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Priya S, Kma L. Identification of novel microRNAs: Biomarkers for pathogenesis of hepatocellular carcinoma in mice model. Biochem Biophys Rep 2025; 41:101896. [PMID: 39881957 PMCID: PMC11774814 DOI: 10.1016/j.bbrep.2024.101896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 11/26/2024] [Accepted: 12/09/2024] [Indexed: 01/31/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the most fatal cancer that has affected both male and female populations globally. With poor diagnosis and patient survival rates, it has become a global need for scientists to come to the aid. The main objective of the study was to profile the miRNAs in the serum of Control and DEN-treated mice at different time intervals (4 Weeks, 8 Weeks, 12 Weeks, and 16 Weeks) and identify HCC-associated miRNA as putative early biomarkers along with the miRNA regulated candidate gene which may be involved in HCC. Our study group involves 4,8,12, & 16 weeks 16-week-old treated male mice. Each group was sacrificed and analyzed for the stages of HCC. We employed in silico techniques for the small RNA-Seq and bioinformatics pipeline for further analysis. Our analysis revealed over 400 differentially expressed miRNAs in each treated sample and 10 novel miRNAs. The downstream analysis of these differentially expressed miRNAs, and their target genes opened an arena of different biological processes and pathways that these miRNAs affect during the development of HCC. The work has a promising role as the miRNAs predicted through this study can be used as biomarkers for early detection of HCC.
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Affiliation(s)
- Shivani Priya
- Department of Chemistry & Biochemistry, Sharda School of Basic Sciences & Research, Sharda University, Noida, UP, India
| | - Lakhon Kma
- Department of Biochemistry, North Eastern Hill University, Shillong, India
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Wang H, Guan W, Zhang X, Wu Y, Ou Y, Zhang Y, Zeng Z, Yao H. TGF-β Promotes Hepatocellular Carcinoma Metastasis Through Through m6A Modification of PCDHGA9. Cancer Biother Radiopharm 2024; 39:644-653. [PMID: 38726609 DOI: 10.1089/cbr.2023.0144] [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] [Indexed: 11/13/2024] Open
Abstract
Objective: Hepatocellular carcinoma (HCC) is a highly lethal cancer with significant mortality, primarily attributed to metastasis. Although Protocadherin Gamma Subfamily A, 9 (PCDHGA9) has been identified as a tumor suppressor gene in cancer metastasis, its role in HCC remains ambiguous. This study clarifies the role of PCDHGA9 in HCC by examining its expression, clinical significance, and molecular activities. Methods: Tissue microarray immunofluorescence analysis evaluated the expression of PCDHGA9 and its clinical relevance. In vitro experiments involved manipulating PCDHGA9 levels in SK-HEP-1 cells to assess migration through wound-healing and transwell assays. In vivo, shPCDHGA9 cell injections were utilized to observe effects on tumor growth and metastasis. Protein analysis and Western Blot validated epithelial-mesenchymal transition (EMT)-related proteins. Subsequent to TGF-β treatment, cell proliferation and apoptosis were quantified using cell counting kit-8 and flow cytometry, respectively, followed by investigation of TGF-β effects on PCDHGA9 N6-methyladenosine (m6A) modification via Methylated RNA immunoprecipitation, RT-qPCR, and Western blot analysis. Results: Downregulation of PCDHGA9 expression in HCC tissues is correlated with poor prognosis. In vitro experiments demonstrated that modulating PCDHGA9 expression influenced HCC cell migration. In vivo, PCDHGA9 knockdown is correlated with increased metastasis. Furthermore, TGF-β stimulation promoted cell proliferation and inhibited apoptosis. Mechanistically, TGF-β-mediated m6A modification led to PCDHGA9 decay, promoting EMT in HCC cells. Conclusion: PCDHGA9 serves as a potential tumor suppressor in HCC by inhibiting EMT. During this process, TGF-β is observed to exert regulatory control over m6A modifications of PCDHGA9.
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Affiliation(s)
- Huamin Wang
- Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
| | - Wen Guan
- Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
| | - Xianzhou Zhang
- Department of Hepatobiliary Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Yanting Wu
- Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
| | - Yanghui Ou
- Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
| | - Yali Zhang
- Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
| | - Zhijun Zeng
- Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
| | - Hongliang Yao
- Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
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Li R, Liu L, Liu Y, Tang J, Li J. Unraveling the Role of PCDH9 in Breast Cancer and Identifying Therapeutic Strategies for PCDH9-Deficient Tumors. BREAST CANCER (DOVE MEDICAL PRESS) 2024; 16:583-593. [PMID: 39279908 PMCID: PMC11401061 DOI: 10.2147/bctt.s476083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 08/28/2024] [Indexed: 09/18/2024]
Abstract
Introduction Protocadherin 9 (PCDH9), a member of the cadherin superfamily of transmembrane proteins, plays a role in cell adhesion and neural development. Recent studies suggest that PCDH9 may function as a tumor suppressor in certain cancers, though its specific role in breast cancer remains unclear. Methods UALCAN database to retrieve information on PCDH9 expression in breast cancer tissues compared with that in normal tissues. The biological effects of PCDH9 in breast cancer cells were analyzed using the DepMap database. Stable knockdown or overexpression of PCDH9 in breast cancer cell lines and subsequently assessed tumor cell proliferation and migration. Synthetic lethal screening was conducted for breast cancer cells with low PCDH9 expression or deficiency. Results In this study, we observed significant downregulation of PCDH9 in breast cancer tissues, with its expression negatively correlated with progression-free survival. Further investigations revealed that decreased PCDH9 expression promotes breast cancer cell proliferation and migration, while overexpression of PCDH9 has the opposite effect. Subsequently, we identified the TAS-102, an approved drug for metastatic colorectal cancer, exhibited selective cytotoxicity against breast cancer cells with low PCDH9 expression. Conclusion and discussion In summary, our study identified PCDH9 as a tumor suppressor in breast cancer and highlighted TAS-102 as a potential therapeutic option for tumors with low PCDH9 expression or deficiency. The specific interaction between TAS-102 and PCDH9 warrants further exploration, providing deeper insights into its mode of action in treating PCDH9-deficient breast cancer.
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Affiliation(s)
- Ruixi Li
- Yueyang Guangji Hospital, Yueyang, Hunan, People's Republic of China
| | - Lulu Liu
- Yueyang Guangji Hospital, Yueyang, Hunan, People's Republic of China
| | - Yong Liu
- Yueyang Guangji Hospital, Yueyang, Hunan, People's Republic of China
| | - Jiang Tang
- Yueyang Guangji Hospital, Yueyang, Hunan, People's Republic of China
| | - Jinsong Li
- Department of Spine Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China
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Kelam J, Kelam N, Filipović N, Komić L, Racetin A, Komić D, Kostić S, Kuzmić Prusac I, Vukojević K. Expression of Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) Candidate Genes EDA2R, PCDH9, and TRAF7 in Normal Human Kidney Development and CAKUT. Genes (Basel) 2024; 15:702. [PMID: 38927638 PMCID: PMC11203332 DOI: 10.3390/genes15060702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 05/23/2024] [Accepted: 05/24/2024] [Indexed: 06/28/2024] Open
Abstract
Approximately half of the cases of chronic kidney disease (CKD) in childhood are caused by congenital anomalies of the kidney and urinary tract (CAKUT). Specific genes were identified as having significant importance in regard to the underlying genetic factors responsible for the CAKUT phenotype, and in our research, we focused on analyzing and comparing the expression levels of ectodysplasin A2 receptor (EDA2R), protocadherin9 (PCDH9), and TNF receptor-associated factor 7 (TRAF7) proteins in the cortex and medulla of healthy control kidneys during developmental phases 2, 3, and 4. We also performed an analysis of the area percentages of the mentioned proteins in the cortical and medullary sections of healthy embryonic and fetal kidneys compared to those affected by CAKUT, including duplex kidneys (DK), horseshoe kidneys (HK), hypoplastic kidneys (HYP), and dysplastic kidneys (DYS). We found that the CAKUT candidate gene proteins EDA2R, PCDH9, and TRAF7 are all expressed during normal human kidney development stages. In DYS, the expression of EDA2R was higher than in normal kidneys, likely due to EDA2R's role in apoptosis, which was upregulated in specific cases and could possibly contribute to the formation of DYS. The expression of PCDH9 was lower in HK, which can be attributed to the possible role of PCDH9 in cell migration suppression. Decreased PCDH9 expression is linked to increased cell migration, potentially contributing to the development of HK. The level of TRAF7 expression was reduced in all examined kidney disorders compared to normal kidneys, suggesting that this reduction might be attributed to the crucial role of TRAF7 in the formation of endothelium and ciliogenesis, both of which are essential for normal kidney development. Further research is required to ascertain the function of these proteins in both the typical development of the kidney and in CAKUT.
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Affiliation(s)
- Jelena Kelam
- Department of Family Medicine, Split-Dalmatia County Health Center, 21000 Split, Croatia; (J.K.); (L.K.)
| | - Nela Kelam
- Department of Anatomy, Histology and Embryology, University of Split School of Medicine, 21000 Split, Croatia; (N.K.); (N.F.); (A.R.); (D.K.); (S.K.)
| | - Natalija Filipović
- Department of Anatomy, Histology and Embryology, University of Split School of Medicine, 21000 Split, Croatia; (N.K.); (N.F.); (A.R.); (D.K.); (S.K.)
| | - Luka Komić
- Department of Family Medicine, Split-Dalmatia County Health Center, 21000 Split, Croatia; (J.K.); (L.K.)
| | - Anita Racetin
- Department of Anatomy, Histology and Embryology, University of Split School of Medicine, 21000 Split, Croatia; (N.K.); (N.F.); (A.R.); (D.K.); (S.K.)
| | - Dora Komić
- Department of Anatomy, Histology and Embryology, University of Split School of Medicine, 21000 Split, Croatia; (N.K.); (N.F.); (A.R.); (D.K.); (S.K.)
| | - Sandra Kostić
- Department of Anatomy, Histology and Embryology, University of Split School of Medicine, 21000 Split, Croatia; (N.K.); (N.F.); (A.R.); (D.K.); (S.K.)
| | - Ivana Kuzmić Prusac
- Department of Pathology, University Hospital Center Split, 21000 Split, Croatia;
| | - Katarina Vukojević
- Department of Anatomy, Histology and Embryology, University of Split School of Medicine, 21000 Split, Croatia; (N.K.); (N.F.); (A.R.); (D.K.); (S.K.)
- Department of Anatomy, School of Medicine, University of Mostar, 88000 Mostar, Bosnia and Herzegovina
- Center for Translational Research in Biomedicine, School of Medicine, University of Split, 21000 Split, Croatia
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Zhang Y, Zhu Y, Chen Y, Wang Y, Liu B, Pan Y, Liao X, Pan J, Gao H, Yang W, Yu G. Nuclear translocation of cleaved PCDH9 impairs gastric cancer metastasis by downregulating CDH2 expression. iScience 2024; 27:109011. [PMID: 38357662 PMCID: PMC10865395 DOI: 10.1016/j.isci.2024.109011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 12/20/2023] [Accepted: 01/22/2024] [Indexed: 02/16/2024] Open
Abstract
Loss of Protocadherin 9 (PCDH9) is associated with the metastasis and the prognosis of gastric cancer patients, while the molecular mechanism of PCDH9-impaired gastric cancer metastasis remains unclear. Here we show that PCDH9 is cleaved in gastric cancer cells. Intracellular domain of PCDH9 translocates into nucleus, where it interacts with DNA methyltransferase 1 (DNMT1) and increases DNMT1 activity. Activated DNMT1 downregulates cadherin 2 (CDH2) expression by increasing DNA methylation at its promoter, thereby dampening the migration and in vivo metastasis of gastric cancer cells. In addition, the levels of nuclear PCDH9 correlate with CDH2 expression, lymph node metastasis, and the prognosis of gastric cancer patients. Our finding demonstrates a unique mechanism of nuclear PCDH9-impaired gastric cancer metastasis by promoting DNA methylation of CDH2 promoter.
