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Wang X, Yang C, Liu Y, Wang J. SUMOylation substrate encoding genes as prognostic biomarkers in pancreatic ductal adenocarcinoma with functional assessment of SAF-B2. Front Pharmacol 2025; 16:1532658. [PMID: 40308776 PMCID: PMC12040899 DOI: 10.3389/fphar.2025.1532658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 03/31/2025] [Indexed: 05/02/2025] Open
Abstract
Background Pancreatic ductal adenocarcinoma (PDAC) is highly malignant with a poor prognosis, posing significant clinical challenges. SUMOylation, a reversible post-translational modification, plays a critical role in tumor progression, yet its prognostic significance in PDAC remains unclear. Methods We assessed SUMOylation expression patterns and function in PDAC using Western blot and the SUMOylation inhibitor TAK-981. Differentially expressed SUMOylation substrate encoding genes (DE-SSEGs) were identified from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression Project (GTEx) datasets. A SUMOylation-based prognostic model, Sscore, was constructed using LASSO and Cox regression. Additional analyses included somatic mutation, immune infiltration, TIDE, drug sensitivity, and single-cell RNA sequencing. The role of SAFB2 in PDAC was validated in vitro. Results PDAC cells showed elevated SUMOylation, and its inhibition reduced cell proliferation. The Sscore model, based on DE-SSEGs (CDK1, AHNAK2, SAFB2), predicted overall survival and correlated with genome variation, immune infiltration, and drug sensitivity. Single-cell analysis further confirmed a link between high Sscore and malignancy. SAFB2, identified as a pivotal gene within the Sscore model, was significantly downregulated in PDAC tissues and cell lines; its overexpression was shown to inhibit PDAC cell proliferation, migration, and invasion by suppressing the Wnt/β-Catenin signaling pathway. Conclusion This study underscores the role of SUMOylation in PDAC and introduces the Sscore as a prognostic tool. SAFB2 is identified as a potential tumor suppressor, offering new therapeutic targets for PDAC.
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Affiliation(s)
| | | | | | - Jian Wang
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Monge C, Waldrup B, Carranza FG, Velazquez-Villarreal E. Molecular Heterogeneity in Early-Onset Colorectal Cancer: Pathway-Specific Insights in High-Risk Populations. Cancers (Basel) 2025; 17:1325. [PMID: 40282501 PMCID: PMC12026214 DOI: 10.3390/cancers17081325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2025] [Revised: 04/04/2025] [Accepted: 04/11/2025] [Indexed: 04/29/2025] Open
Abstract
BACKGROUND/OBJECTIVES The incidence of early-onset colorectal cancer (EOCRC), defined as diagnosis before age 50, has been rising at an alarming rate, with Hispanic/Latino (H/L) individuals experiencing the most significant increases in both incidence and mortality. Despite this growing public health concern, the molecular mechanisms driving EOCRC disparities remain poorly understood. Oncogenic pathways such as WNT, TGF-beta, and RTK/RAS are critical in colorectal cancer (CRC) progression, yet their specific roles in EOCRC across diverse populations have not been extensively studied. This research seeks to identify molecular alterations within these pathways by comparing EOCRC cases in H/L and non-Hispanic White (NHW) individuals. Furthermore, we explore the clinical significance of these findings to inform precision medicine strategies tailored to high-risk populations. METHODS To investigate mutation frequencies in genes associated with the WNT, TGF-beta, and RTK/RAS pathways, we conducted a bioinformatics analysis using publicly available CRC datasets. The study cohort consisted of 3412 patients, including 302 H/L and 3110 NHW individuals. The patients were categorized based on age (EOCRC: <50 years; late-onset CRC [LOCRC]: ≥50 years) and population group (H/L vs. NHW) to assess variations in mutation prevalence. Statistical comparisons of mutation rates between the groups were conducted using chi-squared tests, while Kaplan-Meier survival analysis was employed to evaluate overall survival differences associated with pathway alterations. RESULTS Notable molecular distinctions in the RTK/RAS pathway were identified between EOCRC and LOCRC among the H/L patients, with EOCRC exhibiting a lower frequency of RTK/RAS alterations compared to LOCRC (66.7% vs. 79.3%, p = 0.01). Within this pathway, mutations in CBL (p < 0.05) and NF1 (p < 0.05) were significantly more prevalent in the EOCRC cases (5.8% vs. 1.2% and 11.6% vs. 3.7%, respectively), whereas BRAF mutations were notably less frequent in EOCRC than in LOCRC (5.1% vs. 18.3%, p < 0.05). Comparisons between the EOCRC patients from the H/L and NHW populations