosis. Changes in related protein expression were measured by western blot analysis. Animal analysis was conducted to confirm the impact of TBL1XR1 in vivo.
RESULTS Patients with TBL1XR1-positive tumors had worse overall survival than those with TBL1XR1-negative tumors. Moreover, we found that TBL1XR1 strongly promoted PDAC cell proliferation and inhibited PDAC cell apoptosis. Moreover, knockdown of TBL1XR1 induced G0/G1 phase arrest. In vivo animal studies confirmed that TBL1XR1 accelerated tumor cell growth. The results of western blot analysis showed that TBL1XR1 might play a key role in regulating PDAC cell proliferation and apoptosis via the PI3K/AKT pathway.
CONCLUSION TBL1XR1 promoted PDAC cell progression and might be an effective diagnostic and therapeutic marker for pancreatic cancer.
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Affiliation(s)
- Jian-Feng Gu
- Department of General Surgery, Changshu No. 1 People’s Hospital Affiliated to Soochow University, Changshu 215500, Jiangsu Province, China
| | - Wei Fu
- Department of Oncology, Changshu No. 1 People’s Hospital Affiliated to Soochow University, Changshu 215500, Jiangsu Province, China
| | - Hai-Xin Qian
- Department of General Surgery, the First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Wen-Xiu Gu
- Department of General Surgery, Changshu No. 1 People’s Hospital Affiliated to Soochow University, Changshu 215500, Jiangsu Province, China
| | - Yang Zong
- Department of General Surgery, Changshu No. 1 People’s Hospital Affiliated to Soochow University, Changshu 215500, Jiangsu Province, China
| | - Qian Chen
- Department of General Surgery, Changshu No. 1 People’s Hospital Affiliated to Soochow University, Changshu 215500, Jiangsu Province, China
| | - Long Lu
- Department of Oncology, Changshu No. 1 People’s Hospital Affiliated to Soochow University, Changshu 215500, Jiangsu Province, China
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16
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García P, Rosa L, Vargas S, Weber H, Espinoza JA, Suárez F, Romero-Calvo I, Elgueta N, Rivera V, Nervi B, Obreque J, Leal P, Viñuela E, Aguayo G, Muñiz S, Sagredo A, Roa JC, Bizama C. Hippo-YAP1 Is a Prognosis Marker and Potentially Targetable Pathway in Advanced Gallbladder Cancer. Cancers (Basel) 2020; 12:cancers12040778. [PMID: 32218280 PMCID: PMC7226626 DOI: 10.3390/cancers12040778] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 03/17/2020] [Accepted: 03/20/2020] [Indexed: 12/15/2022] Open
Abstract
Gallbladder cancer is an aggressive disease with late diagnosis and no efficacious treatment. The Hippo-Yes-associated protein 1 (YAP1) signaling pathway has emerged as a target for the development of new therapeutic interventions in cancers. However, the role of the Hippo-targeted therapy has not been addressed in advanced gallbladder cancer (GBC). This study aimed to evaluate the expression of the major Hippo pathway components mammalian Ste20-like protein kinase 1 (MST1), YAP1 and transcriptional coactivator with PDZ-binding motif (TAZ) and examined the effects of Verteporfin (VP), a small molecular inhibitor of YAP1-TEA domain transcription factor (TEAD) protein interaction, in metastatic GBC cell lines and patient-derived organoids (PDOs). Immunohistochemical analysis revealed that advanced GBC patients had high nuclear expression of YAP1. High nuclear expression of YAP1 was associated with poor survival in GBC patients with subserosal invasion (pT2). Additionally, advanced GBC cases showed reduced expression of MST1 compared to chronic cholecystitis. Both VP treatment and YAP1 siRNA inhibited the migration ability in GBC cell lines. Interestingly, gemcitabine resistant PDOs with high nuclear expression of YAP1 were sensitive to VP treatment. Taken together, our results suggest that key components of the Hippo-YAP1 signaling pathway are dysregulated in advanced gallbladder cancer and reveal that the inhibition YAP1 may be a candidate for targeted therapy.
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Affiliation(s)
- Patricia García
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; (P.G.); (L.R.); (F.S.); (N.E.); (V.R.); (J.O.); (A.S.)
| | - Lorena Rosa
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; (P.G.); (L.R.); (F.S.); (N.E.); (V.R.); (J.O.); (A.S.)
- Applied Molecular and Cellular Biology PhD Program, Universidad de La Frontera, Temuco 4811230, Chile
| | - Sergio Vargas
- Department of Hematology Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile; (S.V.); (B.N.); (S.M.)
| | - Helga Weber
- Centre of Excellence in Translational Medicine (CEMT) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de la Frontera, Temuco 4810296, Chile; (H.W.); (P.L.)
| | - Jaime A. Espinoza
- SciLifeLab, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Stockholm 17165, Sweden;
| | - Felipe Suárez
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; (P.G.); (L.R.); (F.S.); (N.E.); (V.R.); (J.O.); (A.S.)
| | - Isabel Romero-Calvo
- Biomedical Visualization Graduate Program, Department of Biomedical and Health Information Sciences. College of Applied Health Sciences. University of Illinois at Chicago, Chicago, IL 60607, USA;
| | - Nicole Elgueta
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; (P.G.); (L.R.); (F.S.); (N.E.); (V.R.); (J.O.); (A.S.)
| | - Vanessa Rivera
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; (P.G.); (L.R.); (F.S.); (N.E.); (V.R.); (J.O.); (A.S.)
| | - Bruno Nervi
- Department of Hematology Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile; (S.V.); (B.N.); (S.M.)
| | - Javiera Obreque
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; (P.G.); (L.R.); (F.S.); (N.E.); (V.R.); (J.O.); (A.S.)
| | - Pamela Leal
- Centre of Excellence in Translational Medicine (CEMT) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de la Frontera, Temuco 4810296, Chile; (H.W.); (P.L.)
| | - Eduardo Viñuela
- Department of Digestive Surgery, Hepato-Bilio-Pancreatic Surgery Unit, Surgery Service, Complejo Asistencial Hospital Dr. Sótero del Río, Santiago 8207257, Chile;
| | - Gloria Aguayo
- Department of Pathology, Complejo Asistencial Hospital Dr. Sótero del Río, Santiago 8207257, Chile;
| | - Sabrina Muñiz
- Department of Hematology Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile; (S.V.); (B.N.); (S.M.)
| | - Alfredo Sagredo
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; (P.G.); (L.R.); (F.S.); (N.E.); (V.R.); (J.O.); (A.S.)
| | - Juan C. Roa
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; (P.G.); (L.R.); (F.S.); (N.E.); (V.R.); (J.O.); (A.S.)
- Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
- Correspondence: (J.C.R.); (C.B); Tel.: +56-22354-9241(C.B.); +56-22354-1061 (J.C.R)
| | - Carolina Bizama
- Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; (P.G.); (L.R.); (F.S.); (N.E.); (V.R.); (J.O.); (A.S.)
- Correspondence: (J.C.R.); (C.B); Tel.: +56-22354-9241(C.B.); +56-22354-1061 (J.C.R)
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17
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Guo Q, Quan M, Dong J, Bai J, Wang J, Han R, Wang W, Cai Y, Lv YQ, Chen Q, Xu H, Lyu HD, Deng L, Zhou D, Xiao X, De Langhe S, Billadeau DD, Lou Z, Zhang JS. The WW domains dictate isoform-specific regulation of YAP1 stability and pancreatic cancer cell malignancy. Theranostics 2020; 10:4422-4436. [PMID: 32292505 PMCID: PMC7150473 DOI: 10.7150/thno.42795] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 03/02/2020] [Indexed: 12/12/2022] Open
Abstract
YAP1 is a key mediator of the Hippo pathway capable of exerting a profound effect on organ size as well as tumorigenesis. Alternative mRNA splicing of human YAP1 results in at least 8 protein isoforms that differ within the 2nd WW motif and the transcriptional activation domain. Methods: To investigate the isoform-specific differences in their mRNA expression, transcriptional activity and tumor-promoting function, we cloned cDNA encoding all of the eight YAP1 protein isoforms. Then, we examined their mRNA expression, subcellular localization, transcriptional regulation properties, interactions with key regulatory partners, and protein stability in response to changes in cell density, as well as their effects on pancreatic cancer cell malignancy both in vitro and in vivo. Results: Multiple YAP1 mRNA isoforms are expressed in commonly used pancreatic cancer lines as well as human pancreatic cancer PDX lines. Based on the analysis of heterologous reporter and endogenous target genes, all YAP1 isoforms are capable of activating transcription, albeit to a different extent. Importantly, we unveiled a marked discrepancy between the mRNA and protein expression levels of the YAP1-1 and YAP1-2 isoforms. We further discovered that the YAP1-2 isoform, which contains two tandem WW motifs, is less stable at the protein level, particularly at high cell densities. Mechanistically, we found that the presence of the 2nd WW motif in YAP1-2 facilitates the de novo formation of the YAP1-2/AMOT/LATS1 complex and contributes to a stronger binding of YAP1-2 to LATS1 and subsequently increased YAP1-2 ubiquitination and degradation by β-TRCP. Conclusion: Our data reveals a potent effect of YAP1-1 on pancreatic cancer malignancy in vitro and in vivo and provides novel mechanistic insight into isoform-specific and cell density-dependent regulation of YAP1 stability, as well as its impact on cancer malignancy.
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Affiliation(s)
- Qiang Guo
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Meiyu Quan
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Jinglai Dong
- Center for Precision Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Jing Bai
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Jie Wang
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Rui Han
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Wei Wang
- Center for Precision Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Yaxin Cai
- Center for Precision Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Yu-Qing Lv
- Center for Precision Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Qianjie Chen
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Huijing Xu
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Han-Deng Lyu
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Liancheng Deng
- Center for Precision Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Depu Zhou
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Xueyuan Xiao
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Beijing Normal University, Beijing 100875, China
| | - Stijn De Langhe
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, 35294-2182 AL, USA
| | - Daniel D. Billadeau
- Division of Oncology Research, and Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - Zhenkun Lou
- Division of Oncology Research, and Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - Jin-San Zhang
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
- Center for Precision Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
- Division of Oncology Research, and Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
- Institute of Life Sciences, Wenzhou University, Wenzhou, Zhejiang 325035, China
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18
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AXL as a Target in Breast Cancer Therapy. JOURNAL OF ONCOLOGY 2020; 2020:5291952. [PMID: 32148495 PMCID: PMC7042526 DOI: 10.1155/2020/5291952] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 01/18/2020] [Indexed: 12/21/2022]
Abstract
AXL is a receptor tyrosine kinase (RTK) that has been implicated in diverse tumor-promoting processes such as proliferation, migration, invasion, survival, and apoptosis. AXL therefore plays a role in cancer progression, and AXL has been implicated in a wide variety of malignancies from solid tumors to hematopoietic cancers where it is often associated with poor prognosis. In cancer, AXL has been shown to promote epithelial to mesenchymal transition (EMT), metastasis formation, drug resistance, and a role for AXL in modulation of the tumor microenvironment and immune response has been identified. In light of these activities multiple AXL inhibitors have been developed, and several of these have entered clinical trials in the U.S. In breast cancer, high levels of AXL expression have been observed. The role of AXL in cancer with a focus on therapeutic implications for breast cancer is discussed.