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Affiliation(s)
- Yajuan Zhang
- Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Yingwei Zhu
- Department of Gastroentrology, Jiangnan University Medical Center, Wuxi 214000, China
| | - Ying Chen
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai 200003, China
| | - Yanli Wang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Bing Liu
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Yating Pan
- Department of Oncology, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Xinyi Liao
- Department of Oncology, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Jun Pan
- Department of Medical Oncology, Cancer Center of Jinling Hospital, Nanjing 210002, China
| | - Hong Gao
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Weiwei Yang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
| | - Guanzhen Yu
- Department of Oncology, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
- Medical Artificial Intelligence Laboratory, Zhejiang Institute of Digital Media, Chinese Academy of Science, Shaoxing 312366, China
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Matsumoto M, Ogawa N, Fukuda T, Bando Y, Nishimura T, Usuda J. Protein interaction networks characterizing the A549 cells Klotho transfected are associated with activated pro-apoptotic Bim and suppressed Wnt/β-catenin signaling pathway. Sci Rep 2024; 14:2130. [PMID: 38267588 PMCID: PMC10808115 DOI: 10.1038/s41598-024-52616-0] [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: 08/08/2023] [Accepted: 01/21/2024] [Indexed: 01/26/2024] Open
Abstract
Invasive assays and lung tumor-bearing mice models using a human lung adenocarcinoma cell line A549 cells transfected with the Klotho (KL) gene, A549/KL cells, have confirmed that KL suppresses invasive/metastatic potential. This study aimed to identify the co-expression protein networks and proteomic profiles associated with A549/KL cells to understand how Klotho protein expression affects molecular networks associated with lung carcinoma malignancy. A two-step application of a weighted network correlation analysis to the cells' quantitative proteome datasets of a total of 6,994 proteins, identified by mass spectrometry-based proteomic analysis with data-independent acquisition (DIA), identified one network module as most significantly associated with the A549/KL trait. Upstream analyses, confirmed by western blot, implicated the pro-apoptotic Bim (Bcl-2-like protein 11) as a master regulator of molecular networks affected by Klotho. GeneMANIA interaction networks and quantitative proteome data implicated that Klotho interacts with two signaling axes: negatively with the Wnt/β-catenin axis, and positively by activating Bim. Our findings might contribute to the development of future therapeutic strategies.
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Affiliation(s)
- Mitsuo Matsumoto
- Department of Thoracic Surgery, Nippon Medical School, Tokyo, 113-8602, Japan
| | - Naomi Ogawa
- Department of Thoracic Surgery, Nippon Medical School, Tokyo, 113-8602, Japan
| | | | | | - Toshihide Nishimura
- Department of Translational Medicine Informatics, St. Marianna University School of Medicine, Kawasaki, Kanagawa, 216-8511, Japan.
| | - Jitsuo Usuda
- Department of Thoracic Surgery, Nippon Medical School, Tokyo, 113-8602, Japan.
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Zhang J, Yang HZ, Liu S, Islam MO, Zhu Y, Wang Z, Chen R. PCDH9 suppresses melanoma proliferation and cell migration. Front Oncol 2022; 12:903554. [PMID: 36452505 PMCID: PMC9703089 DOI: 10.3389/fonc.2022.903554] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 10/12/2022] [Indexed: 07/24/2024] Open
Abstract
BACKGROUND Melanoma has dramatically increased during last 30 years with low 5-year survival and prognosis rate. METHODS Melanoma cells (A375 and G361) were chosen as the in vitro model. The immunohistochemical (IHC) analysis and bioinformatics mining exhibited the suppression of PCDH9 on melanoma. The interference and overexpression of PCDH9 were infected by lentivirus. The effects of PCDH9 on melanoma cells were assessed in terms of alteration of PCDH9 such as cell viability, apoptosis, cell cycle, and wound-healing assay. Moreover, expressions of PCDH9 with other genes (MMP2, MMP9, CCND1, and RAC1) were also assessed by PCR. RESULTS The alteration of PCDH9 has a negative correlation with MMP2, MMP9, and RAC1 but had a positive correlation with CCND1 (Cyclin D1) and apoptosis. Increase of PCDH9 could suppress melanoma cells and inhibit migration but not exert significant effects on cell cycle. IHC showed lower PCDH9 expression in melanoma tissue with main expression in cytoplasm. CONCLUSION Overexpressed PCDH9 suppressed melanoma cells, and PCDH9 can be considered as an independent prognostic factor for melanoma; even re-expression of PCDH9 can serve as a potential therapeutic strategy for melanoma treatment.
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Affiliation(s)
- Jiaojiao Zhang
- Dermatology Department, Dermatology Hospital, Southern Medical University, Guangzhou, Guangdong, China
- College of Food and Health, Zhejiang Agriculture and Forestry University, Hangzhou, Zhejiang, China
| | - Hui-Zhi Yang
- The Seventh Affiliated Hospital of Southern Medical University, Foshan, Guangdong, China
| | - Shuang Liu
- Dermatology Department, Dermatology Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Md Obaidul Islam
- Department of Surgery, University of Miami, Miami, FL, United States
| | - Yue Zhu
- College of Pharmaceutical Sciences, Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China
- Nano-drug Technology Research Center at Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China
| | - Zuhua Wang
- College of Pharmaceutical Sciences, Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China
- Nano-drug Technology Research Center at Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China
| | - RongYi Chen
- Dermatology Department, Dermatology Hospital, Southern Medical University, Guangzhou, Guangdong, China
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Cai G, Zou R, yang H, Xie J, Chen X, Zheng C, Luo S, Wei N, Liu S, Chen R. Circ_0084043-miR-134-5p axis regulates PCDH9 to suppress melanoma. Front Oncol 2022; 12:891476. [PMID: 36387162 PMCID: PMC9641620 DOI: 10.3389/fonc.2022.891476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 09/20/2022] [Indexed: 11/29/2022] Open
Abstract
The low survival rates, poor responses, and drug resistance of patients with melanoma make it urgent to find new therapeutic targets. This study investigated whether the circ_0084043-miR-134-5p axis regulates the antitumor effect of protocadherin 9 (PCDH9) in melanoma. Ectopic expression or knock down (KD) of PCDH9 with a lentivirus vector, we explored its effects on the proliferation, invasion, and apoptosis of melanoma and verified its regulatory effect on ras-related C3 botulinum toxin substrate 1 (RAC1), proline-rich tyrosine kinase 2 (Pyk2), Cyclin D1, matrix metalloproteinase 2 (MMP2), and MMP9. We further observed the effect of KD circ_0084043 on the malignant behavior of melanoma and studied whether circ_0084043 sponged miR-134-5p and regulated PCDH9. We found that circ_0084043 was overexpressed in melanoma and associated with the malignant phenotype. PCDH9 was poorly expressed in human melanoma tissues, and overexpression of PCDH9 inhibited melanoma progression. Quantitative real-time PCR and Western blotting results showed that overexpression of PCDH9 could downregulate RAC1, MMP2, and MMP9 and upregulate Pyk2 and Cyclin D1. Circ_0084043 KD inhibited invasion and promoted apoptosis in melanoma cells. Circ_0084043 could sponge miR-134-5p and thus indirectly regulate PCDH9. Furthermore, we discovered that inhibiting circ_0084043 had an anti–PD-Ll effect. In vivo, PCDH9 overexpression inhibited melanoma tumor growth, but PCDH9 KD promoted it. In conclusion, PCDH9, which is regulated by the circ 0084043-miR-134-5p axis, can suppress malignant biological behavior in melanoma and influence the expression levels of Pyk2, RAC1, Cyclin D1, MMP2, and MMP9.
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Affiliation(s)
- Guiyue Cai
- Dermatology Department, Dermatology Hospital, Southern Medical University, Guangzhou, China
- Clinical School, Guangdong Medical University, Zhanjiang, China
| | - Ruitao Zou
- Dermatology Department, Dermatology Hospital, Southern Medical University, Guangzhou, China
- Clinical School, Guangdong Medical University, Zhanjiang, China
| | - Huizhi yang
- Dermatology Department, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jiahao Xie
- Dermatology Department, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiaoxuan Chen
- Clinical School, Guangdong Medical University, Zhanjiang, China
| | - Chunchan Zheng
- Dermatology Department, Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Sujun Luo
- Dermatology Department, Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Na Wei
- Dermatology Department, Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Shuang Liu
- Dermatology Department, Dermatology Hospital, Southern Medical University, Guangzhou, China
- *Correspondence: Shuang Liu, ; Rongyi Chen,
| | - Rongyi Chen
- Dermatology Department, Dermatology Hospital, Southern Medical University, Guangzhou, China
- Clinical School, Guangdong Medical University, Zhanjiang, China
- *Correspondence: Shuang Liu, ; Rongyi Chen,
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Aljabban J, Rohr M, Syed S, Cohen E, Hashi N, Syed S, Khorfan K, Aljabban H, Borkowski V, Segal M, Mukhtar M, Mohammed M, Boateng E, Nemer M, Panahiazar M, Hadley D, Jalil S, Mumtaz K. Dissecting novel mechanisms of hepatitis B virus related hepatocellular carcinoma using meta-analysis of public data. World J Gastrointest Oncol 2022; 14:1856-1873. [PMID: 36187396 PMCID: PMC9516659 DOI: 10.4251/wjgo.v14.i9.1856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 04/26/2022] [Accepted: 08/07/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) is a cause of hepatocellular carcinoma (HCC). Interestingly, this process is not necessarily mediated through cirrhosis and may in fact involve oncogenic processes. Prior studies have suggested specific oncogenic gene expression pathways were affected by viral regulatory proteins. Thus, identifying these genes and associated pathways could highlight predictive factors for HCC transformation and has implications in early diagnosis and treatment.
AIM To elucidate HBV oncogenesis in HCC and identify potential therapeutic targets.
METHODS We employed our Search, Tag, Analyze, Resource platform to conduct a meta-analysis of public data from National Center for Biotechnology Information’s Gene Expression Omnibus. We performed meta-analysis consisting of 155 tumor samples compared against 185 adjacent non-tumor samples and analyzed results with ingenuity pathway analysis.
RESULTS Our analysis revealed liver X receptors/retinoid X receptor (RXR) activation and farnesoid X receptor/RXR activation as top canonical pathways amongst others. Top upstream regulators identified included the Ras family gene rab-like protein 6 (RABL6). The role of RABL6 in oncogenesis is beginning to unfold but its specific role in HBV-related HCC remains undefined. Our causal analysis suggests RABL6 mediates pathogenesis of HBV-related HCC through promotion of genes related to cell division, epigenetic regulation, and Akt signaling. We conducted survival analysis that demonstrated increased mortality with higher RABL6 expression. Additionally, homeobox A10 (HOXA10) was a top upstream regulator and was strongly upregulated in our analysis. HOXA10 has recently been demonstrated to contribute to HCC pathogenesis in vitro. Our causal analysis suggests an in vivo role through downregulation of tumor suppressors and other mechanisms.
CONCLUSION This meta-analysis describes possible roles of RABL6 and HOXA10 in the pathogenesis of HBV-related HCC. RABL6 and HOXA10 represent potential therapeutic targets and warrant further investigation.