revealed distinct pathway-specific alterations that were more common in the H/L individuals. These included RNF43 mutations (12.3% vs. 6.7%, p < 0.05) in the WNT pathway, BMPR1A mutations (5.1% vs. 1.8%, p < 0.05) in the TGF-beta pathway, and multiple RTK/RAS pathway alterations, such as MAPK3 (3.6% vs. 0.7%, p < 0.05), CBL (5.8% vs. 1.4%, p < 0.05), and NF1 (11.6% vs. 6.1%, p < 0.05). Survival analysis in the H/L EOCRC patients did not reveal statistically significant differences based on pathway alterations. However, in the NHW EOCRC patients, the presence of WNT pathway alterations was associated with significantly improved survival outcomes, suggesting potential ethnicity-specific prognostic implications. CONCLUSIONS This study highlights the substantial molecular heterogeneity present in EOCRC, particularly among high-risk populations. The H/L EOCRC patients exhibited distinct genetic alterations, with a higher prevalence of CBL, NF1, RNF43, BMPR1A, and MAPK3 mutations compared to their NHW counterparts. Additionally, RTK/RAS pathway alterations were less frequent in EOCRC than in LOCRC. Despite these molecular differences, pathway alterations did not significantly impact survival outcomes in the H/L EOCRC patients. However, in the NHW EOCRC patients, the presence of WNT pathway alterations was associated with improved survival. These findings emphasize the necessity for further research to clarify the molecular mechanisms driving EOCRC disparities in high-risk populations and to inform precision medicine strategies for underrepresented groups.
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Affiliation(s)
- Cecilia Monge
- Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Brigette Waldrup
- Department of Integrative Translational Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Francisco G. Carranza
- Department of Integrative Translational Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Enrique Velazquez-Villarreal
- Department of Integrative Translational Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
- City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
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Chen X, Sun F, Wang X, Feng X, Aref AR, Tian Y, Ashrafizadeh M, Wu D. Inflammation, microbiota, and pancreatic cancer. Cancer Cell Int 2025; 25:62. [PMID: 39987122 PMCID: PMC11847367 DOI: 10.1186/s12935-025-03673-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 02/04/2025] [Indexed: 02/24/2025] Open
Abstract
Pancreatic cancer (PC) is a malignancy of gastrointestinal tract threatening the life of people around the world. In spite of the advances in the treatment of PC, the overall survival of this disease in advanced stage is less than 12%. Moreover, PC cells have aggressive behaviour in proliferation and metastasis as well as capable of developing therapy resistance. Therefore, highlighting the underlying molecular mechanisms in PC pathogenesis can provide new insights for its treatment. In the present review, inflammation and related pathways as well as role of gut microbiome in the regulation of PC pathogenesis are highlighted. The various kinds of interleukins and chemokines are able to regulate angiogenesis, metastasis, proliferation, inflammation and therapy resistance in PC cells. Furthermore, a number of molecular pathways including NF-κB, TLRs and TGF-β demonstrate dysregulation in PC aggravating inflammation and tumorigenesis. Therapeutic regulation of these pathways can reverse inflammation and progression of PC. Both chronic and acute pancreatitis have been shown to be risk factors in the development of PC, further highlighting the role of inflammation. Finally, the composition of gut microbiota can be a risk factor for PC development through affecting pathways such as NF-κB to mediate inflammation.
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Affiliation(s)
- XiaoLiang Chen
- Department of General Surgery and Integrated Traditional Chinese and Western Medicine Oncology, Tiantai People'S Hospital of Zhejiang Province(Tiantai Branch of Zhejiang Provincial People'S Hospital), Hangzhou Medical College, Taizhou, Zhejiang, China
| | - Feixia Sun
- Nursing Department, Shandong First Medical University Affiliated Occupational Disease Hospital (Shandong Provincial Occupational Disease Hospital), Jinan, China
| | - Xuqin Wang
- Department of Oncology, Chongqing General Hospital, Chongqing University, Chongqing, 401120, China
| | - Xiaoqiang Feng
- Center of Stem Cell and Regenerative Medicine, Gaozhou People's Hospital, Gaozhou, 525200, Guangdong, China
| | - Amir Reza Aref
- VitroVision Department, DeepkinetiX, Inc, Boston, MA, USA
| | - Yu Tian
- Research Center, the Huizhou Central People'S Hospital, Guangdong Medical University, Huizhou, Guangdong, China.