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Zhang Y, Du P, Li Y, Zhu Q, Song X, Liu S, Hao J, Liu L, Liu F, Hu Y, Jiang L, Ma Q, Lu W, Liu Y. TASP1 Promotes Gallbladder Cancer Cell Proliferation and Metastasis by Up-regulating FAM49B via PI3K/AKT Pathway. Int J Biol Sci 2020; 16:739-751. [PMID: 32071545 PMCID: PMC7019140 DOI: 10.7150/ijbs.40516] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Accepted: 12/06/2019] [Indexed: 12/19/2022] Open
Abstract
The highly conserved protease TASP1 not only takes part in critical site-specific proteolysis, but also plays an important role in numerous liquid and solid malignancies. However, the TASP1 expression and its biological regulation function in malignant gallbladder carcinoma (GBC) remain fully unknown. Here we observed that TASP1 levels were substantially overexpressed in GBC samples compared with non-tumor tissues. High TASP1 level was closely associated with T stage and metastasis, and was also correlated with poor prognosis in GBC patients. The depletion of TASP1 inhibited GBC cell proliferation and metastasis in vitro and in vivo. Furthermore, we first revealed that FAM49B had biological function and was positively regulated by TASP1 activating PI3K/AKT signaling pathway in GBC. At the same time, FAM49B also promoted GBC cell proliferation and migration. Inhibition of PI3K/AKT with LY294002 or FAM49B expression abrogated Myc-TASP1/Lv-shTASP1-induced GBC cell proliferation and motility. In conclusion, these findings demonstrate that TASP1 is critical for GBC progression via TASP1-PI3K/AKT-FAM49B axis and it may be a novel prognostic factor. The therapeutic targeting TASP1 may be a potential treatment approach for GBC patients.
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Affiliation(s)
- Yijian Zhang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai 200092, China
| | - Pengcheng Du
- Department of General Surgery, Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang 330006, China
| | - Yang Li
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai 200092, China
| | - Qin Zhu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai 200092, China
| | - Xiaoling Song
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai 200092, China
| | - Shibo Liu
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai 200092, China
| | - Jiaqi Hao
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai 200092, China
| | - Liguo Liu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai 200092, China
| | - Fatao Liu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai 200092, China
| | - Yunping Hu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai 200092, China
| | - Lin Jiang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai 200092, China
| | - Qiang Ma
- Department of Thyroid Oncology, Shanghai East Hospital Affiliated to Tongji University School of Medicine, 150 Jimo Road, Shanghai 200120, China
| | - Wei Lu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai 200092, China
| | - Yingbin Liu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai 200092, China
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20
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Fang D, Peng J, Wang G, Zhou D, Geng X. Upregulation of eukaryotic translation initiation factor 4E associates with a poor prognosis in gallbladder cancer and promotes cell proliferation in vitro and in vivo. Int J Mol Med 2019; 44:1325-1332. [PMID: 31432159 PMCID: PMC6713416 DOI: 10.3892/ijmm.2019.4317] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 06/11/2019] [Indexed: 01/08/2023] Open
Abstract
Eukaryotic translation initiation factor 4 (eIF4E) has been demonstrated to promote tumorigenesis in different types of cancer; however, whether eIF4E is involved in the development of GBC is unclear. The present study aimed to explore the biological function of eIF4E in gallbladder cancer (GBC) and identified that the expression level of eIF4E was significantly increased in GBC tissues compared with that in normal gallbladder tissues. The overall survival (OS) was also shorter in the group of patients with GBC with increased eIF4E expression. Increased eIF4E was correlated with advanced stage and higher histologic grade. Knockdown of eIF4E significantly inhibited cell proliferation, colony formation and cell cycle-associated protein expression levels in 2 GBC cell lines. The weight of the tumors in the eIF4E knockdown group was remarkably decreased compared with the control group. It also was revealed that knockdown of eIF4E is associated with upregulating cyclin-dependent kinase inhibitor 1B and down-regulating the expression levels of cyclin E1 and cyclin D1 in vitro and in vivo. These data demonstrated that eIF4E is a novel prognostic marker in GBC and may serve a critical role in the regulation of cell proliferation.
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Affiliation(s)
- Debao Fang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230031, P.R China
| | - Jing Peng
- Department of Surgery, The High‑Tech Zone Branch of The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230088, P.R China
| | - Guobing Wang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230031, P.R China
| | - Dachen Zhou
- Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230012, P.R China
| | - Xiaoping Geng
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230031, P.R China
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21
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Zhang Z, Zheng X, Li J, Duan J, Cui L, Yang L, Zhang L, Zhang Q, Wang X. Overexpression of UBR5 promotes tumor growth in gallbladder cancer via PTEN/PI3K/Akt signal pathway. J Cell Biochem 2019; 120:11517-11524. [PMID: 30775814 DOI: 10.1002/jcb.28431] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 12/29/2018] [Accepted: 01/09/2019] [Indexed: 01/24/2023]
Abstract
As a key regulator of the ubiquitin-proteasome system, ubiquitin protein ligase E3 component N-recognin 5 (UBR5) plays an important role in various cancers. In this study, our results showed for the first time that UBR5 was overexpressed in gallbladder cancer (GBC) tumor tissues. UBR5 overexpression was significantly associated with tumor size, histological and tumor differentiation. UBR5 overexpression was also associated with poor prognosis in patients with GBC. The knockdown of UBR5 remarkably inhibited the cell proliferation and colony formation of GBC-Shandong (SD) cells in vitro and in vivo. UBR5 potentially increases the level of protein kinase B phosphorylation via the degradation of phosphatase and tensin homolog, which contributes to tumor growth in GBC. UBR5 may be an important biomarker for predicting the prognosis of patients with GBC.
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Affiliation(s)
- Zhen Zhang
- Department of Gastrointestinal Surgery, Peking University People's Hospital, Beijing, China.,Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin, China
| | - Xin Zheng
- Graduate School of Tianjin Medical University, Tianjin, China.,Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin, China
| | - Jiaxin Li
- Graduate School of Tianjin Medical University, Tianjin, China.,Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin, China
| | - Jutao Duan
- Department of Minimal Invasive Surgery, Tianjin Nankai Hospital, Tianjin, China
| | - Lihua Cui
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin, China
| | - Lei Yang
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin, China
| | - Lanqiu Zhang
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin, China
| | - Qi Zhang
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin, China
| | - Ximo Wang
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin, China
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22
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Sugiura K, Mishima T, Takano S, Yoshitomi H, Furukawa K, Takayashiki T, Kuboki S, Takada M, Miyazaki M, Ohtsuka M. The Expression of Yes-Associated Protein (YAP) Maintains Putative Cancer Stemness and Is Associated with Poor Prognosis in Intrahepatic Cholangiocarcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:1863-1877. [PMID: 31220448 DOI: 10.1016/j.ajpath.2019.05.014] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 04/22/2019] [Accepted: 05/21/2019] [Indexed: 02/07/2023]
Abstract
Intrahepatic cholangiocarcinoma (ICC) is resistant to most chemotherapeutic agents. Yes-associated protein (YAP) is related to tumor progression; however, its role in ICC remains unknown. We investigated the mechanism underlying YAP-mediated cancer progression by focusing on the property of cancer stem cells (CSCs) in ICC. Immunohistochemistry results revealed the positive YAP expression in 37 of 52 resected ICC cases. Those with positive YAP expression showed poor prognosis in Kaplan-Meier analysis (P = 0.023). YAP expression was associated with vimentin and the putative CSC marker, hepatic oval cell marker 6 (OV-6). The knockdown of YAP expression using specific siRNAs in ICC cells decreased octamer-binding transcription factor 4 (OCT4) expression in Western blot analyses and OV-6 and CD133 expression in flow cytometry analysis. Verteporfin, a YAP inhibitor, decreased N-cadherin and OCT4 expression in Western blot analyses. In vitro sphere formation and anoikis resistance assays revealed the impairment in CSC property and anoikis resistance in response to the decrease in YAP expression. Verteporfin treatment activated the protein kinase B/mechanistic target of rapamycin signaling pathway and dramatically impaired IL-6-stimulated STAT3 phosphorylation in ICC cells. The combination of verteporfin and rapamycin, an inhibitor of mechanistic target of rapamycin phosphorylation, inhibited cell proliferation and tumor growth. In conclusion, verteporfin regulates multiple signaling pathways and, in combination with rapamycin, might be a promising therapeutic strategy for ICC treatment.
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Affiliation(s)
- Kensuke Sugiura
- Department of General Surgery, Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Takashi Mishima
- Department of General Surgery, Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Shigetsugu Takano
- Department of General Surgery, Chiba University, Graduate School of Medicine, Chiba, Japan.
| | - Hideyuki Yoshitomi
- Department of General Surgery, Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Katsunori Furukawa
- Department of General Surgery, Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Tsukasa Takayashiki
- Department of General Surgery, Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Satoshi Kuboki
- Department of General Surgery, Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Mamoru Takada
- Department of General Surgery, Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Masaru Miyazaki
- Department of General Surgery, Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Masayuki Ohtsuka
- Department of General Surgery, Chiba University, Graduate School of Medicine, Chiba, Japan.
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23
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Badarni M, Prasad M, Balaban N, Zorea J, Yegodayev KM, Joshua BZ, Dinur AB, Grénman R, Rotblat B, Cohen L, Elkabets M. Repression of AXL expression by AP-1/JNK blockage overcomes resistance to PI3Ka therapy. JCI Insight 2019; 5:125341. [PMID: 30860495 DOI: 10.1172/jci.insight.125341] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
AXL overexpression is a common resistance mechanism to anti-cancer therapies, including the resistance to BYL719 (Alpelisib) - the p110α isoform specific inhibitor of phosphoinositide 3-kinase (PI3K) - in esophagus and head and neck squamous cell carcinoma (ESCC, HNSCC respectively). However, the mechanisms underlying AXL overexpression in resistance to BYL719 remain elusive. Here we demonstrated that the AP-1 transcription factors, c-JUN and c-FOS, regulate AXL overexpression in HNSCC and ESCC. The expression of AXL was correlated with that of c-JUN both in HNSCC patients and in HNSCC and ESCC cell lines. Silencing of c-JUN and c-FOS expression in tumor cells downregulated AXL expression and enhanced the sensitivity of human papilloma virus positive (HPVPos) and negative (HPVNeg) tumor cells to BYL719 in vitro. Blocking of the c-JUN N-terminal kinase (JNK) using SP600125 in combination with BYL719 showed a synergistic anti-proliferative effect in vitro, which was accompanied by AXL downregulation and potent inhibition of the mTOR pathway. In vivo, the BYL719-SP600125 drug combination led to the arrest of tumor growth in cell line-derived and patient-derived xenograft models, and in syngeneic head and neck murine cancer models. Collectively, our data suggests that JNK inhibition in combination with anti-PI3K therapy is a new therapeutic strategy that should be tested in HPVPos and HPVNeg HNSCC and ESCC patients.