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Affiliation(s)
- Jihad Aljabban
- Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
| | - Michael Rohr
- Department of Medicine, University of Central Florida College of Medicine, Orlando, FL 32827, United States
| | - Saad Syed
- Department of Medicine, Northwestern Memorial Hospital, Chicago, IL 60611, United States
| | - Eli Cohen
- Department of Medicine, Vanderbilt Medical Center, Nashville, TN 37232, United States
| | - Naima Hashi
- Department of Medicine, Mayo Clinic, Rochester, MN 55905, United States
| | - Sharjeel Syed
- Department of Medicine, University of Chicago Hospitals, Chicago, IL 60637, United States
| | - Kamal Khorfan
- Department of Gastroenterology and Hepatology, University of California San Francisco-Fresno, Fresno, CA 93701, United States
| | - Hisham Aljabban
- Department of Medicine, Barry University, Miami, FL 33161, United States
| | - Vincent Borkowski
- Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
| | - Michael Segal
- Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
| | - Mohamed Mukhtar
- Department of Medicine, Michigan State University College of Human Medicine, Lansing, MI 49503, United States
| | - Mohammed Mohammed
- Department of Medicine, Windsor University School of Medicine, Frankfort, IL 60423, United States
| | - Emmanuel Boateng
- Department of Medicine, Vanderbilt Medical Center, Nashville, TN 37232, United States
| | - Mary Nemer
- Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
| | - Maryam Panahiazar
- Department of Surgery, University of California San Francisco, San Francisco, CA 94143, United States
| | - Dexter Hadley
- Department of Pathology, University of Central Florida College of Medicine, Orlando, FL 32827, United States
| | - Sajid Jalil
- Department of Gastroenterology and Hepatology, Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
| | - Khalid Mumtaz
- Department of Gastroenterology and Hepatology, Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
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10
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Hernández-Oliveras A, Zarain-Herzberg Á. Expression and associated epigenetic mechanisms of the Ca 2+-signaling genes in breast cancer subtypes and epithelial-to-mesenchymal transition. J Cell Commun Signal 2022; 16:461-474. [PMID: 34762262 PMCID: PMC9411462 DOI: 10.1007/s12079-021-00655-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 10/26/2021] [Indexed: 12/30/2022] Open
Abstract
Breast cancer-associated deaths are related mainly to specific molecular subtypes and the presence of metastasis. The Epithelial-to-Mesenchymal Transition (EMT) and Ca2+ signaling pathways are involved in breast cancer metastasis, and they are regulated in part by epigenetic mechanisms. Moreover, activation of EMT modulates Ca2+ concentration and in turn, Ca2+ signaling regulates the expression of EMT markers. Also, activation of Ca2+ signaling genes with epigenetic inhibitors reverts the EMT. Thus, Ca2+ signaling might have an important role in breast cancer metastasis and EMT, particularly through the epigenetic regulation of genes involved in its signaling. However, little is known due to that an estimate of 1670 genes participate in the Ca2+ signaling and only a few genes have been studied. Here, we aimed to explore the expression of all genes involved in Ca2+ signaling in all breast cancer subtypes and EMT, and whether modulation of epigenetic mechanisms is related to their expression. Several genes of the Ca2+ signaling are altered in all breast cancer subtypes, being the cadherins and voltage channels the most frequent altered genes. Also, DNA methylation and histone posttranslational modifications showed a good correlation with their altered expression. The expression of the cadherins and voltage channels is also modulated during breast EMT, and ATAC-seq results suggest that chromatin rearrangement at their promoter is involved. In conclusion, the expression of the genes involved in Ca2+ signaling is altered in all breast cancer subtypes and during EMT, and epigenetic mechanisms are an attractive target to regulate their expression.
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Affiliation(s)
- Andrés Hernández-Oliveras
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, México
| | - Ángel Zarain-Herzberg
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, México.
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11
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Is my PET in my genes? Pediatr Nephrol 2022; 37:1175-1178. [PMID: 35079873 DOI: 10.1007/s00467-022-05452-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 12/28/2021] [Accepted: 12/28/2021] [Indexed: 10/19/2022]
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12
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COP1 Acts as a Ubiquitin Ligase for PCDH9 Ubiquitination and Degradation in Human Glioma. Mol Neurobiol 2022; 59:2378-2388. [PMID: 35084653 DOI: 10.1007/s12035-021-02634-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 11/02/2021] [Indexed: 10/19/2022]
Abstract
Constitutive photomorphogenic 1 (COP1, also known as RFWD2), a ring-finger-type E3 ubiquitin ligase, has been reported to play a pivotal role in the regulation of cell growth, apoptosis, and DNA repair. Accumulating evidence has suggested that COP1 plays a role in tumorigenesis by triggering the ubiquitination and degradation of its substrates, but the potential mechanism remains unclear. In this study, COP1 was used as a bait in a yeast two-hybrid experiment to screen COP1-interacting proteins in a human brain cDNA library, and the results indicated that protocadherin 9 (PCDH9) was a potential binding protein of COP1. The interaction between and colocalization of COP1 and PCDH9 was further confirmed by coimmunoprecipitation (co-IP) assay and immunofluorescent staining. Subsequently, we demonstrated that COP1 acted as an E3 ligase to promote the ubiquitination and degradation of PCDH9 through the proteasome pathway in glioma cells. Furthermore, we identified that the type of COP1 mediated PCDH9 ubiquitination was Lys48-linked polyubiquitination. Finally, we found that the COP1 protein level was inversely correlated with the PCDH9 protein level in human glioma tissues. Taken together, our results suggest that COP1 is an E3 ubiquitin ligase for PCDH9 and reveal an important mechanism for PCDH9 regulation in human glioma.
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13
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Mehrotra R, Stanaway IB, Jarvik GP, Lambie M, Morelle J, Perl J, Himmelfarb J, Heimburger O, Johnson DW, Imam TH, Robinson B, Stenvinkel P, Devuyst O, Davies SJ. A genome-wide association study suggests correlations of common genetic variants with peritoneal solute transfer rates in patients with kidney failure receiving peritoneal dialysis. Kidney Int 2021; 100:1101-1111. [PMID: 34197840 PMCID: PMC8545920 DOI: 10.1016/j.kint.2021.05.037] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 05/19/2021] [Accepted: 05/27/2021] [Indexed: 12/17/2022]
Abstract
Movement of solutes across the peritoneum allows for the use of peritoneal dialysis to treat kidney failure. However, there is a large inter-individual variability in the peritoneal solute transfer rate (PSTR). Here, we tested the hypothesis that common genetic variants are associated with variability in PSTR. Of the 3561 participants from 69 centers in six countries, 2850 with complete data were included in a genome-wide association study. PSTR was defined as the four-hour dialysate/plasma creatinine ratio from the first peritoneal equilibration test after starting PD. Heritability of PSTR was estimated using genomic-restricted maximum-likelihood analysis, and the association of PSTR with a genome-wide polygenic risk score was also tested. The mean four-hour dialysate/plasma creatinine ratio in participants was 0.70. In 2212 participants of European ancestry, no signal reached genome-wide significance but 23 single nucleotide variants at four loci demonstrated suggestive associations with PSTR. Meta-analysis of ancestry-stratified regressions in 2850 participants revealed five single-nucleotide variants at four loci with suggestive correlations with PSTR. Association across ancestry strata was consistent for rs28644184 at the KDM2B locus. The estimated heritability of PSTR was 19%, and a permuted model polygenic risk score was significantly associated with PSTR. Thus, this genome-wide association study of patients receiving peritoneal dialysis bolsters evidence for a genetic contribution to inter-individual variability in PSTR.
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Affiliation(s)
- Rajnish Mehrotra
- Kidney Research Institute, Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington, USA.
| | - Ian B Stanaway
- Kidney Research Institute, Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Gail P Jarvik
- Department of Medicine (Medical Genetics), University of Washington, Seattle, Washington, USA; Department of Genome Sciences, University of Washington, Seattle, Washington, USA
| | - Mark Lambie
- School of Medicine, Faculty of Medicine and Health Sciences, Keele University, Keele, UK
| | - Johann Morelle
- Division of Nephrology, Cliniques Universitaires Saint-Luc, Brussels, Belgium; Institut de Recherche Experimentale et Clinique, UClouvain, Brussels, Belgium
| | - Jeffrey Perl
- Division of Nephrology, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Jonathan Himmelfarb
- Kidney Research Institute, Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Olof Heimburger
- Division of Renal Medicine, Department of Clinical Science, Intervention, and Technology, Karolinska Institute, Stockholm, Sweden
| | - David W Johnson
- Australasian Trials Network, University of Queensland, Brisbane, Australia
| | - Talha H Imam
- Department of Nephrology, Kaiser Permanente, Fontana, California, USA
| | - Bruce Robinson
- Arbor Research Collaborative for Health, Ann Arbor, Michigan, USA
| | - Peter Stenvinkel
- Division of Renal Medicine, Department of Clinical Science, Intervention, and Technology, Karolinska Institute, Stockholm, Sweden
| | - Olivier Devuyst
- Division of Nephrology, Cliniques Universitaires Saint-Luc, Brussels, Belgium; Institut de Recherche Experimentale et Clinique, UClouvain, Brussels, Belgium
| | - Simon J Davies
- School of Medicine, Faculty of Medicine and Health Sciences, Keele University, Keele, UK
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14
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Buccarelli M, Lulli V, Giuliani A, Signore M, Martini M, D'Alessandris QG, Giannetti S, Novelli A, Ilari R, Giurato G, Boe A, Castellani G, Spartano S, Marangi G, Biffoni M, Genuardi M, Pallini R, Marziali G, Ricci-Vitiani L. Deregulated expression of the imprinted DLK1-DIO3 region in glioblastoma stemlike cells: tumor suppressor role of lncRNA MEG3. Neuro Oncol 2021; 22:1771-1784. [PMID: 32459347 PMCID: PMC7746944 DOI: 10.1093/neuonc/noaa127] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Background Glioblastoma (GBM) stemlike cells (GSCs) are thought to be responsible for the maintenance and aggressiveness of GBM, the most common primary brain tumor in adults. This study aims at elucidating the involvement of deregulations within the imprinted delta-like homolog 1 gene‒type III iodothyronine deiodinase gene (DLK-DIO3) region on chromosome 14q32 in GBM pathogenesis. Methods Real-time PCR analyses were performed on GSCs and GBM tissues. Methylation analyses, gene expression, and reverse-phase protein array profiles were used to investigate the tumor suppressor function of the maternally expressed 3 gene (MEG3). Results Loss of expression of genes and noncoding RNAs within the DLK1-DIO3 region was observed in GSCs and GBM tissues compared with normal brain. This downregulation is mainly mediated by epigenetic silencing. Kaplan–Meier analysis indicated that low expression of MEG3 and MEG8 long noncoding (lnc)RNAs significantly correlated with short survival in GBM patients. MEG3 restoration impairs tumorigenic abilities of GSCs in vitro by inhibiting cell growth, migration, and colony formation and decreases in vivo tumor growth, reducing infiltrative growth. These effects were associated with modulation of genes involved in cell adhesion and epithelial-to-mesenchymal transition (EMT). Conclusion In GBM, MEG3 acts as a tumor suppressor mainly regulating cell adhesion, EMT, and cell proliferation, thus providing a potential candidate for novel GBM therapies.