- School of Public Health, Benedictine University, No. 5700 College Road, Lisle, IL, 60532, USA.
| | - Milad Ashrafizadeh
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250000, Shandong, China.
| | - Dengfeng Wu
- Department of Emergency, The People'S Hospital of Gaozhou, No. 89 Xiguan Road, Gaozhou, 525200, Guangdong, China.
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Samant C, Kale R, Pai KSR, Nandakumar K, Bhonde M. Role of Wnt/β-catenin pathway in cancer drug resistance: Insights into molecular aspects of major solid tumors. Biochem Biophys Res Commun 2024; 729:150348. [PMID: 38986260 DOI: 10.1016/j.bbrc.2024.150348] [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: 04/27/2024] [Revised: 06/23/2024] [Accepted: 07/03/2024] [Indexed: 07/12/2024]
Abstract
Adaptive resistance to conventional and targeted therapies remains one of the major obstacles in the effective management of cancer. Aberrant activation of key signaling mechanisms plays a pivotal role in modulating resistance to drugs. An evolutionarily conserved Wnt/β-catenin pathway is one of the signaling cascades which regulate resistance to drugs. Elevated Wnt signaling confers resistance to anticancer therapies, either through direct activation of its target genes or via indirect mechanisms and crosstalk over other signaling pathways. Involvement of the Wnt/β-catenin pathway in cancer hallmarks like inhibition of apoptosis, promotion of invasion and metastasis and cancer stem cell maintenance makes this pathway a potential target to exploit for addressing drug resistance. Accumulating evidences suggest a critical role of Wnt/β-catenin pathway in imparting resistance across multiple cancers including PDAC, NSCLC, TNBC, etc. Here we present a comprehensive assessment of how Wnt/β-catenin pathway mediates cancer drug resistance in majority of the solid tumors. We take a deep dive into the Wnt/β-catenin signaling-mediated modulation of cellular and downstream molecular mechanisms and their impact on cancer resistance.
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Affiliation(s)
- Charudatt Samant
- Department of Pharmacology, Novel Drug Discovery and Development (NDDD), Lupin Limited, Survey No. 46A/47A, Village Nande, Taluka Mulshi, Pune, 412115, Maharashtra, India.
| | - Ramesh Kale
- Department of Pharmacology, Novel Drug Discovery and Development (NDDD), Lupin Limited, Survey No. 46A/47A, Village Nande, Taluka Mulshi, Pune, 412115, Maharashtra, India
| | - K Sreedhara Ranganath Pai
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, 576104, India
| | - Krishnadas Nandakumar
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, 576104, India
| | - Mandar Bhonde
- Department of Pharmacology, Novel Drug Discovery and Development (NDDD), Lupin Limited, Survey No. 46A/47A, Village Nande, Taluka Mulshi, Pune, 412115, Maharashtra, India
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5
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Li H, Yao Y, Hao R, Long C. Selective and effective suppression of pancreatic cancer through MNK inhibition. Immunopharmacol Immunotoxicol 2024:1-11. [PMID: 39138614 DOI: 10.1080/08923973.2024.2391462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 08/04/2024] [Indexed: 08/15/2024]
Abstract
Objective: The study aimed to explore the role of the Wnt/β-catenin signaling pathway in pancreatic cancer progression and chemoresistance, with a focus on identifying specific factors that distinguish between normal and tumor cells, thereby offering potential therapeutic targets. Materials and Methods: We analyzed levels of total and phosphorylated eukaryotic translation initiation factor 4E (eIF4E) and β-catenin in pancreatic cancer and normal pancreatic tissues. Functional assays were used to assess the impact of eIF4E phosphorylation on β-catenin signaling, cell proliferation, and chemoresistance, with MNK kinase involvement determined through gene depletion studies. The MNK kinase inhibitor eFT508 was evaluated for its effects on eIF4E phosphorylation, β-catenin activation, and cell viability in both in vitro and in vivo models of pancreatic cancer. Results: Both total and phosphorylated eIF4E, along with β-catenin, were significantly elevated in pancreatic cancer tissues compared to normal tissues. Phosphorylation of eIF4E at serine 209 was shown to activate β-catenin signaling, enhance cell proliferation, and contribute to chemoresistance in pancreatic cancer. Importantly, these effects were dependent on MNK kinase activity. Depletion of eIF4E reduced cell viability in both pancreatic cancer and normal cells, while depletion of MNK selectively decreased viability in pancreatic cancer cells. Treatment with eFT508 effectively inhibited eIF4E phosphorylation, suppressed β-catenin activation, and reduced pancreatic cancer cell growth and survival in vitro and in vivo, with minimal impact on normal cells. Conclusions: The MNK-eIF4E-β-catenin axis plays a critical role in pancreatic cancer progression and chemoresistance, distinguishing pancreatic cancer cells from normal cells. Targeting MNK kinases with inhibitors like eFT508 presents a promising therapeutic strategy for pancreatic cancer, with potential for selective efficacy and reduced toxicity.