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Affiliation(s)
- Mai Badarni
- The Shraga Segal Department of Microbiology, Immunology and Genetics, and.,Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Manu Prasad
- The Shraga Segal Department of Microbiology, Immunology and Genetics, and.,Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Noa Balaban
- The Shraga Segal Department of Microbiology, Immunology and Genetics, and.,Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Jonathan Zorea
- The Shraga Segal Department of Microbiology, Immunology and Genetics, and.,Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Ksenia M Yegodayev
- The Shraga Segal Department of Microbiology, Immunology and Genetics, and.,Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Ben-Zion Joshua
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.,Department of Otolaryngology - Head & Neck Surgery, Soroka University Medical Center, Beer-Sheva, Israel
| | - Anat Bahat Dinur
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.,Department of Otolaryngology - Head & Neck Surgery, Soroka University Medical Center, Beer-Sheva, Israel
| | - Reidar Grénman
- Department of Otorhinolaryngology - Head & Neck Surgery, Turku University and Turku University Hospital, Turku, Finland
| | - Barak Rotblat
- Department of Life Sciences, Ben-Gurion University of the Negev, and.,The National Institute for Biotechnology in the Negev, Beer Sheva, Israel
| | - Limor Cohen
- The Shraga Segal Department of Microbiology, Immunology and Genetics, and.,Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Moshe Elkabets
- The Shraga Segal Department of Microbiology, Immunology and Genetics, and.,Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
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24
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Guo L, Chen Y, Luo J, Zheng J, Shao G. YAP1 overexpression is associated with poor prognosis of breast cancer patients and induces breast cancer cell growth by inhibiting PTEN. FEBS Open Bio 2019; 9:437-445. [PMID: 30868052 PMCID: PMC6396162 DOI: 10.1002/2211-5463.12597] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 11/11/2018] [Accepted: 12/10/2018] [Indexed: 01/09/2023] Open
Abstract
YES‐associated protein 1 (YAP1) plays a key role as a transcriptional coactivator in the Hippo tumor suppressor pathway. YAP1 is overexpressed in a variety of cancers and is considered to be encoded by a proto‐oncogene. However, the role of YAP1 remains debatable, because both gain and loss of YAP1 expression have both been reported in breast cancer (BC). Here, we found that elevated expression of YAP1 mRNA in BC was negatively correlated with relapse‐free, distant metastases‐free and overall survival rates. We then knocked down or overexpressed YAP1 in human BC cells, and examined cell proliferation, apoptosis, and tumorigenic ability in vivo. We identified that YAP1 promotes cell growth and inhibits cell apoptosis of BC through the phosphatase and tensin homolog deleted on chromosome 10–AKT signaling pathway, and thus suggest that YAP1 might serve as a new target for inhibiting BC progression.
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Affiliation(s)
- Liwen Guo
- Department of Interventional Radiology Zhejiang Cancer Hospital Hangzhou China
| | - Yutang Chen
- Department of Interventional Radiology Zhejiang Cancer Hospital Hangzhou China
| | - Jun Luo
- Department of Interventional Radiology Zhejiang Cancer Hospital Hangzhou China
| | - Jiaping Zheng
- Department of Interventional Radiology Zhejiang Cancer Hospital Hangzhou China
| | - Guoliang Shao
- Department of Interventional Radiology Zhejiang Cancer Hospital Hangzhou China
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25
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Ma Q, Zhang Y, Liang H, Zhang F, Liu F, Chen S, Hu Y, Jiang L, Hao Y, Li M, Liu Y. RETRACTED: EMP3, which is regulated by miR-663a, suppresses gallbladder cancer progression via interference with the MAPK/ERK pathway. Cancer Lett 2018; 430:97-108. [PMID: 29778567 DOI: 10.1016/j.canlet.2018.05.022] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2018] [Revised: 05/14/2018] [Accepted: 05/15/2018] [Indexed: 12/15/2022]
Abstract
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor. Following the publication of the above article, the Editor was notified that images were duplicated in the migration and invasion experiments in Figures 3A, 6C, 7D and 8D: https://pubpeer.com/publications/76E82FD26E33503D7CCAC01C324AFA. The Editor has taken the decision to retract the paper as it is no longer acceptable in its current form
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Affiliation(s)
- Qiang Ma
- Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, No. 1665 Kongjiang Road, Shanghai, 200092, China.
| | - Yijian Zhang
- Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, No. 1665 Kongjiang Road, Shanghai, 200092, China.
| | - Haibin Liang
- Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, No. 1665 Kongjiang Road, Shanghai, 200092, China.
| | - Fei Zhang
- Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, No. 1665 Kongjiang Road, Shanghai, 200092, China.
| | - Fatao Liu
- Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, No. 1665 Kongjiang Road, Shanghai, 200092, China.
| | - Shili Chen
- Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, No. 1665 Kongjiang Road, Shanghai, 200092, China.
| | - Yunping Hu
- Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, No. 1665 Kongjiang Road, Shanghai, 200092, China.
| | - Lin Jiang
- Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, No. 1665 Kongjiang Road, Shanghai, 200092, China.
| | - Yajuan Hao
- Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, No. 1665 Kongjiang Road, Shanghai, 200092, China.
| | - Maolan Li
- Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, No. 1665 Kongjiang Road, Shanghai, 200092, China.
| | - Yingbin Liu
- Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai, 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, No. 1665 Kongjiang Road, Shanghai, 200092, China.
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26
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Hippo pathway affects survival of cancer patients: extensive analysis of TCGA data and review of literature. Sci Rep 2018; 8:10623. [PMID: 30006603 PMCID: PMC6045671 DOI: 10.1038/s41598-018-28928-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 06/29/2018] [Indexed: 12/12/2022] Open
Abstract
The disruption of the Hippo pathway occurs in many cancer types and is associated with cancer progression. Herein, we investigated the impact of 32 Hippo genes on overall survival (OS) of cancer patients, by both analysing data from The Cancer Genome Atlas (TCGA) and reviewing the related literature. mRNA and protein expression data of all solid tumors except pure sarcomas were downloaded from TCGA database. Thirty-two Hippo genes were considered; for each gene, patients were dichotomized based on median expression value. Survival analyses were performed to identify independent predictors, taking into account the main clinical-pathological features affecting OS. Finally, independent predictors were correlated with YAP1 oncoprotein expression. At least one of the Hippo genes is an independent prognostic factor in 12 out of 13 considered tumor datasets. mRNA levels of the independent predictors coherently correlate with YAP1 in glioma, kidney renal clear cell, head and neck, and bladder cancer. Moreover, literature data revealed the association between YAP1 levels and OS in gastric, colorectal, hepatocellular, pancreatic, and lung cancer. Herein, we identified cancers in which Hippo pathway affects OS; these cancers should be candidates for YAP1 inhibitors development and testing.
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27
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Hirschi KM, Chapman S, Hall P, Ostergar A, Winden DR, Reynolds PR, Arroyo JA. Gas6 protein induces invasion and reduces inflammatory cytokines in oral squamous cell carcinoma. J Oral Pathol Med 2018; 47:748-754. [PMID: 29856094 DOI: 10.1111/jop.12738] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/28/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND Gas6 protein is involved in the progression of cancers and has been demonstrated to have a role in inflammation. Oral squamous cell carcinoma is a common form of oral cancer, and it commonly expresses Gas6. Our objective was to determine the effects of Gas6 on oral squamous cell carcinoma invasion and identify signaling molecules and cytokines associated with Gas6-mediated invasion. METHODS Ca9-22 cells were cultured in the presence or absence of Gas6. Real-time cell invasion was evaluated, and cultured cells were lysed for Western blot analysis. Cell medium was collected and assayed for cytokine elaboration. RESULTS Treatment of cells with Gas6 resulted in: (i) increased invasion, (ii) increased expression of Gas6 and AXL receptor, (iii) reduced invasion when AXL was inhibited, (iv) decreased ERK activation, (v) increased AKT activation, and (vi) decreased secretion of G-CSF, IL-2, IL-6, and IL-8. CONCLUSIONS Gas6 increases invasion of oral squamous cell carcinoma, and the invasion correlates with the increased AKT and the downregulation of pro-inflammatory cytokines. These results may prove useful in providing avenues that explain the role of Gas6 in the development and progression of oral squamous cell carcinoma.
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Affiliation(s)
- Kelsey M Hirschi
- Lung and Placenta Research Laboratory, Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT, USA
| | - Steven Chapman
- Lung and Placenta Research Laboratory, Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT, USA
| | - Parker Hall
- Lung and Placenta Research Laboratory, Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT, USA
| | - Adam Ostergar
- Lung and Placenta Research Laboratory, Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT, USA
| | - Duane R Winden
- College of Dental Medicine, Roseman University of Health Sciences, South Jordan, UT, USA
| | - Paul R Reynolds
- Lung and Placenta Research Laboratory, Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT, USA
| | - Juan A Arroyo
- Lung and Placenta Research Laboratory, Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT, USA
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Dehghanian F, Hojati Z, Hosseinkhan N, Mousavian Z, Masoudi-Nejad A. Reconstruction of the genome-scale co-expression network for the Hippo signaling pathway in colorectal cancer. Comput Biol Med 2018; 99:76-84. [PMID: 29890510 DOI: 10.1016/j.compbiomed.2018.05.023] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Revised: 05/24/2018] [Accepted: 05/24/2018] [Indexed: 01/22/2023]
Abstract
The Hippo signaling pathway (HSP) has been identified as an essential and complex signaling pathway for tumor suppression that coordinates proliferation, differentiation, cell death, cell growth and stemness. In the present study, we conducted a genome-scale co-expression analysis to reconstruct the HSP in colorectal cancer (CRC). Five key modules were detected through network clustering, and a detailed discussion of two modules containing respectively 18 and 13 over and down-regulated members of HSP was provided. Our results suggest new potential regulatory factors in the HSP. The detected modules also suggest novel genes contributing to CRC. Moreover, differential expression analysis confirmed the differential expression pattern of HSP members and new suggested regulatory factors between tumor and normal samples. These findings can further reveal the importance of HSP in CRC.