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Affiliation(s)
| | | | | | - Michele Signore
- Core Facilities, Higher Institute of Health (Istituto Superiore di Sanità), Rome, Italy
| | - Maurizio Martini
- A. Gemelli University Polyclinic Foundation, Scientific Hospitalization and Care Institute (IRCCS), Rome, Italy.,Institutes of Pathology, Catholic University School of Medicine, Rome, Italy
| | - Quintino G D'Alessandris
- A. Gemelli University Polyclinic Foundation, Scientific Hospitalization and Care Institute (IRCCS), Rome, Italy.,Neurosurgery, Catholic University School of Medicine, Rome, Italy
| | - Stefano Giannetti
- A. Gemelli University Polyclinic Foundation, Scientific Hospitalization and Care Institute (IRCCS), Rome, Italy.,Human Anatomy, Catholic University School of Medicine, Rome, Italy
| | - Agnese Novelli
- Genomic Medicine, Catholic University School of Medicine, Rome, Italy
| | - Ramona Ilari
- Department of Oncology and Molecular Medicine Rome, Italy
| | - Giorgio Giurato
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery, and Dentistry, "Scuola Medica Salernitana," University of Salerno, Baronissi, Salerno, Italy.,Genomix4Life Srl, University of Salerno, Baronissi, Salerno, Italy
| | - Alessandra Boe
- Core Facilities, Higher Institute of Health (Istituto Superiore di Sanità), Rome, Italy
| | | | - Serena Spartano
- Genomic Medicine, Catholic University School of Medicine, Rome, Italy
| | - Giuseppe Marangi
- Department of Oncology and Molecular Medicine Rome, Italy.,Genomic Medicine, Catholic University School of Medicine, Rome, Italy
| | - Mauro Biffoni
- Department of Oncology and Molecular Medicine Rome, Italy
| | - Maurizio Genuardi
- A. Gemelli University Polyclinic Foundation, Scientific Hospitalization and Care Institute (IRCCS), Rome, Italy.,Genomic Medicine, Catholic University School of Medicine, Rome, Italy
| | - Roberto Pallini
- A. Gemelli University Polyclinic Foundation, Scientific Hospitalization and Care Institute (IRCCS), Rome, Italy.,Neurosurgery, Catholic University School of Medicine, Rome, Italy
| | - Giovanna Marziali
- Department of Oncology and Molecular Medicine Rome, Italy.,Genomic Medicine, Catholic University School of Medicine, Rome, Italy
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15
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Jao TM, Fang WH, Ciou SC, Yu SL, Hung YL, Weng WT, Lin TY, Tsai MH, Yang YC. PCDH10 exerts tumor-suppressor functions through modulation of EGFR/AKT axis in colorectal cancer. Cancer Lett 2020; 499:290-300. [PMID: 33271263 DOI: 10.1016/j.canlet.2020.11.017] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 11/12/2020] [Accepted: 11/13/2020] [Indexed: 02/07/2023]
Abstract
Protocadherin 10 (PCDH10) is identified as a tumor suppressor in multiple cancers. The molecular mechanisms that mediate the functions of PCDH10 have yet to be fully elucidated. Here, we demonstrated that ectopic expression of PCDH10 in colorectal cancer (CRC) cells induced cell cycle retardation and increased apoptosis through regulation of the p53/p21/Rb axis and Bcl-2 expression. Overexpression of PCDH10 reversed the epithelial-mesenchymal transition (EMT) process with morphological changes and EMT marker alterations. Mechanistic study revealed that PCDH10 inhibited AKT/GSK3β signaling pathway which in turn reduced β-catenin activity and thus attenuated Snail and Twist1 expression. Furthermore, PCDH10 inhibited the stemness of CRC cells, including spheroid formation and stem cell markers. A proteomics approach revealed that PCDH10 could interact with EGFR, which was further verified by co-immunoprecipitation. Moreover, restoration of PCDH10 expression reduced EGFR phosphorylation. Accordingly, our work proposes a novel pathway by which PCDH10 directly engages in the negative regulation of EGFR/AKT/β-catenin signaling pathway, resulting in tumor suppression.
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Affiliation(s)
- Tzu-Ming Jao
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, 100, Taiwan; Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung City, 813, Taiwan
| | - Woei-Horng Fang
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, 100, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan
| | - Shih-Ci Ciou
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, 100, Taiwan
| | - Sung-Liang Yu
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, 100, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan
| | - Yu-Lin Hung
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, 100, Taiwan
| | - Wei-Ting Weng
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, 100, Taiwan
| | - Tsai-Yi Lin
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, 100, Taiwan
| | - Ming-Hong Tsai
- Department of Surgery, Cardinal Tien Hospital, New Taipei City, 231, Taiwan; School of Medicine, Fu-Jen Catholic University, New Taipei City, 242, Taiwan.
| | - Ya-Chien Yang
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, 100, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan.
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16
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Moroney JB, Vasudev A, Pertsemlidis A, Zan H, Casali P. Integrative transcriptome and chromatin landscape analysis reveals distinct epigenetic regulations in human memory B cells. Nat Commun 2020; 11:5435. [PMID: 33116135 PMCID: PMC7595102 DOI: 10.1038/s41467-020-19242-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Accepted: 10/01/2020] [Indexed: 01/08/2023] Open
Abstract
Memory B cells (MBCs) are long-lived and produce high-affinity, generally, class-switched antibodies. Here, we use a multiparameter approach involving CD27 to segregate naïve B cells (NBC), IgD+ unswitched (unsw)MBCs and IgG+ or IgA+ class-switched (sw)MBCs from humans of different age, sex and race. Conserved antibody variable gene expression indicates that MBCs emerge through unbiased selection from NBCs. Integrative analyses of mRNAs, miRNAs, lncRNAs, chromatin accessibility and cis-regulatory elements uncover a core mRNA-ncRNA transcriptional signature shared by IgG+ and IgA+ swMBCs and distinct from NBCs, while unswMBCs display a transitional transcriptome. Some swMBC transcriptional signature loci are accessible but not expressed in NBCs. Profiling miRNAs reveals downregulated MIR181, and concomitantly upregulated MIR181 target genes such as RASSF6, TOX, TRERF1, TRPV3 and RORα, in swMBCs. Finally, lncRNAs differentially expressed in swMBCs cluster proximal to the IgH chain locus on chromosome 14. Our findings thus provide new insights into MBC transcriptional programs and epigenetic regulation, opening new investigative avenues on these critical cell elements in human health and disease. Human memory B cells differentiate from naïve B cells and can express different immunoglobulin (Ig) isotypes resulted from class-switch recombination. Here the authors describe, using transcriptional and epigenetic data from human memory B cells and integrated multi-omics analyses, the differentiation regulation and trajectory of IgG+, IgA+ and IgD+ memory B cells.
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Affiliation(s)
- Justin B Moroney
- Department of Microbiology, Immunology & Molecular Genetics, University of Texas Long School of Medicine, UT Health Science Center, San Antonio, TX, 78229, USA
| | - Anusha Vasudev
- Department of Microbiology, Immunology & Molecular Genetics, University of Texas Long School of Medicine, UT Health Science Center, San Antonio, TX, 78229, USA
| | - Alexander Pertsemlidis
- Greehey Children's Cancer Research Institute, University of Texas Long School of Medicine, UT Health Science Center, San Antonio, TX, 78229, USA
| | - Hong Zan
- Department of Microbiology, Immunology & Molecular Genetics, University of Texas Long School of Medicine, UT Health Science Center, San Antonio, TX, 78229, USA
| | - Paolo Casali
- Department of Microbiology, Immunology & Molecular Genetics, University of Texas Long School of Medicine, UT Health Science Center, San Antonio, TX, 78229, USA.
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17
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Zhao Y, Ye X, Chen R, Gao Q, Zhao D, Ling C, Qian Y, Xu C, Tao M, Xie Y. Sirtuin 7 promotes non‑small cell lung cancer progression by facilitating G1/S phase and epithelial‑mesenchymal transition and activating AKT and ERK1/2 signaling. Oncol Rep 2020; 44:959-972. [PMID: 32705247 PMCID: PMC7388485 DOI: 10.3892/or.2020.7672] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 05/29/2020] [Indexed: 12/11/2022] Open
Abstract
Increasing evidence has indicated the roles of sirtuin 7 (SIRT7) in numerous human cancers. However, the effects and the clinical significance of SIRT7 in human lung cancer is largely unknown. The present research demonstrated that SIRT7 was increased in human lung cancer tumor tissues. SIRT7 upregulation was associated with clinicopathological characteristics of lung cancer malignancy including positive lymph node metastasis, high pathologic stage and large tumor size. SIRT7 was also upregulated in human non-small cell lung cancer (NSCLC) cell lines. Furthermore SIRT7-overexpressed A549 (A549-SIRT7) and SIRT7-knocked down H292 (H292-shSIRT7) human NSCLC cell lines were established. Using these NSCLC cells and xenograft mouse models, it was revealed that SIRT7 overexpression markedly promoted growth and G1 to S cell cycle phase transition as well as migration, invasion and distant lung metastasis in A549 NSCLC cells, whereas SIRT7 knockdown suppressed these processes in H292 NSCLC cells. Mechanistically, in A549 NSCLC cells, SIRT7 overexpression significantly activated not only protein kinase B (AKT) signaling but also extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. SIRT7 overexpression also significantly downregulated cyclin-dependent kinase (CDK) inhibitors including p21 and p27 as well as upregulated cyclins including cyclin D1 and cyclin E1, and CDKs including CDK2 and CDK4. Notably, the epithelial-mesenchymal transition (EMT) process of A549 NSCLC cells was facilitated by SIRT7 overexpression, as evidenced by E-cadherin epithelial marker downregulation and mesenchymal markers (N-cadherin, vimentin, Snail and Slug) upregulation. In addition, SIRT7 knockdown in H292 NSCLC cells exhibited the opposite regulatory effects. Moreover, inhibition of AKT signaling abated the promoting effects of SIRT7 in NSCLC cell proliferation and EMT progression. The present data indicated that SIRT7 accelerated human NSCLC cell growth and metastasis possibly by promotion of G1 to S-phase transition and EMT through modulation of the expression of G1-phase checkpoint molecules and EMT markers as well as activation of AKT and ERK1/2 signaling. SIRT7 could be an innovative potential target for human NSCLC therapy.
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Affiliation(s)
- Yingying Zhao
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Xia Ye
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Ruifang Chen
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Qian Gao
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Daguo Zhao
- Department of Respiratory Medicine, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Chunhua Ling
- Department of Respiratory Medicine, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Yulan Qian
- Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Chun Xu
- Department of Cardio‑Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Min Tao
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Yufeng Xie
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
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18
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Pancho A, Aerts T, Mitsogiannis MD, Seuntjens E. Protocadherins at the Crossroad of Signaling Pathways. Front Mol Neurosci 2020; 13:117. [PMID: 32694982 PMCID: PMC7339444 DOI: 10.3389/fnmol.2020.00117] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 06/08/2020] [Indexed: 12/25/2022] Open
Abstract
Protocadherins (Pcdhs) are cell adhesion molecules that belong to the cadherin superfamily, and are subdivided into clustered (cPcdhs) and non-clustered Pcdhs (ncPcdhs) in vertebrates. In this review, we summarize their discovery, expression mechanisms, and roles in neuronal development and cancer, thereby highlighting the context-dependent nature of their actions. We furthermore provide an extensive overview of current structural knowledge, and its implications concerning extracellular interactions between cPcdhs, ncPcdhs, and classical cadherins. Next, we survey the known molecular action mechanisms of Pcdhs, emphasizing the regulatory functions of proteolytic processing and domain shedding. In addition, we outline the importance of Pcdh intracellular domains in the regulation of downstream signaling cascades, and we describe putative Pcdh interactions with intracellular molecules including components of the WAVE complex, the Wnt pathway, and apoptotic cascades. Our overview combines molecular interaction data from different contexts, such as neural development and cancer. This comprehensive approach reveals potential common Pcdh signaling hubs, and points out future directions for research. Functional studies of such key factors within the context of neural development might yield innovative insights into the molecular etiology of Pcdh-related neurodevelopmental disorders.