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Affiliation(s)
- Fariba Dehghanian
- Division of Genetics, Department of Biology, Faculty of Sciences, University of Isfahan, P.O. Box 81746-73441, Isfahan, Iran
| | - Zohreh Hojati
- Division of Genetics, Department of Biology, Faculty of Sciences, University of Isfahan, P.O. Box 81746-73441, Isfahan, Iran.
| | - Nazanin Hosseinkhan
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Laboratory of Systems Biology and Bioinformatics (LBB), Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Zaynab Mousavian
- Department of Computer Science, School of Mathematics, Statistics, and Computer Science, University of Tehran, Tehran, Iran; Laboratory of Systems Biology and Bioinformatics (LBB), Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Ali Masoudi-Nejad
- Laboratory of Systems Biology and Bioinformatics (LBB), Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
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Warren JSA, Xiao Y, Lamar JM. YAP/TAZ Activation as a Target for Treating Metastatic Cancer. Cancers (Basel) 2018; 10:cancers10040115. [PMID: 29642615 PMCID: PMC5923370 DOI: 10.3390/cancers10040115] [Citation(s) in RCA: 116] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 04/01/2018] [Accepted: 04/03/2018] [Indexed: 12/20/2022] Open
Abstract
Yes-Associated Protein (YAP) and Transcriptional Co-activator with PDZ-binding Motif (TAZ) have both emerged as important drivers of cancer progression and metastasis. YAP and TAZ are often upregulated or nuclear localized in aggressive human cancers. There is abundant experimental evidence demonstrating that YAP or TAZ activation promotes cancer formation, tumor progression, and metastasis. In this review we summarize the evidence linking YAP/TAZ activation to metastasis, and discuss the roles of YAP and TAZ during each step of the metastatic cascade. Collectively, this evidence strongly suggests that inappropriate YAP or TAZ activity plays a causal role in cancer, and that targeting aberrant YAP/TAZ activation is a promising strategy for the treatment of metastatic disease. To this end, we also discuss several potential strategies for inhibiting YAP/TAZ activation in cancer and the challenges each strategy poses.
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Affiliation(s)
- Janine S A Warren
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY 12208, USA.
| | - Yuxuan Xiao
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY 12208, USA.
| | - John M Lamar
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY 12208, USA.
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Bo X, Wang J, Suo T, Ni X, Liu H, Shen S, Li M, Wang Y, Liu H, Xu J. Tumor-infiltrating mast cells predict prognosis and gemcitabine-based adjuvant chemotherapeutic benefit in biliary tract cancer patients. BMC Cancer 2018; 18:313. [PMID: 29562907 PMCID: PMC5863450 DOI: 10.1186/s12885-018-4220-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2017] [Accepted: 03/13/2018] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Recent studies have reported TIMs play an important role in tumors progression or regression, but the effect of TIMs in biliary tract cancer remains unclear. The aim of this study is to investigate the prognostic value of tumor infiltrating mast cells (TIMs) and its influence on gemcitabine-based adjuvant chemotherapy (ACT) benefits in biliary tract cancer patients after surgery. METHODS TIMs were evaluated by immunohistochemical staining of tryptase in 250 patients with resected gallbladder carcinoma (GBC) or extrahepatic bile duct carcinoma (EBDC) from Zhongshan Hospital. The relationships between TIMs and clinicopathological factors and postoperative prognosis were analyzed respectively. RESULTS High TIMs infiltration was significantly correlated with prolonged overall survival (OS). Furthermore, multivariate analysis indicated TNM stage and TIMs as independent prognostic factors for OS. Patients with high TIMs infiltration appeared to significantly benefit from Gemcitabine-based ACT in the discovery and validation cohorts. Spearman analysis identified that TIMs infiltration were positively correlated with anti-tumor CD8+ T cells. CONCLUSION TIMs infiltration is an independent favorable prognostic factor in GBC and EBDC patients, which could better stratify patients with different prognosis and predict benefit from gemcitabine-based ACT.
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Affiliation(s)
- Xiaobo Bo
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
| | - Jie Wang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
| | - Tao Suo
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
| | - Xiaoling Ni
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
| | - Han Liu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
| | - Sheng Shen
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
| | - Min Li
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
| | - Yueqi Wang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
| | - Houbao Liu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
| | - Jiejie Xu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032 China
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Ye YY, Mei JW, Xiang SS, Li HF, Ma Q, Song XL, Wang Z, Zhang YC, Liu YC, Jin YP, Hu YP, Jiang L, Liu FT, Zhang YJ, Hao YJ, Liu YB. MicroRNA-30a-5p inhibits gallbladder cancer cell proliferation, migration and metastasis by targeting E2F7. Cell Death Dis 2018; 9:410. [PMID: 29540696 PMCID: PMC5852001 DOI: 10.1038/s41419-018-0444-x] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Revised: 02/07/2018] [Accepted: 02/15/2018] [Indexed: 12/12/2022]
Abstract
Gallbladder carcinoma (GBC), the most common malignant tumour of the bile duct, is highly aggressive and has a poor prognosis. MicroRNA-30a-5p (miR-30a-5p) is an important tumour suppressor that participates in many aspects of carcinogenesis and cancer development. However, the role of miR-30a-5p in GBC development remains to be determined, as do the mechanisms underlying its effects in GBC. Using samples collected from 42 subjects with gallbladder carcinoma (GBC), we showed decreased miR-30a-5p expression in the primary lesions vs. non-tumour adjacent tissues (NATs). Decreased miR-30a-5p was associated with shorter disease-free survival (DFS) and overall survival (OS). Inhibiting miR-30a-5p expression in 2 representative GBC cell lines (GBC-SD and NOZ) increased cell proliferation, migration, invasiveness, as well as β-catenin nuclear translocation, vice versa. In nude mice, NOZ cells transfected with miR-30a-5p mimics grew slower (vs. miR-NC) upon subcutaneous inoculation, and had lower rate of hepatic metastasis upon spleen inoculation. Dual luciferase assay confirmed that E2F transcription factor 7 (E2F7) was a direct target of miR-30a-5p and antagonized the effects induced by miR-30a-5p downregulation in GBC cells. MiR-30a-5p attenuates the EMT and metastasis in GBC cells by targeting E2F7, suggesting miR-30a-5p is a tumour suppressor that may serve as a novel potential prognostic biomarker or molecular therapeutic target for GBC.
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Affiliation(s)
- Yuan-Yuan Ye
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Jia-Wei Mei
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Shan-Shan Xiang
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Huai-Feng Li
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Qiang Ma
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Xiao-Ling Song
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Zheng Wang
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Yi-Chi Zhang
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Yong-Chen Liu
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Yun-Peng Jin
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Yun-Ping Hu
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Lin Jiang
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Fa-Tao Liu
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Yi-Jian Zhang
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Ya-Juan Hao
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China.
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China.
| | - Ying-Bin Liu
- Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai, 200092, China.
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092, China.
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Sun D, Li X, He Y, Li W, Wang Y, Wang H, Jiang S, Xin Y. YAP1 enhances cell proliferation, migration, and invasion of gastric cancer in vitro and in vivo. Oncotarget 2018; 7:81062-81076. [PMID: 27835600 PMCID: PMC5348376 DOI: 10.18632/oncotarget.13188] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Accepted: 10/31/2016] [Indexed: 12/14/2022] Open
Abstract
Yes-associated protein 1 (YAP1) plays an important role in the development of carcinomas such as breast, colorectal, and gastric (GC) cancers, but the role of YAP1 in GC has not been investigated comprehensively. The present study strongly suggests that YAP1 and P62 were significantly up-regulated in GC specimens, compared with normal gastric mucosa. In addition, the YAP1high P62high expression was independently associated with poor prognosis in GC (hazard ratio: 1.334, 95% confidence interval: 1.045–1.704, P = 0.021). Stable YAP1 silencing inhibited the proliferation, migration, and invasion of BGC-823 GC cells in vitro and inhibited the growth of xenograft tumor and hematogenous metastasis of BGC-823 GC cells in vivo. The mechanism was associated with inhibited extracellular signal-regulated kinases (ERK)1/2 phosphorylation, elevated E-cadherin protein expression and decreased vimentin protein expression, down-regulated β-catenin protein expression and elevated α-catenin protein expression, and down-regulated long non-coding RNA (lncRNA) expressions including HOX transcript antisense RNA (HOTAIR), H19, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), human large tumor suppressor-2 (LATS2)-AS1-001, and LATS2. YAP1 over-expression promoted the proliferation, migration, and invasion of human immortalized normal gastric mucosa GES-1 cells in vitro by reversing the above signal molecules. Subcutaneous inoculation of GES-1 cells and YAP1-over-expressing GES-1 cells into nude mice did not generate tumors. We successfully established the xenograft tumor models using MKN-45 GC cells, but immunochemistry showed that there was no YAP1 expression in MKN-45 cells. These results suggest that YAP1 is not a direct factor affecting tumor formation, but could accelerate tumor growth and metastasis. Collectively, this study highlights an important role for YAP1 as a promoter of GC growth and metastasis, and suggests that YAP1 could possibly be a potential treatment target for GC.
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Affiliation(s)
- Dan Sun
- Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute and General Surgery Institute, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Xiaoting Li
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - Yingjian He
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - Wenhui Li
- Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute and General Surgery Institute, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Ying Wang
- Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute and General Surgery Institute, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Huan Wang
- Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute and General Surgery Institute, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Shanshan Jiang
- Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute and General Surgery Institute, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Yan Xin
- Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute and General Surgery Institute, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
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Wu DW, Wang YC, Wang L, Chen CY, Lee H. A low microRNA-630 expression confers resistance to tyrosine kinase inhibitors in EGFR-mutated lung adenocarcinomas via miR-630/YAP1/ERK feedback loop. Am J Cancer Res 2018; 8:1256-1269. [PMID: 29507618 PMCID: PMC5835934 DOI: 10.7150/thno.22048] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 11/28/2017] [Indexed: 02/06/2023] Open
Abstract
Purpose: MicroRNA-630 plays dual roles in apoptosis and drug resistance in human cancers. However, the role of miR-630 in resistance to tyrosine kinase inhibitors (TKIs) in lung adenocarcinoma remains to be elucidated. Methods: Manipulation of miR-630 and its targeted gene YAP1 and/or combination of inhibitor treatments was performed to explore whether low miR-630 could confer TKI resistance due to de-targeting YAP1, and this could decrease proapoptotic protein Bad expression through the miR-630/YAP1/ERK feedback loop. A retrospective study was conducted to examine whether the expression of miR-630 and YAP1 could be associated with TKI therapeutic response in patients with lung adenocarcinoma. Results: Low miR-630 expression may confer TKI resistance via increased SP1 binding to the miR-630 promoter due to ERK activation by YAP1 de-targeting. Persistent activation of ERK signaling via the miR-630/YAP1/ERK feedback loop may be responsible for TKI resistance in EGFR-mutated cells. Moreover, a decrease in Bad expression by its phosphorylation at Serine 75 through ERK activation conferred low miR-630-mediated TKI resistance by modulating the apoptotic pathway. Xenographic tumors induced by miR-630-knockdown PC9 and PC9GR cells in nude mice were nearly suppressed by the combination of gefitinib with the YAP1 inhibitor verteporfin or an MEK/ERK inhibitor AZD6244. Patients with low miR-630 and high YAP1 expressing tumors had a higher prevalence of unfavorable responses to TKI therapy and poorer outcomes when compared with their counterparts. Conclusion: MiR-630 may be a potential biomarker for the prediction of TKI therapeutic response and outcome in patients with lung adenocarcinoma.
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Abstract
A major challenge in anticancer treatment is the pre-existence or emergence of resistance to therapy. AXL and MER are two members of the TAM (TYRO3-AXL-MER) family of receptor tyrosine kinases, which, when activated, can regulate tumor cell survival, proliferation, migration and invasion, angiogenesis, and tumor-host interactions. An increasing body of evidence strongly suggests that these receptors play major roles in resistance to targeted therapies and conventional cytotoxic agents. Multiple resistance mechanisms exist, including the direct and indirect crosstalk of AXL and MER with other receptors and the activation of feedback loops regulating AXL and MER expression and activity. These mechanisms may be innate, adaptive, or acquired. A principal role of AXL appears to be in sustaining a mesenchymal phenotype, itself a major mechanism of resistance to diverse anticancer therapies. Both AXL and MER play a role in the repression of the innate immune response which may also limit response to treatment. Small molecule and antibody inhibitors of AXL and MER have recently been described, and some of these have already entered clinical trials. The optimal design of treatment strategies to maximize the clinical benefit of these AXL and MER targeting agents are discussed in relation to the different cancer types and the types of resistance encountered. One of the major challenges to successful development of these therapies will be the application of robust predictive biomarkers for clear-cut patient stratification.
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Liao T, Wen D, Ma B, Hu JQ, Qu N, Shi RL, Liu L, Guan Q, Li DS, Ji QH. Yes-associated protein 1 promotes papillary thyroid cancer cell proliferation by activating the ERK/MAPK signaling pathway. Oncotarget 2017; 8:11719-11728. [PMID: 28036290 PMCID: PMC5355298 DOI: 10.18632/oncotarget.14319] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Accepted: 12/12/2016] [Indexed: 01/29/2023] Open
Abstract
Yes-associated protein 1 (YAP1) stimulates cell proliferation, epithelial-to-mesenchymal transition, invasion and metastasis in several cancers. Here, we investigated the involvement of YAP1 in papillary thyroid carcinoma (PTC) by assessing YAP1 mRNA and protein levels in PTC tissues and matched normal thyroid epithelial tissues from 50 patients. YAP1 mRNA and protein levels were higher in PTC tumor tissues than in control tissues, and correlated positively with the levels of proliferation-related genes (KI67 and c-MYC). We also used lentiviral vectors to overexpress or silence YAP1 expression in the K1 PTC cell line so that we could investigate the effects of YAP1 on cancer cell proliferation. YAP1 overexpression enhanced PTC cell proliferation by activating ERK1/2 and AKT, and these effects were impaired by treating the cells with the MEK inhibitor U0126 or the AKT inhibitor GSK690693. Finally, YAP1 overexpression dramatically induced growth of tumors from PTC cells in a xenograft mouse model. These results suggest that YAP1 enhances cell proliferation in PTC, and thus may be a promising target in the treatment of PTC.
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Affiliation(s)
- Tian Liao
- Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Duo Wen
- Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Ben Ma
- Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Jia-Qian Hu
- Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Ning Qu
- Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Rong-Liang Shi
- Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Liang Liu
- Department of Breast Surgery, Breast Cancer Institute, Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Qing Guan
- Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Duan-Shu Li
- Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Qing-Hai Ji
- Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
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Salcedo Allende MT, Zeron-Medina J, Hernandez J, Macarulla T, Balsells J, Merino X, Allende H, Tabernero J, Ramon Y Cajal S. Overexpression of Yes Associated Protein 1, an Independent Prognostic Marker in Patients With Pancreatic Ductal Adenocarcinoma, Correlated With Liver Metastasis and Poor Prognosis. Pancreas 2017; 46:913-920. [PMID: 28697132 DOI: 10.1097/mpa.0000000000000867] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer. Overexpression of Yes associated protein 1 (YAP1), a downstream target of Hippo pathway, implicated in regulation of cell growth and apoptosis, has been reported in several human tumor types. The objective of this study was to investigate YAP1 expression in patients with PDAC and its prognostic values. METHODS We evaluated YAP1 expression in 64 PDAC and 15 chronic pancreatitis (CP) cases and its related pancreatic intraepithelial neoplasia (PanIN) lesions and in 5 control subjects. Yes associated protein 1 expression was determined by immunohistochemistry. Association of YAP1 with clinicopathologic features in PDAC, disease-free survival, and overall survival was analyzed. RESULTS We found a higher positive rate of nuclear expression of YAP1 in PDAC than in CP (P = 0.000) and lower expression of YAP1 in PanIN lesions in CP in contrast with expression in PanIN lesions in PDAC. Nuclear overexpression of YAP1 in PDAC is associated with hepatic metastasis (P = 0.0280) and is a prognostic factor (P = 0.0320), as well as surgical margin involvement (P = 0.0013) and tumoral stage (P = 0.0109). CONCLUSIONS Overexpression of YAP1 may occur as a part of tumorigenesis of PDAC. Yes associated protein 1 is an independent prognostic marker for overall survival of PDAC and associated with liver metastasis, being a potential therapeutic target.
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Affiliation(s)
- Maria Teresa Salcedo Allende
- From the *Pathology, †Oncology, ‡Surgery, and §Radiology Departments, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
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Lee K, Lee KB, Jung HY, Yi NJ, Lee KW, Suh KS, Jang JJ. The correlation between poor prognosis and increased yes-associated protein 1 expression in keratin 19 expressing hepatocellular carcinomas and cholangiocarcinomas. BMC Cancer 2017. [PMID: 28645247 PMCID: PMC5481924 DOI: 10.1186/s12885-017-3431-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/20/2023] Open
Abstract
Background The Hippo pathway plays a vital role in liver regeneration and development by determining cellular lineage and regulating cell proliferation and apoptosis. In this study, we aimed to assess the role of the Hippo pathway in hepatic carcinogenesis and morphogenesis by examining Yes-associated protein 1 (YAP1) expression in the spectrum of hepatic carcinomas based on cellular lineage. Methods We examined 913 primary hepatic carcinomas, including hepatocellular carcinomas (HCCs), combined hepatocellular and cholangiocarcinomas (cHC-CCAs), intrahepatic cholangiocarcinomas (IHCCAs) and perihilar extrahepatic bile duct carcinomas (EHBCAs). Our study group was categorized into 8 disease groups, based on histological diagnosis and cytokeratin 19 (CK19) expression, and immunohistochemistry was used to detect and compare YAP1 expression levels between the groups. The eight disease groups we identified were: 1) CK19(−) HCC, 2) CK19(−) scirrhous HCC, 3) CK19(+) HCC, 4) stem cell feature of cHC-CCA, 5) classical cHC-CCA, 6) cholangiolocellular IHCCA, 7) non-cholangiolocellular IHCCA, and 8) EHBCA. Results Positive rates of YAP1 were the highest in the EHBCA group (21%). CK19(+) HCC and non-cholangiolocellular IHCCA groups also showed high expression levels (10% -11%), while the CK19 (−) HCC, CK19 (−) scirrhous HCC, cHC-CCA, and cholangiolocellular IHCCA groups showed low expression levels, ranging between 0% and 5%. Survival analysis, restricted to pT1 stage HCCs and IHCCAs, showed poor overall survival for YAP1(+) IHCCA patients (39 ± 17 vs. 109 ± 10 months, mean ± SD, log rank p-value 0.005). For HCCs, a trend of poor progression-free survival for YAP1(+) HCCs was observed (39 ± 18 vs. 81 ± 5 months, mean ± SD, log rank p-value 0.205) Conclusions YAP1 activation was more commonly found in CCAs than in pure HCCs. However, a differing pattern of YAP1 expression between cHC-CCAs and CK19(+) HCCs and the poor prognosis of YAP1 positive hepatic carcinomas suggests that YAP1 may have a preferential role in aggressive tumor behavior, rather than in the determination of cellular lineage in hepatic carcinomas. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3431-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- KyuHo Lee
- Department of Pathology, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea
| | - Kyoung-Bun Lee
- Department of Pathology, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea.
| | - Hae Yoen Jung
- Department of Pathology, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea
| | - Nam-Joon Yi
- Department of Surgery, Seoul National University College of Medicine, Seoul, 110-744, South Korea
| | - Kwang-Woong Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, 110-744, South Korea
| | - Kyung-Suk Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, 110-744, South Korea
| | - Ja-June Jang
- Department of Pathology, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea
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Zhang F, Xiang S, Cao Y, Li M, Ma Q, Liang H, Li H, Ye Y, Zhang Y, Jiang L, Hu Y, Zhou J, Wang X, Zhang Y, Nie L, Liang X, Gong W, Liu Y. EIF3D promotes gallbladder cancer development by stabilizing GRK2 kinase and activating PI3K-AKT signaling pathway. Cell Death Dis 2017; 8:e2868. [PMID: 28594409 PMCID: PMC5520919 DOI: 10.1038/cddis.2017.263] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 05/07/2017] [Accepted: 05/08/2017] [Indexed: 02/05/2023]
Abstract
Recent evidence suggests that dysregulated eIF3d expression may be critical in various genetic disorders as well as cancer. In this study, we observed that EIF3d levels increased in gallbladder cancer (GBC) samples compared with non-tumor tissue. High eIF3d levels were associated with advanced tumor stage and metastasis and were correlated with poor prognosis in 92 patients with GBC. Depletion of EIF3d in GBC cell lines inhibited cell proliferation, colony formation and metastasis and induced apoptosis and cell cycle arrest in vitro and in vivo. In contrast, ectopic expression of eIF3d had the opposite effects. Moreover, in this study, we revealed that a novel non-translational factor function of eIF3d mediated its protumoral effects. In details, eIF3d stabilizes GRK2 protein by blocking ubiquitin-mediated degradation, consequently activates PI3K/Akt signaling, and promotes GBC cell proliferation and migration. In conclusion, eIF3d promotes GBC progression mainly via eIF3d-GRK2-AKT axis and it may be used as a prognostic factor. The therapeutic targeting of eIF3d-GRK2 axis may be a potential treatment approach for GBC.