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Affiliation(s)
- Anna Pancho
- Laboratory of Developmental Neurobiology, Department of Biology, KU Leuven, Leuven, Belgium
| | - Tania Aerts
- Laboratory of Developmental Neurobiology, Department of Biology, KU Leuven, Leuven, Belgium
| | - Manuela D Mitsogiannis
- Laboratory of Developmental Neurobiology, Department of Biology, KU Leuven, Leuven, Belgium
| | - Eve Seuntjens
- Laboratory of Developmental Neurobiology, Department of Biology, KU Leuven, Leuven, Belgium
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19
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Clinical relevance and functional significance of cell-free microRNA-1260b expression profiles in infiltrative myxofibrosarcoma. Sci Rep 2020; 10:9414. [PMID: 32523124 PMCID: PMC7287053 DOI: 10.1038/s41598-020-66120-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Accepted: 05/13/2020] [Indexed: 12/24/2022] Open
Abstract
Infiltrative tumor growth into adjacent soft tissues is a major cause of the frequent recurrence and tumor-related death of myxofibrosarcoma (MFS), but no useful biomarkers reflecting tumor burden and infiltrative growth are available. While emerging evidence suggests a diagnostic and functional role of extracellular/circulating microRNA (miRNA) in various malignant diseases, their significance in MFS patients remains unknown. Global miRNA profiling identified four upregulated miRNAs in MFS patient sera and culture media of MFS cells. Among these, serum miR-1260b level was significantly upregulated in patient serum discriminating from healthy individuals and closely correlated with clinical status and tumor dynamics in MFS-bearing mice. In addition, high miR-1260b expression in serum was correlated with radiological tail-like patterns, characteristic of the infiltrative MFS. The extracellular miR-1260b was embedded in tumor-derived extracellular vesicles (EVs) and promoted cellular invasion of MFS through the downregulation of PCDH9 in the adjacent normal fibroblasts. Collectively, circulating miR-1260b expression may represent a novel diagnostic target for tumor monitoring of this highly aggressive sarcoma. Moreover, EV-miR-1260b could act as a transfer messenger to adjacent cells and mediate the infiltrative growth of MFS, providing new insights into the mechanism of infiltrative nature via crosstalk between tumor cells and their microenvironment.
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20
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Family-wide Structural and Biophysical Analysis of Binding Interactions among Non-clustered δ-Protocadherins. Cell Rep 2020; 30:2655-2671.e7. [PMID: 32101743 PMCID: PMC7082078 DOI: 10.1016/j.celrep.2020.02.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Revised: 11/02/2019] [Accepted: 01/31/2020] [Indexed: 01/21/2023] Open
Abstract
Non-clustered δ1- and δ2-protocadherins, close relatives of clustered protocadherins, function in cell adhesion and motility and play essential roles in neural patterning. To understand the molecular interactions underlying these functions, we used solution biophysics to characterize binding of δ1- and δ2-protocadherins, determined crystal structures of ectodomain complexes from each family, and assessed ectodomain assembly in reconstituted intermembrane junctions by cryoelectron tomography (cryo-ET). Homophilic trans (cell-cell) interactions were preferred for all δ-protocadherins, with additional weaker heterophilic interactions observed exclusively within each subfamily. As expected, δ1- and δ2-protocadherin trans dimers formed through antiparallel EC1-EC4 interfaces, like clustered protocadherins. However, no ectodomain-mediated cis (same-cell) interactions were detectable in solution; consistent with this, cryo-ET of reconstituted junctions revealed dense assemblies lacking the characteristic order observed for clustered protocadherins. Our results define non-clustered protocadherin binding properties and their structural basis, providing a foundation for interpreting their functional roles in neural patterning.
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21
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Vychytilova-Faltejskova P, Slaby O. MicroRNA-215: From biology to theranostic applications. Mol Aspects Med 2019; 70:72-89. [PMID: 30904345 DOI: 10.1016/j.mam.2019.03.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 03/10/2019] [Accepted: 03/17/2019] [Indexed: 02/07/2023]
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22
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Shishodia G, Koul S, Koul HK. Protocadherin 7 is overexpressed in castration resistant prostate cancer and promotes aberrant MEK and AKT signaling. Prostate 2019; 79:1739-1751. [PMID: 31449679 DOI: 10.1002/pros.23898] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 07/29/2019] [Indexed: 11/11/2022]
Abstract
BACKGROUND Castrate resistant prostate cancer (CRPC) accounts for almost all prostate cancer (PCa) deaths. Aberrant activation of ERK/MEK and PI3K/AKT signaling pathways plays an important role in subsets of patients with CRPC. The role of protocadherin 7 (PCDH7) in modulating these signaling pathways is investigated for the first time in PCa in the present investigation. METHODS PCDH7 expression was analyzed in CRPC/neuroendocrine prostate cancer (NEPC) dataset. Protein expression was assessed by Western blotting and immunohistochemistry, and messenger RNA (mRNA) by quantitative real-time polymerase chain reaction. Small hairpin ribonucleic acid was used to knockdown PCDH7. Colony formation, cell migration, and invasion studies were done using standard protocols. RESULTS PCDH7 amplification/mRNA upregulation was observed in 41% of patients in CRPC/NEPC dataset. PCDH7 was also overexpressed in CRPC cells. Increased PCDH protein expression was observed during tumor progression in PCa tissues and in TRAMP mice. Epidermal growth factor treatment resulted in aberrant activation of ERK/AKT. Knockdown of PCDH7 decreased ERK, AKT, and RB phosphorylation and reduced colony formation, decreased cell invasion, and cell migration. CONCLUSIONS These data show for the first time that PCDH7 is overexpressed in a large number of patients with CRPC and suggest that PCDH7 may be an attractive target in subsets of patients with CRPC for whom there is no cure to-date.
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Affiliation(s)
- Gauri Shishodia
- Department of Biochemistry and Molecular Biology, LSU Health Sciences Center, Shreveport, Louisiana
- Feist Weiller Cancer Center, Shreveport, Louisiana
| | - Sweaty Koul
- Feist Weiller Cancer Center, Shreveport, Louisiana
- Department of Urology, LSU Health Sciences Center, Shreveport, Louisiana
| | - Hari K Koul
- Department of Biochemistry and Molecular Biology, LSU Health Sciences Center, Shreveport, Louisiana
- Feist Weiller Cancer Center, Shreveport, Louisiana
- Overton Brooks Veterans Administrative Medical Center, Shreveport, Louisiana
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23
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Chauhan R, Shimizu Y, Watashi K, Wakita T, Fukasawa M, Michalak TI. Retrotransposon elements among initial sites of hepatitis B virus integration into human genome in the HepG2-NTCP cell infection model. Cancer Genet 2019; 235-236:39-56. [PMID: 31064734 DOI: 10.1016/j.cancergen.2019.04.060] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 04/11/2019] [Accepted: 04/18/2019] [Indexed: 02/07/2023]
Abstract
Integration of hepatitis B virus (HBV) DNA into host's genome is evident in all stages and models of HBV infection. Investigations of the initial virus-host junctions have been just recently initiated since their nature may promote liver oncogenesis immediately following infection. We examined the time-frame and host sites at which HBV integrates in HepG2 cells overexpressing sodium taurocholate co-transporting polypeptide (NTCP) receptor mediating HBV entry. HepG2-NTCP cells were analyzed from 15 min to 13 days post-infection (p.i.). The results showed that except for 15 min p.i., HBV-host integrations were detected at all time points thereafter. At 30 min p.i., virus junctions with retrotransposon SINE and with neuroblastoma breakpoint family member 1 gene were detected. At one-hour p.i., HBV integration with retrotransposon THE-1B-LTR was identified, while virus insertions into proline-rich protein and protein kinase cGMP-dependent type 1 encoding genes were found at 3 h p.i. Fusion with runt-related transcription factor 1 was detected at 24 h p.i. and merges with 9 different genes at 13 day p.i. The data showed that retrotransposon elements are frequent among first-hit sites of HBV insertion. This may suggest a mechanism by which HBV DNA may spread across host's genome from earliest stages of infection.
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Affiliation(s)
- Ranjit Chauhan
- Molecular Virology and Hepatology Research Group, Division of BioMedical Sciences, Faculty of Medicine, Health Science Centre, Memorial University, St. John's, NL, Canada
| | - Yoshimi Shimizu
- Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, Japan
| | - Koichi Watashi
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Takaji Wakita
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Masayoshi Fukasawa
- Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, Japan
| | - Tomasz I Michalak
- Molecular Virology and Hepatology Research Group, Division of BioMedical Sciences, Faculty of Medicine, Health Science Centre, Memorial University, St. John's, NL, Canada.
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24
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Robbins CJ, Bou-Dargham MJ, Sanchez K, Rosen MC, Sang QXA. Decoding Somatic Driver Gene Mutations and Affected Signaling Pathways in Human Medulloblastoma Subgroups. J Cancer 2018; 9:4596-4610. [PMID: 30588243 PMCID: PMC6299398 DOI: 10.7150/jca.27993] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Accepted: 09/08/2018] [Indexed: 01/02/2023] Open
Abstract
Medulloblastoma is the most common malignant pediatric brain tumor. Prior studies have concentrated their efforts studying the four molecular subgroups: SHH, Wnt, group 3, and group 4. SHH and Wnt are driven by their canonical pathways. Groups 3 and 4 are highly metastatic and associated with aberrations in epigenetic regulators. Recent developments in the field have revealed that these subgroups are not as homogenous as previously believed. The objective of this study is to investigate the involvement of somatic driver gene mutations in these medulloblastoma subgroups. We obtained medulloblastoma data from the Catalogue of Somatic Mutations in Cancer (COSMIC), which contains distinct samples that were not previously studied in a large cohort. We identified somatic driver gene mutations and the signaling pathways affected by these driver genes for medulloblastoma subgroups using bioinformatics tools. We have revealed novel infrequent drivers in these subgroups that contribute to our understanding of tumor heterogeneity in medulloblastoma. Normally SHH signaling is activated in the SHH subgroup, however, we determined gain-of-function mutations in ubiquitin ligase (CUL1) that inhibit Gli-mediated transcription. This suggests a potential hindrance in SHH signaling for some patients. For group 3, gain-of-function in the inhibitor of proinflammatory cytokines (HIVEP3) suggests an immunosuppressive phenotype and thus a more hostile tumor microenvironment. Surprisingly, group 4 tumors possess mutations that may prompt the activation of Wnt signaling through gain-of-function mutations in MUC16 and PCDH9. These infrequent mutations detected in this study could be due to subclonal or spatially restricted alterations. The investigation of aberrant driver gene mutations can lead to the identification of new drug targets and a greater understanding of human medulloblastoma heterogeneity.
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Affiliation(s)
- Charles J Robbins
- Department of Chemistry & Biochemistry, Institute of Molecular Biophysics, Florida State University
| | - Mayassa J Bou-Dargham
- Department of Chemistry & Biochemistry, Institute of Molecular Biophysics, Florida State University
| | - Kevin Sanchez
- Department of Chemistry & Biochemistry, Institute of Molecular Biophysics, Florida State University
| | - Matthew C Rosen
- Department of Chemistry & Biochemistry, Institute of Molecular Biophysics, Florida State University
| | - Qing-Xiang Amy Sang
- Department of Chemistry & Biochemistry, Institute of Molecular Biophysics, Florida State University
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25
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Zhang T, Guan G, Chen T, Jin J, Zhang L, Yao M, Qi X, Zou J, Chen J, Lu F, Chen X. Methylation of PCDH19 predicts poor prognosis of hepatocellular carcinoma. Asia Pac J Clin Oncol 2018; 14:e352-e358. [PMID: 29749051 DOI: 10.1111/ajco.12982] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Accepted: 04/05/2018] [Indexed: 01/08/2023]
Abstract
OBJECTIVE Several members of protocadherins (PCDHs) have been identified as tumor suppressor genes in human carcinogenesis, but little is known about PCDH19. The aim of the present study was to assess the expression and methylation of PCDH19 in hepatocellular carcinoma (HCC). METHODS The RNA-seq data from The Cancer Genome Atlas Database were downloaded and used for analyzing PCDH19 expression in HCC patients and normal liver tissues. We collected 63 paired tumor and nontumor liver tissues from hepatitis B virus-related HCC patients. The expression of PCDH19 was detected by real-time quantitative RT-PCR assay. The methylation of PCDH19 gene was analyzed by DNA methylation-sensitive endonuclease digestion and the sequential quantitative PCR. The prognostic value of PCDH19 gene methylation was evaluated by Kaplan-Meier analyses. RESULTS PCDH19 expression was downregulated in HCC tissues and seven HCC cell lines compared to nontumor tissues. PCHD19 promoter was frequently hypermethylated in three (SMMC7721, Hep3B and SNU387) of seven HCC cell lines and 5-aza-dC treatment could significantly increased the PCDH19 expression in these methylated cells. In addition, HCC tumor tissues exhibited significantly increased PCDH19 hypermethylation both in frequency (30.15% vs 9.52%, P = 0.003) and in intensity (P = 0.002) compared to that in nontumor tissues. Kaplan-Meier survival analysis revealed that PCDH19 hypermethylation was correlated with the poor overall survival of HCC patients. CONCLUSION PCDH19 expression was downregulated in HCC, which was mediated at least in part by promoter hypermethylation. PCDH19 hypermethylation might present a potential prognostic marker in HCC patients.