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Affiliation(s)
- Fei Zhang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Shanshan Xiang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Yang Cao
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Maolan Li
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Qiang Ma
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Haibin Liang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Huaifeng Li
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Yuanyuan Ye
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Yijian Zhang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Lin Jiang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Yunping Hu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Jian Zhou
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Xuefeng Wang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Yong Zhang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Lei Nie
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xiao Liang
- Department of General Surgery, Sir Runrun Shaw Hospital Affiliated to Zhejiang University, Hangzhou, China
| | - Wei Gong
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Yingbin Liu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
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Song X, Wang Z, Liang H, Zhang W, Ye Y, Li H, Hu Y, Zhang Y, Weng H, Lu J, Wang X, Li M, Liu Y, Gu J. Dioscin Induces Gallbladder Cancer Apoptosis by Inhibiting ROS-Mediated PI3K/AKT Signalling. Int J Biol Sci 2017; 13:782-793. [PMID: 28656003 PMCID: PMC5485633 DOI: 10.7150/ijbs.18732] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Accepted: 03/25/2017] [Indexed: 12/30/2022] Open
Abstract
Gallbladder cancer (GBC), highly aggressive form of cancer with an extremely poor prognosis, is the most common malignancy of the biliary tract. In this study, we investigated the effects of dioscin (DSN) on human GBC and the potential mechanisms underlying these effects. The results showed that DSN significantly inhibited GBC cell proliferation and migration. Moreover, DSN induced GBC cell apoptosis via mitochondrial dependent apoptotic signalling. Reactive oxygen species (ROS) and glutathione (GSH) levels were measured, and ROS scavengers completely inhibited DSN-induced apoptosis and migration, indicating that ROS play an essential role in GBC progression. Western blot analysis showed that AKT activity was significantly downregulated after DSN treatment, and that inhibition/ectopic expression of AKT enhanced/abolished DSN-induced apoptosis but not migration. Furthermore, we confirmed the relationship between ROS and the PI3K/AKT pathway and found that DSN induced apoptosis by regulating ROS-mediated PI3K/AKT signaling. Taken together, these findings indicate that DSN induces GBC apoptosis through inhibiting ROS-mediated PI3K/AKT signalling.
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Affiliation(s)
- Xiaoling Song
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Zheng Wang
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Haibin Liang
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Wenjie Zhang
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Yuanyuan Ye
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - HuaiFeng Li
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Yunping Hu
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Yijian Zhang
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Hao Weng
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Jianhua Lu
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Xuefeng Wang
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Maolan Li
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Yingbin Liu
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Jun Gu
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
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Rybarczyk A, Klacz J, Wronska A, Matuszewski M, Kmiec Z, Wierzbicki PM. Overexpression of the YAP1 oncogene in clear cell renal cell carcinoma is associated with poor outcome. Oncol Rep 2017; 38:427-439. [DOI: 10.3892/or.2017.5642] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Accepted: 04/27/2017] [Indexed: 11/05/2022] Open
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Zhang F, Ma Q, Xu Z, Liang H, Li H, Ye Y, Xiang S, Zhang Y, Jiang L, Hu Y, Wang Z, Wang X, Zhang Y, Gong W, Liu Y. Dihydroartemisinin inhibits TCTP-dependent metastasis in gallbladder cancer. J Exp Clin Cancer Res 2017; 36:68. [PMID: 28506239 PMCID: PMC5433060 DOI: 10.1186/s13046-017-0531-3] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Accepted: 04/11/2017] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Patients with metastatic or relapsed gallbladder cancer generally have a poor prognosis. Therefore, targeting metastasis is one arm of therapeutic strategies to treat gallbladder cancer. METHODS Levels of translationally controlled tumor protein (TCTP) were measured in samples of gallbladder cancer by immunohistochemical staining. Wound healing, migration and invasion assays were used to investigate the motility of cells. Western blot assay was used to investigate the levels of TCTP and other proteins. Liver metastasis models and lung metastasis models were established to investigate the inhibitory effect of Dihydroartemisinin on gallbladder cancer metastasis. RESULTS TCTP is aberrantly expressed in gallbladder cancer patients and associated with metastasis and a poor prognosis. Depleting TCTP significantly inhibited gallbladder cancer cell migration and invasion. We found that Dihydroartemisinin as a potent inhibitor of TCTP inhibited TCTP-dependent cell migration and invasion by reducing cell division control protein 42 homolog (Cdc42) activation. In addition, in mice with xenografted tumors, treatment with Dihydroartemisinin decreased gallbladder cancer cell metastases and improved survival. CONCLUSIONS These findings provide new insights into the therapeutic activity of Dihydroartemisinin as a treatment for gallbladder cancer metastasis.
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Affiliation(s)
- Fei Zhang
- Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Room 517, Building 22, Xinhua Hospital, 1665 Kongjiang Rd., Shanghai, 200092 China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092 China
| | - Qiang Ma
- Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Room 517, Building 22, Xinhua Hospital, 1665 Kongjiang Rd., Shanghai, 200092 China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092 China
| | - Zihang Xu
- Laboratory of Integrative Medicine, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203 China
| | - Haibin Liang
- Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Room 517, Building 22, Xinhua Hospital, 1665 Kongjiang Rd., Shanghai, 200092 China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092 China
| | - Huaifeng Li
- Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Room 517, Building 22, Xinhua Hospital, 1665 Kongjiang Rd., Shanghai, 200092 China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092 China
| | - Yuanyuan Ye
- Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Room 517, Building 22, Xinhua Hospital, 1665 Kongjiang Rd., Shanghai, 200092 China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092 China
| | - Shanshan Xiang
- Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Room 517, Building 22, Xinhua Hospital, 1665 Kongjiang Rd., Shanghai, 200092 China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092 China
| | - Yijian Zhang
- Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Room 517, Building 22, Xinhua Hospital, 1665 Kongjiang Rd., Shanghai, 200092 China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092 China
| | - Lin Jiang
- Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Room 517, Building 22, Xinhua Hospital, 1665 Kongjiang Rd., Shanghai, 200092 China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092 China
| | - Yunping Hu
- Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Room 517, Building 22, Xinhua Hospital, 1665 Kongjiang Rd., Shanghai, 200092 China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092 China
| | - Zheng Wang
- Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Room 517, Building 22, Xinhua Hospital, 1665 Kongjiang Rd., Shanghai, 200092 China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092 China
| | - Xuefeng Wang
- Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Room 517, Building 22, Xinhua Hospital, 1665 Kongjiang Rd., Shanghai, 200092 China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092 China
| | - Yong Zhang
- Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Room 517, Building 22, Xinhua Hospital, 1665 Kongjiang Rd., Shanghai, 200092 China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092 China
| | - Wei Gong
- Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Room 517, Building 22, Xinhua Hospital, 1665 Kongjiang Rd., Shanghai, 200092 China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092 China
| | - Yingbin Liu
- Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Room 517, Building 22, Xinhua Hospital, 1665 Kongjiang Rd., Shanghai, 200092 China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai, 200092 China
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Davidsen KT, Haaland GS, Lie MK, Lorens JB, Engelsen AST. The Role of Axl Receptor Tyrosine Kinase in Tumor Cell Plasticity and Therapy Resistance. BIOMARKERS OF THE TUMOR MICROENVIRONMENT 2017:351-376. [DOI: 10.1007/978-3-319-39147-2_15] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Ma MZ, Zhang Y, Weng MZ, Wang SH, Hu Y, Hou ZY, Qin YY, Gong W, Zhang YJ, Kong X, Wang JD, Quan ZW. Long Noncoding RNA GCASPC, a Target of miR-17-3p, Negatively Regulates Pyruvate Carboxylase-Dependent Cell Proliferation in Gallbladder Cancer. Cancer Res 2016; 76:5361-5371. [PMID: 27450454 DOI: 10.1158/0008-5472.can-15-3047] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2015] [Accepted: 06/15/2016] [Indexed: 02/05/2023]
Abstract
Long noncoding RNAs (lncRNA) are being implicated in the development of many cancers. Here, we report the discovery of a critical role for the lncRNA GCASPC in determining the progression of gallbladder cancer. Differentially expressed lncRNAs and mRNAs between gallbladder cancer specimens and paired adjacent nontumor tissues from five patients were identified and validated by an expression microarray analysis. Quantitative real-time PCR was used to measure GCASPC levels in tissues from 42 gallbladder cancer patients, and levels of GCASPC were confirmed further in a separate cohort of 89 gallbladder cancer patients. GCASPC was overexpressed or silenced in several gallbladder cancer cell lines where molecular and biological analyses were performed. GCASPC levels were significantly lower in gallbladder cancer than adjacent nontumor tissues and were associated with tumor size, American Joint Committee on Cancer tumor stage, and patient outcomes. GCASPC overexpression suppressed cell proliferation in vitro and in vivo, whereas GCASPC silencing had opposite effects. By RNA pull-down and mass spectrometry, we identified pyruvate carboxylase as an RNA-binding protein that associated with GCASPC. Because GCASPC is a target of miR-17-3p, we confirmed that both miR-17-3p and GCASPC downregulated pyruvate carboxylase level and activity by limiting protein stability. Taken together, our results defined a novel mechanism of lncRNA-regulated cell proliferation in gallbladder cancer, illuminating a new basis for understanding its pathogenicity. Cancer Res; 76(18); 5361-71. ©2016 AACR.
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Affiliation(s)
- Ming-Zhe Ma
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Department of Gastric Cancer and Soft Tissue Sarcoma, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yan Zhang
- Department of Gastroenterology, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, China
| | - Ming-Zhe Weng
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shou-Hua Wang
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ye Hu
- State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhao-Yuan Hou
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yi-Yu Qin
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei Gong
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yong-Jie Zhang
- Second Department of Biliary Surgery and Department of Special Treatment, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Xiang Kong
- Department of Endocrinology, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, China.
| | - Jian-Dong Wang
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Zhi-Wei Quan
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Zhao S, Cao Y, Liu SB, Wang XA, Bao RF, Shu YJ, Hu YP, Zhang YJ, Jiang L, Zhang F, Liang HB, Li HF, Ma Q, Xu Y, Wang Z, Zhang YC, Chen L, Zhou J, Liu YB. The E545K mutation of PIK3CA promotes gallbladder carcinoma progression through enhanced binding to EGFR. J Exp Clin Cancer Res 2016; 35:97. [PMID: 27317099 PMCID: PMC4912708 DOI: 10.1186/s13046-016-0370-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2016] [Accepted: 06/02/2016] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Gallbladder carcinoma (GBC) is the most common malignancy of the bile duct and patients with GBC have extremely poor prognoses. PIK3CA, which encodes the phosphoinositide 3-kinase (PI3K) subunit p110α, is frequently mutated in many cancers, including GBC. The function of the E545K mutation in GBC is not fully understood. METHODS E545K mutation was determined in human GBC tissues by targeted sequencing. The effects of E545K mutation and PI3K selective inhibitor, A66 on GBC cells were evaluated using Cell Counting Kit-8 (CCK-8) cell Viability and transwell assays. The mechanisms of E545K mutation and A66 were analyzed by western blot and co-immunoprecipitation (Co-IP) assay. Subcutaneous xenograft models in nude mice were employed to evaluate the role of E545K mutation and A66 in GBC progression. RESULTS The rate of PIK3CA E545K mutation in GBC patients was 6.15 %. And the survival of GBC patients was correlated with E545K mutation significantly (P < 0.05). The E545K mutation promoted proliferation, migration and invasion of GBC cells in vitro and tumor proliferation in vivo. A66 suppressed proliferation of GBC cells in vitro and tumor proliferation in vivo. CONCLUSION The prognoses of patients with E545K mutation were worse than patients without this mutation. The E545K mutation promoted GBC progression through enhanced binding to EGFR and activating downstream akt activity. The PI3K selective inhibitor, A66, suppressed gallbladder carcinoma proliferation.
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Affiliation(s)
- Shuai Zhao
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China
- Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China
| | - Yang Cao
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China
- Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China
| | - Shi-Bo Liu
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China
- Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China
| | - Xu-An Wang
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China
- Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China
| | - Run-Fa Bao
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China
- Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China
| | - Yi-Jun Shu
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China
- Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China
| | - Yun-Ping Hu
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China
- Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China
| | - Yi-Jian Zhang
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China
- Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China
| | - Lin Jiang
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China
- Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China
| | - Fei Zhang
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China
- Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China
| | - Hai-Bin Liang
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China
- Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China
| | - Huai-Feng Li
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China
- Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China
| | - Qiang Ma
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China
- Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China
| | - Yi Xu
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China
- Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China
| | - Zheng Wang
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China
- Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China
| | - Yi-Chi Zhang
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 200092, People's Republic of China
- Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China
| | - Lei Chen
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
| | - Jian Zhou
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
| | - Ying-Bin Liu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
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Jia J, Li C, Luo S, Liu-Smith F, Yang J, Wang X, Wang N, Lai B, Lei T, Wang Q, Xiao S, Shao Y, Zheng Y. Yes-Associated Protein Contributes to the Development of Human Cutaneous Squamous Cell Carcinoma via Activation of RAS. J Invest Dermatol 2016; 136:1267-1277. [PMID: 26902922 DOI: 10.1016/j.jid.2016.02.005] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Revised: 01/06/2016] [Accepted: 02/02/2016] [Indexed: 11/17/2022]
Abstract
Cutaneous squamous cell carcinoma (cSCC) is one of the most common skin malignant tumors with an increasing incidence. Studies have shown that Yes-associated protein (YAP) participates in the development of a variety of tumors as an oncogene, but to our knowledge its role in cSCC has not been reported. In this study, we used immunohistochemistry to show that YAP expression was elevated in cSCC samples of different stages versus in normal skin and that it was well correlated with the progression of the disease. Down-regulation of YAP in cSCC cell lines A431 and SCL-1 inhibited cell proliferation by inducing growth arrest during the G1/S phase transition, promoted apoptosis, and reduced invasion and migration abilities in vitro. Conversely, overexpression of YAP promoted cell proliferation and protected cells against basal and chemotherapy-induced apoptosis. These oncogenic effects of YAP were associated with activation of the RAS protein and its downstream AKT and ERK. Using a mouse xenograft model, we further showed that YAP depletion inhibited cSCC tumor growth in vivo. Our results suggested that YAP is involved in the carcinogenesis and development of cSCC and that it may serve as a biomarker or therapeutic target of this disease.
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Affiliation(s)
- Jinjing Jia
- Department of Dermatology, the Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Changji Li
- Department of Dermatology, the Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Suju Luo
- Department of Dermatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Feng Liu-Smith
- Departments of Epidemiology and Medicine, University of California Irvine, Irvine, CA, USA
| | - Jiao Yang
- Department of Dermatology, the Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Xin Wang
- Department of Dermatology, the Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Nanping Wang
- Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Baochang Lai
- Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Ting Lei
- Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China; Department of Pathology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Qiongyu Wang
- Department of Dermatology, the Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Shengxiang Xiao
- Department of Dermatology, the Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Yongping Shao
- Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China; Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China.
| | - Yan Zheng
- Department of Dermatology, the Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China.
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Zhang Y, Liu S, Wang L, Wu Y, Hao J, Wang Z, Lu W, Wang XA, Zhang F, Cao Y, Liang H, Li H, Ye Y, Ma Q, Zhao S, Shu Y, Bao R, Jiang L, Hu Y, Zhou J, Chen L, Liu Y. A novel PI3K/AKT signaling axis mediates Nectin-4-induced gallbladder cancer cell proliferation, metastasis and tumor growth. Cancer Lett 2016; 375:179-189. [PMID: 26949052 DOI: 10.1016/j.canlet.2016.02.049] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Revised: 02/21/2016] [Accepted: 02/24/2016] [Indexed: 01/25/2023]
Abstract
Nectin-4 is a Ca(2+)-independent immunoglobulin-like cell adhesion molecule which has diverse functions in cell-cell adhesion via homophilic and heterophilic interactions. Cell-cell adhesive processes are central to cell polarization, differentiation, proliferation, survival and movement. Here we report that Nectin-4 is substantially overexpressed in gallbladder cancer (GBC), the most common biliary tract malignancy with a high risk of local tumor spread and invasion. Further, Nectin-4 high expression in GBC patients was associated with pathologic T stage and lymph node metastasis status, and the expression level of the downstream target Rac1 and poor prognoses were also correlated with Nectin-4. Ectopic expression of Nectin-4 promoted GBC cell growth, motility and tumor growth in a mouse model. The depletion of Nectin-4 inhibited GBC cell proliferation and migration both in cell culture and in mice. Our data suggest that activation of the PI3K/AKT pathway was involved in the oncogenic function of Nectin-4 to activate Rac1 in GBC. Inhibition of PI3K/AKT with LY294002 and/or Rac1 with NSC23766 impaired Nectin-4-mediated GBC cell proliferation and motility. We hypothesize that Nectin-4 is critical for GBC progression via PI3K/AKT pathway activation of Rac1. Nectin-4 may be a novel prognostic factor and therapeutic target in GBC patients.
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Affiliation(s)
- Yijian Zhang
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
| | - Shibo Liu
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
| | - Lei Wang
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
| | - Yaoshi Wu
- Department of Gastroenterology, Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang 330006, China
| | - Jiaqi Hao
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
| | - Zheng Wang
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
| | - Wei Lu
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
| | - Xu-An Wang
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
| | - Fei Zhang
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
| | - Yang Cao
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
| | - Haibin Liang
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
| | - Huaifeng Li
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
| | - Yuanyuan Ye
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
| | - Qiang Ma
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
| | - Shuai Zhao
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
| | - Yijun Shu
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
| | - Runfa Bao
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
| | - Lin Jiang
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
| | - Yunping Hu
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
| | - Jian Zhou
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
| | - Lei Chen
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
| | - Yingbin Liu
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China; Institute of Biliary Tract Diseases Research, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China.
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Bao RF, Shu YJ, Hu YP, Wang XA, Zhang F, Liang HB, Ye YY, Li HF, Xiang SS, Weng H, Cao Y, Wu XS, Li ML, Wu WG, Zhang YJ, Jiang L, Dong Q, Liu YB. miR-101 targeting ZFX suppresses tumor proliferation and metastasis by regulating the MAPK/Erk and Smad pathways in gallbladder carcinoma. Oncotarget 2016; 7:22339-22354. [PMID: 26968949 PMCID: PMC5008364 DOI: 10.18632/oncotarget.7970] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Accepted: 02/23/2016] [Indexed: 12/13/2022] Open
Abstract
Gallbladder cancer (GBC), the most common malignancy of the bile duct, is highly aggressive and has an extremely poor prognosis, which is a result of early metastasis. As it is regulated being at multiple levels, the metastatic cascade in GBC is complex. Recent evidence suggests that microRNAs (miRNAs) are involved in cancer metastasis and are promising therapeutic targets. In this study, miR-101 was significantly downregulated in tumor tissues, particularly in metastatic tissues. In GBC patients, low miR-101 expression was correlated with tumor size, tumor invasion, lymph node metastasis, TNM stage, and poor survival. Moreover, miR-101 was an independent prognostic marker for GBC. Additionally, miR-101 inhibited GBC cell proliferation, migration, invasion, and TGF-β-induced epithelial-mesenchymal transition (EMT) in vitro and in vivo. Mechanistically, the gene encoding the zinc finger protein X-linked (ZFX) was identified as a direct target of miR-101. More importantly, miR-101 significantly reduced activation of the MAPK/Erk and Smad signaling pathways, resulting in inhibition of TGF-β-mediated induction of EMT. Altogether, our findings demonstrate a novel mechanism by which miR-101 attenuates the EMT and metastasis in GBC cells and suggest that miR-101 can serve as a potential biomarker and therapeutic target for GBC management.
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Affiliation(s)
- Run-Fa Bao
- Department and laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Yi-Jun Shu
- Department and laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Yun-Ping Hu
- Department and laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Xu-An Wang
- Department and laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Fei Zhang
- Department and laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Hai-Bin Liang
- Department and laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Yuan-Yuan Ye
- Department and laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Huai-Feng Li
- Department and laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Shan-Shan Xiang
- Department and laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Hao Weng
- Department and laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Yang Cao
- Department and laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Xiang-Song Wu
- Department and laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Mao-Lan Li
- Department and laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Wen-guang Wu
- Department and laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Yi-Jian Zhang
- Department and laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Lin Jiang
- Department and laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Qian Dong
- Department and laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Ying-Bin Liu
- Department and laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
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Cao Y, Liang H, Zhang F, Luan Z, Zhao S, Wang XA, Liu S, Bao R, Shu Y, Ma Q, Zhu J, Liu Y. Prohibitin overexpression predicts poor prognosis and promotes cell proliferation and invasion through ERK pathway activation in gallbladder cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2016; 35:68. [PMID: 27084680 PMCID: PMC4833931 DOI: 10.1186/s13046-016-0346-7] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/31/2016] [Accepted: 04/11/2016] [Indexed: 12/17/2022]
Abstract
Background Prohibitin (PHB), a pleiotropic protein overexpressed in several tumor types, has been implicated in the regulation of cell proliferation, invasive migration and survival. However, PHB expression and its biological function in gallbladder cancer (GBC) remain largely unknown. Methods PHB and p-ERK protein expressions were determined in human GBC tissues by immunohistochemistry (IHC). The effects of PHB knockdown on GBC cell proliferation and invasiveness were evaluated using Cell Counting Kit-8 (CCK-8) cell viability, cell cycle analysis, transwell invasion and gelatin zymography assays. Subcutaneous xenograft and tail vein-lung metastasis tumor models in nude mice were employed to further substantiate the role of PHB in GBC progression. Results PHB protein was overexpressed in GBC tissues and was significantly associated with histological grade, tumor stage and perineural invasion. Furthermore, PHB expression was negatively associated with overall survival in GBC patients. In vitro experimental studies demonstrated that the downregulation of PHB expression by lentivirus-mediated shRNA interference not only inhibited the ERK pathway activation but also reduced the proliferative and invasive capacities of GBC cells. Moreover, PD0325901, a specific inhibitor of MEK, markedly impaired PHB- mediated phosphorylation of ERK protein. IHC statistical analyses further validated that PHB expression was positively correlated with ERK protein phosphorylation levels in GBC tissue samples. In vivo, PHB depletion also resulted in dramatic reductions in the growth and metastasis of GBC cells. Conclusion Our findings demonstrate that PHB overexpression predicts poor survival in GBC patients. PHB could serve as a novel prognostic biomarker and a potential therapeutic target for GBCs. Electronic supplementary material The online version of this article (doi:10.1186/s13046-016-0346-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yang Cao
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, P.R. China.,Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 1665 Kongjiang Road, Shanghai, P.R. China
| | - Haibin Liang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, P.R. China.,Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 1665 Kongjiang Road, Shanghai, P.R. China
| | - Fei Zhang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, P.R. China.,Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 1665 Kongjiang Road, Shanghai, P.R. China
| | - Zhou Luan
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Road, Wuhan, Hubei, 430030, P.R. China
| | - Shuai Zhao
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, P.R. China.,Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 1665 Kongjiang Road, Shanghai, P.R. China
| | - Xu-An Wang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, P.R. China.,Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 1665 Kongjiang Road, Shanghai, P.R. China
| | - Shibo Liu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, P.R. China.,Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 1665 Kongjiang Road, Shanghai, P.R. China
| | - Runfa Bao
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, P.R. China.,Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 1665 Kongjiang Road, Shanghai, P.R. China
| | - Yijun Shu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, P.R. China.,Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 1665 Kongjiang Road, Shanghai, P.R. China
| | - Qiang Ma
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, P.R. China.,Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 1665 Kongjiang Road, Shanghai, P.R. China
| | - Jian Zhu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, P.R. China. .,Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 1665 Kongjiang Road, Shanghai, P.R. China.
| | - Yingbin Liu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, P.R. China. .,Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 1665 Kongjiang Road, Shanghai, P.R. China.