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Affiliation(s)
- Ting Zhang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Guiwen Guan
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Tingting Chen
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Jingling Jin
- Departments of Pediatrics-Oncology and Surgery, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas, USA
| | - Lichun Zhang
- Department of Liver Disease, Taiyuan Third People's Hospital, Taiyuan, China
| | - Mingjie Yao
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Xuewei Qi
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Jun Zou
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Jiacheng Chen
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Fengmin Lu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Xiangmei Chen
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
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26
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Świerczewska M, Klejewski A, Brązert M, Kaźmierczak D, Iżycki D, Nowicki M, Zabel M, Januchowski R. New and Old Genes Associated with Primary and Established Responses to Paclitaxel Treatment in Ovarian Cancer Cell Lines. Molecules 2018; 23:molecules23040891. [PMID: 29649113 PMCID: PMC6017641 DOI: 10.3390/molecules23040891] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 04/04/2018] [Accepted: 04/10/2018] [Indexed: 01/10/2023] Open
Abstract
Development of drug resistance is the main reason for low chemotherapy effectiveness in treating ovarian cancer. Paclitaxel (PAC) is a chemotherapeutic drug used in the treatment of this cancer. We analysed the development of PAC resistance in two ovarian cancer cell lines. Exposure of drug-sensitive cell lines (A2780 and W1) to PAC was used to determine the primary response. An established response was determined in PAC-resistant sublines of the A2780 and W1 cell lines. qRT-PCR was performed to measure the expression levels of specific genes. We observed decreased expression of the PCDH9, NSBP1, MCTP1 and SEMA3A genes in the PAC-resistant cell lines. Short-term exposure to PAC led to increased expression of the MDR1 and BCRP genes in the A2780 and W1 cell lines. In the A2780 cell line, we also observed increased expression of the C4orf18 gene and decreased expression of the PCDH9 and SEMA3A genes after PAC treatment. In the W1 cell line, short-term treatment with PAC upregulated the expression of the ALDH1A1 gene, a marker of Cancer stem cells (CSCs). Our results suggest that downregulation of the PCDH9, NSBP1, MCTP1 and SEMA3A genes and upregulation of the MDR1, BCRP, C4orf18 and ALDH1A1 genes may be related to PAC resistance.
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Affiliation(s)
- Monika Świerczewska
- Department of Histology and Embryology, Poznan University of Medical Sciences, Święcickiego 6 St., 61-781 Poznań, Poland.
| | - Andrzej Klejewski
- Department of Nursing, Poznan University of Medical Sciences, Smoluchowskiego 11 St., 60-179 Poznan, Poland.
- Department of Obstetrics and Women's Diseases, Poznan University of Medical Sciences, Smoluchowskiego 11 St., 60-179 Poznan, Poland.
| | - Maciej Brązert
- Division of Infertility and Reproductive Endocrinology, Department of Gynecology, Obstetrics and Gynecological Oncology, Poznan University of Medical Sciences, Polna 33 St., 60-535 Poznań, Poland.
| | - Dominika Kaźmierczak
- Department of Histology and Embryology, Poznan University of Medical Sciences, Święcickiego 6 St., 61-781 Poznań, Poland.
| | - Dariusz Iżycki
- Department of Cancer Immunology, Poznan University of Medical Sciences, Garbary 15 St., 61-866 Poznań, Poland.
| | - Michał Nowicki
- Department of Histology and Embryology, Poznan University of Medical Sciences, Święcickiego 6 St., 61-781 Poznań, Poland.
| | - Maciej Zabel
- Department of Histology and Embryology, Poznan University of Medical Sciences, Święcickiego 6 St., 61-781 Poznań, Poland.
| | - Radosław Januchowski
- Department of Histology and Embryology, Poznan University of Medical Sciences, Święcickiego 6 St., 61-781 Poznań, Poland.
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27
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Li M, Sun Q, Wang X. Transcriptional landscape of human cancers. Oncotarget 2018; 8:34534-34551. [PMID: 28427185 PMCID: PMC5470989 DOI: 10.18632/oncotarget.15837] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2016] [Accepted: 02/08/2017] [Indexed: 12/21/2022] Open
Abstract
The homogeneity and heterogeneity in somatic mutations, copy number alterations and methylation across different cancer types have been extensively explored. However, the related exploration based on transcriptome data is lacking. In this study we explored gene expression profiles across 33 human cancer types using The Cancer Genome Atlas (TCGA) data. We identified consistently upregulated genes (such as E2F1, EZH2, FOXM1, MYBL2, PLK1, TTK, AURKA/B and BUB1) and consistently downregulated genes (such as SCARA5, MYOM1, NKAPL, PEG3, USP2, SLC5A7 and HMGCLL1) across various cancers. The dysregulation of these genes is likely to be associated with poor clinical outcomes in cancer. The dysregulated pathways commonly in cancers include cell cycle, DNA replication, repair, and recombination, Notch signaling, p53 signaling, Wnt signaling, TGFβ signaling, immune response etc. We also identified genes consistently upregulated or downregulated in highly-advanced cancers compared to lowly-advanced cancers. The highly (low) expressed genes in highly-advanced cancers are likely to have higher (lower) expression levels in cancers than in normal tissue, indicating that common gene expression perturbations drive cancer initiation and cancer progression. In addition, we identified a substantial number of genes exclusively dysregulated in a single cancer type or inconsistently dysregulated in different cancer types, demonstrating the intertumor heterogeneity. More importantly, we found a number of genes commonly dysregulated in various cancers such as PLP1, MYOM1, NKAPL and USP2 which were investigated in few cancer related studies, and thus represent our novel findings. Our study provides comprehensive portraits of transcriptional landscape of human cancers.
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Affiliation(s)
- Mengyuan Li
- School of Science, China Pharmaceutical University, Nanjing 211198, China
| | - Qingrong Sun
- School of Science, China Pharmaceutical University, Nanjing 211198, China
| | - Xiaosheng Wang
- Department of Basic Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China
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28
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Wu Y, Zheng S, Yao J, Li M, Yang G, Zhang N, Zhang S, Zhong B. Decreased expression of protocadherin 20 is associated with poor prognosis in hepatocellular carcinoma. Oncotarget 2018; 8:3018-3028. [PMID: 27935871 PMCID: PMC5356860 DOI: 10.18632/oncotarget.13822] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Accepted: 11/22/2016] [Indexed: 12/20/2022] Open
Abstract
Recently, protocadherin 20 has been reported as a tumor suppressor gene in hepatocellular carcinoma (HCC); however, the prognostic value of protocadherin 20 in HCC remains unclear. Hence, the purpose of this study was to investigate the clinical and prognostic values of protocadherin 20 in HCC patients. The expression of protocadherin 20 was assessed by quantitative real-time polymerase chain reaction, western blot, and immunohistochemistry. Kaplan-Meier curves were created to calculate the overall survival of the patients, and Cox regression models were used to identify the risk factors associated with prognosis. Of 317 primary HCC patients, decreased expression of protocadherin 20 was observed in 184 (58.0%) patients (P < 0.001). Reduced protocadherin 20 protein expression correlated with portal hypertension, poor tumor differentiation, advanced Okuda stage, and Cancer of the Liver Italian Program score (all P < 0.05). Low protocadherin 20 expression was an independent risk factor for mortality (P = 0.018). Furthermore, in our newly developed simple risk score based on protocadherin 20, patients with total score > 1.11 showed significantly poorer outcome; and the predictive value of the score was better than the Barcelona Clinic Liver Cancer stage, Okuda stage, and Child-Pugh classification (Harrell's concordance index = 0.614). Taken together, these findings suggest that protocadherin 20 may represent a novel prognostic biomarker for HCC patients.
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Affiliation(s)
- Yanqin Wu
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P.R. China
| | - Shuhui Zheng
- Research Center of Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P.R. China
| | - Jiayan Yao
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P.R. China
| | - Minrui Li
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P.R. China
| | - Guang Yang
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P.R. China
| | - Ning Zhang
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P.R. China
| | - Shenghong Zhang
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P.R. China
| | - Bihui Zhong
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P.R. China
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29
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Wang C, Chen Q, Li S, Li S, Zhao Z, Gao H, Wang X, Li B, Zhang W, Yuan Y, Ming L, He H, Tao B, Zhong J. Dual inhibition of PCDH9 expression by miR-215-5p up-regulation in gliomas. Oncotarget 2018; 8:10287-10297. [PMID: 28055966 PMCID: PMC5354659 DOI: 10.18632/oncotarget.14396] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Accepted: 12/12/2016] [Indexed: 12/25/2022] Open
Abstract
The clinical prognosis of malignant gliomas is poor and PCDH9 down-regulation is strongly associated with its poor prognosis. But the mechanism of PCDH9 down-regulation is unknown. Abnormal miRNAs profiles regulate tumor phenotypes through inhibiting their target genes and miRNAs could inhibit target genes more efficiently by binding to both the promoter and 3′UTR of target genes. In this study, to search the dual inhibitory miRNAs which suppress PCDH9 expression in gliomas, we performed an integrative analysis of databases including miRDB, TargetScan, microPIR and miRCancer. We identified three candidate miRNAs which were predicted to bind both the promoter and 3′UTR of PCDH9 and up-regulated in gliomas. Then, we validated miR-215-5p up-regulation and PCDH9 down-regulation in glioma samples and demonstrated that miR-215-5p could inhibit the mRNA and protein levels of PCDH9 in glioma cell lines by targeting its promoter and 3′ UTR at the same time. Moreover, miR-215-5p could increase glioma cell proliferation, clone formation, in-vitro migration and reduce apoptosis via inhibiting PCDH9 expression. Our study provides evidence for a novel dual inhibition of PCDH9 by miR-215-5p in gliomas and suggests that miR-215-5p might be a therapeutic target for the treatment of gliomas.
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Affiliation(s)
- Chunlin Wang
- Department of Neurosurgery, The 105th Hospital of PLA, Hefei, Anhui 230000, China
| | - Qi Chen
- Department of Anesthesiology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200003, China
| | - Shu Li
- Department of Pathophysiology, Wannan Medical College, Wuhu 241002, China; Department of Neurosurgery, Wuxi Second People's Hospital, Wuxi, Jiangsu, 214002, China
| | - Shiting Li
- Department of Neurosurgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200003, China
| | - Zhenyu Zhao
- Department of Neurosurgery, Chinese PLA General Hospital, Beijing 100003, China
| | - Hongliang Gao
- Department of Pathophysiology, Wannan Medical College, Wuhu 241002, China; Department of Neurosurgery, Wuxi Second People's Hospital, Wuxi, Jiangsu, 214002, China
| | - Xiaoqiang Wang
- Department of Neurosurgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200003, China
| | - Bin Li
- Department of Neurosurgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200003, China
| | - Wenchuan Zhang
- Department of Neurosurgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200003, China
| | - Yan Yuan
- Department of Neurosurgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200003, China
| | - Linzhao Ming
- Department of Neurosurgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200003, China
| | - Hua He
- Department of Neurosurgery, Changzheng Hospital, The Second Hospital affiliated with The Second Military Medical University, Shanghai 200003, China
| | - Bangbao Tao
- Department of Neurosurgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200003, China
| | - Jun Zhong
- Department of Neurosurgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200003, China
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30
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McCubrey JA, Fitzgerald TL, Yang LV, Lertpiriyapong K, Steelman LS, Abrams SL, Montalto G, Cervello M, Neri LM, Cocco L, Martelli AM, Laidler P, Dulińska-Litewka J, Rakus D, Gizak A, Nicoletti F, Falzone L, Candido S, Libra M. Roles of GSK-3 and microRNAs on epithelial mesenchymal transition and cancer stem cells. Oncotarget 2017; 8:14221-14250. [PMID: 27999207 PMCID: PMC5355173 DOI: 10.18632/oncotarget.13991] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Accepted: 12/13/2016] [Indexed: 12/12/2022] Open
Abstract
Various signaling pathways exert critical roles in the epithelial to mesenchymal transition (EMT) and cancer stem cells (CSCs). The Wnt/beta-catenin, PI3K/PTEN/Akt/mTORC, Ras/Raf/MEK/ERK, hedgehog (Hh), Notch and TP53 pathways elicit essential regulatory influences on cancer initiation, EMT and progression. A common kinase involved in all these pathways is moon-lighting kinase glycogen synthase kinase-3 (GSK-3). These pathways are also regulated by micro-RNAs (miRs). TP53 and components of these pathways can regulate the expression of miRs. Targeting members of these pathways may improve cancer therapy in those malignancies that display their abnormal regulation. This review will discuss the interactions of the multi-functional GSK-3 enzyme in the Wnt/beta-catenin, PI3K/PTEN/Akt/mTORC, Ras/Raf/MEK/ERK, Hh, Notch and TP53 pathways. The regulation of these pathways by miRs and their effects on CSC generation, EMT, invasion and metastasis will be discussed.
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Affiliation(s)
- James A McCubrey
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA
| | - Timothy L Fitzgerald
- Department of Surgery, Brody School of Medicine at East Carolina University, Greenville, NC, USA
| | - Li V Yang
- Department of Internal Medicine, Hematology/Oncology Section, Brody School of Medicine at East Carolina University, Greenville, NC, USA
| | - Kvin Lertpiriyapong
- Department of Comparative Medicine, Brody School of Medicine at East Carolina University, Greenville, NC, USA
| | - Linda S Steelman
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA
| | - Stephen L Abrams
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA
| | - Giuseppe Montalto
- Biomedical Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy.,Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare "Alberto Monroy", Palermo, Italy
| | - Melchiorre Cervello
- Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare "Alberto Monroy", Palermo, Italy
| | - Luca M Neri
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Lucio Cocco
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
| | - Alberto M Martelli
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
| | - Piotr Laidler
- Chair of Medical Biochemistry, Jagiellonian University Medical College, Kraków, Poland
| | | | - Dariusz Rakus
- Department of Animal Molecular Physiology, Institute of Experimental Biology, Wroclaw University, Wroclaw, Poland
| | - Agnieszka Gizak
- Department of Animal Molecular Physiology, Institute of Experimental Biology, Wroclaw University, Wroclaw, Poland
| | - Ferdinando Nicoletti
- Department of Biomedical and Biotechnological Sciences - Oncological, Clinical and General Pathology Section, University of Catania, Catania, Italy
| | - Luca Falzone
- Department of Biomedical and Biotechnological Sciences - Oncological, Clinical and General Pathology Section, University of Catania, Catania, Italy
| | - Saverio Candido
- Department of Biomedical and Biotechnological Sciences - Oncological, Clinical and General Pathology Section, University of Catania, Catania, Italy
| | - Massimo Libra
- Department of Biomedical and Biotechnological Sciences - Oncological, Clinical and General Pathology Section, University of Catania, Catania, Italy
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31
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Mah KM, Weiner JA. Regulation of Wnt signaling by protocadherins. Semin Cell Dev Biol 2017; 69:158-171. [PMID: 28774578 PMCID: PMC5586504 DOI: 10.1016/j.semcdb.2017.07.043] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Revised: 07/21/2017] [Accepted: 07/28/2017] [Indexed: 12/23/2022]
Abstract
The ∼70 protocadherins comprise the largest group within the cadherin superfamily. Their diversity, the complexity of the mechanisms through which their genes are regulated, and their many critical functions in nervous system development have engendered a growing interest in elucidating the intracellular signaling pathways through which they act. Recently, multiple protocadherins across several subfamilies have been implicated as modulators of Wnt signaling pathways, and through this as potential tumor suppressors. Here, we review the extant data on the regulation by protocadherins of Wnt signaling pathways and components, and highlight some key unanswered questions that could shape future research.
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Affiliation(s)
- Kar Men Mah
- Department of Biology, The University of Iowa, Iowa City, IA, USA.
| | - Joshua A Weiner
- Department of Biology, The University of Iowa, Iowa City, IA, USA; Department of Psychiatry, The University of Iowa, Iowa City, IA, USA; Iowa Neuroscience Institute, The University of Iowa, Iowa City, IA, USA.
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Lv J, Zhu P, Zhang X, Zhang L, Chen X, Lu F, Yu Z, Liu S. PCDH9 acts as a tumor suppressor inducing tumor cell arrest at G0/G1 phase and is frequently methylated in hepatocellular carcinoma. Mol Med Rep 2017; 16:4475-4482. [PMID: 28791409 PMCID: PMC5647006 DOI: 10.3892/mmr.2017.7193] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2016] [Accepted: 05/26/2017] [Indexed: 12/17/2022] Open
Abstract
Tumor suppressor genes (TSGs) are frequently involved in the pathogenesis of hepatocellular carcinoma (HCC). The epigenetic and genetic alterations of a novel TSG-protocadherin 9 (PCDH9) and its functions in the pathogenesis of HCC were investigated. The methylation status of the PCDH9 promoter was quantitatively analyzed, and the PCDH9 expression was analyzed in HCC cell lines treated with 5-azacytidine. The effects of PCDH9 re-expression and knockdown on growth, proliferation and tumorigenic potential were determined. The results indicated that expression of PCDH9 mRNA was restored in hypermethylation HCC cells following treatment with the DNA de-methylation reagent 5′-Aza. Methylation of the PCDH9 promoter was observed in 22% primary HCC tissues (24/111 tumors). Among the primary HCC cases, the methylated PCDH9 appeared to be associated with a larger tumor size (≥5 cm; P=0.0139) and a more pronounced intrahepatic dissemination (P=0.0312). In addition, it was observed that restored PCDH9 expression could inhibit tumor cell proliferation and xenograft tumor formation. Furthermore, restored PCDH9 expression could inhibit cell proliferation of HCC cell lines via inducing cell cycle arrest at G0/G1 phase. Thus, it is suggested that PCDH9 may act as a novel tumor suppressor candidate gene in HCC pathogenesis.
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Affiliation(s)
- Jun Lv
- Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Pengfei Zhu
- Department of Microbiology & Infectious Disease Center, Peking University Health Science Center, Beijing 100191, P.R. China
| | - Xiaolei Zhang
- Department of Microbiology & Infectious Disease Center, Peking University Health Science Center, Beijing 100191, P.R. China
| | - Ling Zhang
- Department of Hepatobiliary Surgery, Henan Cancer Hospital, Zhengzhou, Henan 450008, P.R. China
| | - Xiangmei Chen
- Department of Microbiology & Infectious Disease Center, Peking University Health Science Center, Beijing 100191, P.R. China
| | - Fengmin Lu
- Department of Microbiology & Infectious Disease Center, Peking University Health Science Center, Beijing 100191, P.R. China
| | - Zujiang Yu
- Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Shuang Liu
- Beijing Artificial Liver Treatment & Training Center, Beijing Youan Hospital Capital Medical University, Beijing 100069, P.R. China
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Januchowski R, Sterzyńska K, Zawierucha P, Ruciński M, Świerczewska M, Partyka M, Bednarek-Rajewska K, Brązert M, Nowicki M, Zabel M, Klejewski A. Microarray-based detection and expression analysis of new genes associated with drug resistance in ovarian cancer cell lines. Oncotarget 2017; 8:49944-49958. [PMID: 28611294 PMCID: PMC5564819 DOI: 10.18632/oncotarget.18278] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Accepted: 04/24/2017] [Indexed: 12/24/2022] Open
Abstract
PURPOSE The present study is to discover a new genes associated with drug resistance development in ovarian cancer. METHODS We used microarray analysis to determine alterations in the level of expression of genes in cisplatin- (CisPt), doxorubicin- (Dox), topotecan- (Top), and paclitaxel- (Pac) resistant variants of W1 and A2780 ovarian cancer cell lines. Immunohistochemistry assay was used to determine protein expression in ovarian cancer patients. RESULTS We observed alterations in the expression of 22 genes that were common to all three cell lines that were resistant to the same cytostatic drug. The level of expression of 13 genes was upregulated and that of nine genes was downregulated. In the CisPt-resistant cell line, we observed downregulated expression of ABCC6, BST2, ERAP2 and MCTP1; in the Pac-resistant cell line, we observe upregulated expression of ABCB1, EPHA7 and RUNDC3B and downregulated expression of LIPG, MCTP1, NSBP1, PCDH9, PTPRK and SEMA3A. The expression levels of three genes, ABCB1, ABCB4 and IFI16, were upregulated in the Dox-resistant cell lines. In the Top-resistant cell lines, we observed increased expression levels of ABCG2, HERC5, IFIH1, MYOT, S100A3, SAMD4A, SPP1 and TGFBI and decreased expression levels of MCTP1 and PTPRK. The expression of EPHA7, IFI16, SPP1 and TGFBI was confirmed at protein level in analyzed ovarian cancer patients.. CONCLUSIONS The expression profiles of the investigated cell lines indicated that new candidate genes are related to the development of resistance to the cytostatic drugs that are used in first- and second-line chemotherapy of ovarian cancer.