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Li M, Zhang F, Wang X, Wu X, Zhang B, Zhang N, Wu W, Wang Z, Weng H, Liu S, Gao G, Mu J, Shu Y, Bao R, Cao Y, Lu J, Gu J, Zhu J, Liu Y. Magnolol inhibits growth of gallbladder cancer cells through the p53 pathway. Cancer Sci 2015; 106:1341-50. [PMID: 26250568 PMCID: PMC4638010 DOI: 10.1111/cas.12762] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2015] [Revised: 07/29/2015] [Accepted: 08/02/2015] [Indexed: 12/24/2022] Open
Abstract
Magnolol, the major active compound found in Magnolia officinalis has a wide range of clinical applications due to its anti-inflammation and anti-oxidation effects. This study investigated the effects of magnolol on the growth of human gallbladder carcinoma (GBC) cell lines. The results indicated that magnolol could significantly inhibit the growth of GBC cell lines in a dose- and time-dependent manner. Magnolol also blocked cell cycle progression at G0 /G1 phase and induced mitochondrial-related apoptosis by upregulating p53 and p21 protein levels and by downregulating cyclin D1, CDC25A, and Cdk2 protein levels. When cells were pretreated with a p53 inhibitor (pifithrin-a), followed by magnolol treatment, pifithrin-a blocked magnolol-induced apoptosis and G0 /G1 arrest. In vivo, magnolol suppressed tumor growth and activated the same mechanisms as were activated in vitro. In conclusion, our study is the first to report that magnolol has an inhibitory effect on the growth of GBC cells and that this compound may have potential as a novel therapeutic agent for the treatment of GBC.
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Affiliation(s)
- Maolan Li
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghai, China
| | - Fei Zhang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghai, China
| | - Xu’an Wang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghai, China
| | - Xiangsong Wu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghai, China
| | - Bingtai Zhang
- Department of General Surgery, Shanxi Medical University Second HospitalTaiyuan, China
| | - Ning Zhang
- Department of General Surgery, Shanxi Medical University Second HospitalTaiyuan, China
| | - Wenguang Wu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghai, China
| | - Zheng Wang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghai, China
| | - Hao Weng
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghai, China
| | - Shibo Liu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghai, China
| | - Guofeng Gao
- Department of General Surgery, Shanxi Medical University Second HospitalTaiyuan, China
| | - Jiasheng Mu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghai, China
| | - Yijun Shu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghai, China
| | - Runfa Bao
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghai, China
| | - Yang Cao
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghai, China
| | - Jianhua Lu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghai, China
| | - Jun Gu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghai, China
| | - Jian Zhu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghai, China
| | - Yingbin Liu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Laboratory of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong, University School of MedicineShanghai, China
- Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of MedicineShanghai, China
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50
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Weng H, Wang X, Li M, Wu X, Wang Z, Wu W, Zhang Z, Zhang Y, Zhao S, Liu S, Mu J, Cao Y, Shu Y, Bao R, Zhou J, Lu J, Dong P, Gu J, Liu Y. Zinc finger X-chromosomal protein (ZFX) is a significant prognostic indicator and promotes cellular malignant potential in gallbladder cancer. Cancer Biol Ther 2015; 16:1462-70. [PMID: 26230915 DOI: 10.1080/15384047.2015.1070994] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The Zinc finger X-chromosomal protein (ZFX), a novel member of the Krueppel C2H2-type zinc finger protein family, has been implicated in multiple human cancers. However, the clinical significance of ZFX expression in gallbladder cancer (GBC) remains largely unknown. In this study, we focused on the clinical significance, biological function and mechanism of ZFX in GBC, and found that ZFX protein overexpression was frequently detected in GBC tissues. The expression of ZFX was significantly correlated with histological grade, perineural invasion, and margin status and lead to a significantly poorer prognosis in GBC patients(P <0.001). Furthermore, knockdown of ZFX result in significant inhibition of proliferation, migration, invasion and cause cell cycle arrest in GBC-SD cells, while over-expression of ZFX in NOZ shows the opposite results. Activation of PI3K/AKT pathway maybe the potential mechanism behind these effects. In conclusion, ZFX may serve as a oncogene and could be used as a potential prognostic marker and genetic treatment target for GBC patients.
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Affiliation(s)
- Hao Weng
- a Department of General Surgery ; Xinhua hospital ; School of Medicine ; Shanghai Jiaotong University ; & Research Institute of Biliary Tract Disease Affiliated to School of Medicine ; Shanghai Jiao Tong University ; Shanghai , P. R. China
| | - Xu'an Wang
- a Department of General Surgery ; Xinhua hospital ; School of Medicine ; Shanghai Jiaotong University ; & Research Institute of Biliary Tract Disease Affiliated to School of Medicine ; Shanghai Jiao Tong University ; Shanghai , P. R. China
| | - Maolan Li
- a Department of General Surgery ; Xinhua hospital ; School of Medicine ; Shanghai Jiaotong University ; & Research Institute of Biliary Tract Disease Affiliated to School of Medicine ; Shanghai Jiao Tong University ; Shanghai , P. R. China
| | - Xiangsong Wu
- a Department of General Surgery ; Xinhua hospital ; School of Medicine ; Shanghai Jiaotong University ; & Research Institute of Biliary Tract Disease Affiliated to School of Medicine ; Shanghai Jiao Tong University ; Shanghai , P. R. China
| | - Zheng Wang
- a Department of General Surgery ; Xinhua hospital ; School of Medicine ; Shanghai Jiaotong University ; & Research Institute of Biliary Tract Disease Affiliated to School of Medicine ; Shanghai Jiao Tong University ; Shanghai , P. R. China
| | - Wenguang Wu
- a Department of General Surgery ; Xinhua hospital ; School of Medicine ; Shanghai Jiaotong University ; & Research Institute of Biliary Tract Disease Affiliated to School of Medicine ; Shanghai Jiao Tong University ; Shanghai , P. R. China
| | - Zhou Zhang
- a Department of General Surgery ; Xinhua hospital ; School of Medicine ; Shanghai Jiaotong University ; & Research Institute of Biliary Tract Disease Affiliated to School of Medicine ; Shanghai Jiao Tong University ; Shanghai , P. R. China
| | - Yijian Zhang
- a Department of General Surgery ; Xinhua hospital ; School of Medicine ; Shanghai Jiaotong University ; & Research Institute of Biliary Tract Disease Affiliated to School of Medicine ; Shanghai Jiao Tong University ; Shanghai , P. R. China
| | - Shuai Zhao
- a Department of General Surgery ; Xinhua hospital ; School of Medicine ; Shanghai Jiaotong University ; & Research Institute of Biliary Tract Disease Affiliated to School of Medicine ; Shanghai Jiao Tong University ; Shanghai , P. R. China
| | - Shibo Liu
- a Department of General Surgery ; Xinhua hospital ; School of Medicine ; Shanghai Jiaotong University ; & Research Institute of Biliary Tract Disease Affiliated to School of Medicine ; Shanghai Jiao Tong University ; Shanghai , P. R. China
| | - Jiasheng Mu
- a Department of General Surgery ; Xinhua hospital ; School of Medicine ; Shanghai Jiaotong University ; & Research Institute of Biliary Tract Disease Affiliated to School of Medicine ; Shanghai Jiao Tong University ; Shanghai , P. R. China
| | - Yang Cao
- a Department of General Surgery ; Xinhua hospital ; School of Medicine ; Shanghai Jiaotong University ; & Research Institute of Biliary Tract Disease Affiliated to School of Medicine ; Shanghai Jiao Tong University ; Shanghai , P. R. China
| | - Yijun Shu
- a Department of General Surgery ; Xinhua hospital ; School of Medicine ; Shanghai Jiaotong University ; & Research Institute of Biliary Tract Disease Affiliated to School of Medicine ; Shanghai Jiao Tong University ; Shanghai , P. R. China
| | - Runfa Bao
- a Department of General Surgery ; Xinhua hospital ; School of Medicine ; Shanghai Jiaotong University ; & Research Institute of Biliary Tract Disease Affiliated to School of Medicine ; Shanghai Jiao Tong University ; Shanghai , P. R. China
| | - Jian Zhou
- a Department of General Surgery ; Xinhua hospital ; School of Medicine ; Shanghai Jiaotong University ; & Research Institute of Biliary Tract Disease Affiliated to School of Medicine ; Shanghai Jiao Tong University ; Shanghai , P. R. China
| | - Jianhua Lu
- a Department of General Surgery ; Xinhua hospital ; School of Medicine ; Shanghai Jiaotong University ; & Research Institute of Biliary Tract Disease Affiliated to School of Medicine ; Shanghai Jiao Tong University ; Shanghai , P. R. China
| | - Ping Dong
- a Department of General Surgery ; Xinhua hospital ; School of Medicine ; Shanghai Jiaotong University ; & Research Institute of Biliary Tract Disease Affiliated to School of Medicine ; Shanghai Jiao Tong University ; Shanghai , P. R. China
| | - Jun Gu
- a Department of General Surgery ; Xinhua hospital ; School of Medicine ; Shanghai Jiaotong University ; & Research Institute of Biliary Tract Disease Affiliated to School of Medicine ; Shanghai Jiao Tong University ; Shanghai , P. R. China
| | - Yingbin Liu
- a Department of General Surgery ; Xinhua hospital ; School of Medicine ; Shanghai Jiaotong University ; & Research Institute of Biliary Tract Disease Affiliated to School of Medicine ; Shanghai Jiao Tong University ; Shanghai , P. R. China
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