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Affiliation(s)
- Radosław Januchowski
- Department of Histology and Embryology, Poznań University of Medical Sciences, Poznań, 60-781, Poland
| | - Karolina Sterzyńska
- Department of Histology and Embryology, Poznań University of Medical Sciences, Poznań, 60-781, Poland
| | - Piotr Zawierucha
- Department of Histology and Embryology, Poznań University of Medical Sciences, Poznań, 60-781, Poland
- Department of Anatomy, Poznań University of Medical Sciences, Poznań, 60-781, Poland
| | - Marcin Ruciński
- Department of Histology and Embryology, Poznań University of Medical Sciences, Poznań, 60-781, Poland
| | - Monika Świerczewska
- Department of Histology and Embryology, Poznań University of Medical Sciences, Poznań, 60-781, Poland
| | - Małgorzata Partyka
- Department of Histology and Embryology, Poznań University of Medical Sciences, Poznań, 60-781, Poland
| | | | - Maciej Brązert
- Division of Infertility and Reproductive Endocrinology, Department of Gynecology, Obstetrics and Gynecological Oncology, Poznań University of Medical Sciences, Poznań, 60-535, Poland
| | - Michał Nowicki
- Department of Histology and Embryology, Poznań University of Medical Sciences, Poznań, 60-781, Poland
| | - Maciej Zabel
- Department of Histology and Embryology, Poznań University of Medical Sciences, Poznań, 60-781, Poland
- Department of Histology and Embryology, Wrocław Medical University, Wrocław, 50-368, Poland
| | - Andrzej Klejewski
- Department of Nursing, Poznań University of Medical Sciences, Poznań, 60-179, Poland
- Departament of Obstetrics and Womens Dieseases, Poznań University of Medical Sciences, Poznań, 60-535, Poland
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Zhou D, Tang W, Su G, Cai M, An HX, Zhang Y. PCDH18 is frequently inactivated by promoter methylation in colorectal cancer. Sci Rep 2017; 7:2819. [PMID: 28588296 PMCID: PMC5460281 DOI: 10.1038/s41598-017-03133-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Accepted: 04/25/2017] [Indexed: 12/23/2022] Open
Abstract
Protocadherin18 (PCDH18) was found to be preferentially methylated and inactivated in colorectal cancer (CRC) using bioinformatics tools. However, its biologic role in tumorgenesis remains unclear. Herein, we aimed to elucidate its epigenetic regulation and biological functions in CRC. The methylation status of PCDH18 was significant higher in CRC tissues than in adjacent non-tumor tissues (median, 15.17% vs. median, 0.4438%). Expression level of PCDH18 was significantly lower in primary CRCs than in nonmalignant tissues. Importantly, methylation status of PCDH18 in cell-free DNA of CRC patients was also significantly higher than in healthy subjects. PCDH18 was readily expressed in NCM460 cells, but downregulated in 100% (4/4) of CRC cell lines by promoter methylation, despite its expression could be restored through demethylation treatment. Overexpression of PCDH18 suppressed CRC cell viability, colony formation and migration. Meanwhile, the depletion of PCDH18 by siRNA in NCM460 cells enhanced the colonogenicity and migration ability and promoted β-catenin nuclear accumulation, whereas it inhibited cell cycle arrest. These effects were associated with upregulation of phospho-GSK-3β and cyclin D1, and downregulation of caspase3 and p21. Our results suggested that PCDH18 was a putative tumor suppressor with epigenetic silencing in CRC and a potential biomarker for CRC diagnosis.
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Affiliation(s)
- Dan Zhou
- Key Laboratory of Design and Assembly of Functional Nanostructures, Fujian Provincial Key Laboratory of Nanomaterials, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fujian, China.,Department of Medical Oncology, Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China.,Xiamen Institute of Rare Earth Materials, Chinese Academy of Sciences, Xiamen, Fujian, China
| | - Weiwei Tang
- Department of Medical Oncology, Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China
| | - Guoqiang Su
- Department of Gastrointestinal surgery, Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China
| | - Mingquan Cai
- Department of Medical Oncology, Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China
| | - Han-Xiang An
- Department of Medical Oncology, Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China.
| | - Yun Zhang
- Key Laboratory of Design and Assembly of Functional Nanostructures, Fujian Provincial Key Laboratory of Nanomaterials, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fujian, China. .,Department of Medical Oncology, Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China. .,Xiamen Institute of Rare Earth Materials, Chinese Academy of Sciences, Xiamen, Fujian, China.
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Chen HF, Ma RR, He JY, Zhang H, Liu XL, Guo XY, Gao P. Protocadherin 7 inhibits cell migration and invasion through E-cadherin in gastric cancer. Tumour Biol 2017; 39:1010428317697551. [PMID: 28381163 DOI: 10.1177/1010428317697551] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The protocadherin 7 is a member of the protocadherin family that expressed aberrantly in many types of human cancers. However, its expression, function, and underlying mechanisms are little known in gastric cancer. In this study, we detected protocadherin 7 expression in gastric cancer tissues and non-tumorous gastric mucosa tissues by real-time quantitative polymerase chain reaction and immunohistochemistry. The association of protocadherin 7 expression with the clinicopathological characteristics and the prognosis was subsequently analyzed. MTS ((3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium)) and transwell assays were performed to assess the effect of protocadherin 7 on proliferation, migration, and invasion in gastric cancer cell lines. Moreover, real-time quantitative polymerase chain reaction and western blot were used to detect the expression of epithelial-mesenchymal transition markers. Protocadherin 7 expression was decreased gradiently from normal tissue to gastric cancer, especially in gastric cancer tissue with lymph node metastasis. Low expression of protocadherin 7 was significantly associated with Lauren's classification ( p = 0.0005), lymph node metastases ( p = 0.0002), and tumor node metastasis stage ( p = 0.0221), as well as poor prognosis ( p < 0.05). Furthermore, down-regulation of protocadherin 7 in gastric cancer cell lines significantly increased their migration and invasion abilities (both p < 0.05), while it had no influence on the gastric cancer cell proliferation ( p > 0.05). Additionally, our results demonstrated that E-cadherin expression was down-regulated in gastric cancer cells with protocadherin 7 depletion. Our data indicated that protocadherin 7 may play important roles in the invasion and metastasis of gastric cancer, and protocadherin 7 could suppress cell migration and invasion through E-cadherin inhibition. Protocadherin 7 can serve as a novel biomarker for diagnostic and prognosis in patients with gastric cancer.
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Affiliation(s)
- Hong-Fang Chen
- 1 Department of Pathology, Qilu Hospital, Shandong University, Jinan, China.,2 Department of Pathology, Yidu Central Hospital of Weifang, Weifang, China
| | - Ran-Ran Ma
- 1 Department of Pathology, Qilu Hospital, Shandong University, Jinan, China.,3 Department of Pathology, School of Medicine, Shandong University, Jinan, China
| | - Jun-Yi He
- 1 Department of Pathology, Qilu Hospital, Shandong University, Jinan, China.,3 Department of Pathology, School of Medicine, Shandong University, Jinan, China
| | - Hui Zhang
- 1 Department of Pathology, Qilu Hospital, Shandong University, Jinan, China.,3 Department of Pathology, School of Medicine, Shandong University, Jinan, China
| | - Xiao-Ling Liu
- 2 Department of Pathology, Yidu Central Hospital of Weifang, Weifang, China
| | - Xiang-Yu Guo
- 1 Department of Pathology, Qilu Hospital, Shandong University, Jinan, China.,3 Department of Pathology, School of Medicine, Shandong University, Jinan, China
| | - Peng Gao
- 1 Department of Pathology, Qilu Hospital, Shandong University, Jinan, China.,3 Department of Pathology, School of Medicine, Shandong University, Jinan, China
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Shan M, Su Y, Kang W, Gao R, Li X, Zhang G. Aberrant expression and functions of protocadherins in human malignant tumors. Tumour Biol 2016; 37:12969-12981. [PMID: 27449047 DOI: 10.1007/s13277-016-5169-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Accepted: 07/12/2016] [Indexed: 12/11/2022] Open
Abstract
Protocadherins (PCDHs) are a group of transmembrane proteins belonging to the cadherin superfamily and are subdivided into "clustered" and "non-clustered" groups. PCDHs vary in both structure and interaction partners and thus regulate multiple biological responses in complex and versatile patterns. Previous researches showed that PCDHs regulated the development of brain and were involved in some neuronal diseases. Recently, studies have revealed aberrant expression of PCDHs in various human malignant tumors. The down-regulation or absence of PCDHs in malignant cells has been associated with cancer progression. Further researches suggest that PCDHs may play major functions as tumor suppressor by inhibiting the proliferation and metastasis of cancer cells. In this review, we focus on the altered expression of PCDHs and their roles in the development of cancer progression. We also discuss the potential mechanisms, by which PCDHs are aberrantly expressed, and its implications in regulating cancers.
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Affiliation(s)
- Ming Shan
- Department of Breast Surgery, the Affiliated Tumor Hospital of Harbin Medical University, Harbin, China
| | - Yonghui Su
- Department of Breast Surgery, the Affiliated Tumor Hospital of Harbin Medical University, Harbin, China
| | - Wenli Kang
- Department of Oncology, General Hospital of Hei Longjiang Province Land Reclamation Headquarter, Harbin, China
| | - Ruixin Gao
- Department of Breast Surgery, The First Hospital of Qiqihaer City, Qiqihaer, China
| | - Xiaobo Li
- Department of Pathology, Harbin Medical University, Harbin, China.
| | - Guoqiang Zhang
- Department of Breast Surgery, the Affiliated Tumor Hospital of Harbin Medical University, Harbin, China.
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Zhai L, Ma C, Li W, Yang S, Liu Z. miR-143 suppresses epithelial-mesenchymal transition and inhibits tumor growth of breast cancer through down-regulation of ERK5. Mol Carcinog 2015; 55:1990-2000. [PMID: 26618772 DOI: 10.1002/mc.22445] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Revised: 09/05/2015] [Accepted: 11/17/2015] [Indexed: 12/30/2022]
Abstract
Epithelial-mesenchymal transition (EMT) plays a pivotal role in the development of cancer invasion and metastasis. Many studies have significantly enhanced the knowledge on EMT through the characterization of microRNAs (miRNAs) influencing the signaling pathways and downstream events that define EMT on a molecular level. In this study, we found that miR-143 suppressed EMT. Up-regulating miR-143 enhanced E-cadherin-mediated cell-cell adhesion ability, reduced mesenchymal markers, and decreased cell proliferation, migration, and invasion in vitro. In vivo, the xenograft mouse model also unveiled the suppressive effects of miR-143 on tumor growth. Additionally, we demonstrated that up-regulating extracellular signal regulated kinase 5 (ERK5) was associated with poor prognosis of breast cancer patients. Moreover, we observed an inverse correlation between miR-143 and ERK5 in breast cancer tissues. miR-143 directly targeted seed sequences in the 3'-untranslated regions of ERK5. Furthermore, we revealed that the downstream molecules of glycogen synthase kinase 3 beta (GSK-3β)/Snail signaling were involved in EMT and modulated by ERK5. In summary, our findings demonstrated that miR-143 down-regulated its target ERK5, leading to the suppression of EMT induced by GSK-3β/Snail signaling of breast cancer. © 2015 Wiley Periodicals, Inc.
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Affiliation(s)
- Limin Zhai
- Department of Pathology, Weifang Medical University, Weifang, Shandong Province, P.R. China
| | - Chuanxiang Ma
- Department of Pathology, Afflidated Hospital of Weifang Medical University, Weifang, Shandong Province, P.R. China
| | - Wentong Li
- Department of Pathology, Weifang Medical University, Weifang, Shandong Province, P.R. China
| | - Shuo Yang
- Department of Pathology, Weifang Medical University, Weifang, Shandong Province, P.R. China
| | - Zhijun Liu
- Department of Medical Biology, Weifang Medical University, Weifang, Shandong Province, P.R. China
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Thompson MJ, Rubbi L, Dawson DW, Donahue TR, Pellegrini M. Pancreatic cancer patient survival correlates with DNA methylation of pancreas development genes. PLoS One 2015; 10:e0128814. [PMID: 26039411 PMCID: PMC4454596 DOI: 10.1371/journal.pone.0128814] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Accepted: 04/30/2015] [Indexed: 02/07/2023] Open
Abstract
DNA methylation is an epigenetic mark associated with regulation of transcription and genome structure. These markers have been investigated in a variety of cancer settings for their utility in differentiating normal tissue from tumor tissue. Here, we examine the direct correlation between DNA methylation and patient survival. We find that changes in the DNA methylation of key pancreatic developmental genes are strongly associated with patient survival.
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Affiliation(s)
- Michael J. Thompson
- Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, California, 90095, United States of America
| | - Liudmilla Rubbi
- Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, California, 90095, United States of America
| | - David W. Dawson
- Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California, 90095, United States of America
- Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California, 90095, United States of America
| | - Timothy R. Donahue
- Department of Surgery, University of California Los Angeles, Los Angeles, California, 90095, United States of America
- Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California, 90095, United States of America
- Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, California, 90095, United States of America
| | - Matteo Pellegrini
- Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, California, 90095, United States of America
- * E-mail:
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