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Affiliation(s)
- Hui Li
- Department of Oncology, Xiangyang Central Hospital, Hubei University of Arts and Science, Xiangyang, People's Republic of China
| | - Yang Yao
- Department of Oncology, Xiangyang Central Hospital, Hubei University of Arts and Science, Xiangyang, People's Republic of China
| | - Rui Hao
- Department of Oncology, Xiangyang Central Hospital, Hubei University of Arts and Science, Xiangyang, People's Republic of China
| | - Cheng Long
- Department of Oncology, Xiangyang Central Hospital, Hubei University of Arts and Science, Xiangyang, People's Republic of China
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Yu M, Qin K, Fan J, Zhao G, Zhao P, Zeng W, Chen C, Wang A, Wang Y, Zhong J, Zhu Y, Wagstaff W, Haydon RC, Luu HH, Ho S, Lee MJ, Strelzow J, Reid RR, He TC. The evolving roles of Wnt signaling in stem cell proliferation and differentiation, the development of human diseases, and therapeutic opportunities. Genes Dis 2024; 11:101026. [PMID: 38292186 PMCID: PMC10825312 DOI: 10.1016/j.gendis.2023.04.042] [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: 08/23/2022] [Revised: 03/18/2023] [Accepted: 04/12/2023] [Indexed: 02/01/2024] Open
Abstract
The evolutionarily conserved Wnt signaling pathway plays a central role in development and adult tissue homeostasis across species. Wnt proteins are secreted, lipid-modified signaling molecules that activate the canonical (β-catenin dependent) and non-canonical (β-catenin independent) Wnt signaling pathways. Cellular behaviors such as proliferation, differentiation, maturation, and proper body-axis specification are carried out by the canonical pathway, which is the best characterized of the known Wnt signaling paths. Wnt signaling has emerged as an important factor in stem cell biology and is known to affect the self-renewal of stem cells in various tissues. This includes but is not limited to embryonic, hematopoietic, mesenchymal, gut, neural, and epidermal stem cells. Wnt signaling has also been implicated in tumor cells that exhibit stem cell-like properties. Wnt signaling is crucial for bone formation and presents a potential target for the development of therapeutics for bone disorders. Not surprisingly, aberrant Wnt signaling is also associated with a wide variety of diseases, including cancer. Mutations of Wnt pathway members in cancer can lead to unchecked cell proliferation, epithelial-mesenchymal transition, and metastasis. Altogether, advances in the understanding of dysregulated Wnt signaling in disease have paved the way for the development of novel therapeutics that target components of the Wnt pathway. Beginning with a brief overview of the mechanisms of canonical and non-canonical Wnt, this review aims to summarize the current knowledge of Wnt signaling in stem cells, aberrations to the Wnt pathway associated with diseases, and novel therapeutics targeting the Wnt pathway in preclinical and clinical studies.
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Affiliation(s)
- Michael Yu
- School of Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Kevin Qin
- School of Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Jiaming Fan
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Ministry of Education Key Laboratory of Diagnostic Medicine, and Department of Clinical Biochemistry, The School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Guozhi Zhao
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Orthopedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Piao Zhao
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Orthopedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Wei Zeng
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Neurology, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong 523475, China
| | - Connie Chen
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Annie Wang
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Yonghui Wang
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Clinical Laboratory Medicine, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China
| | - Jiamin Zhong
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Ministry of Education Key Laboratory of Diagnostic Medicine, and Department of Clinical Biochemistry, The School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Yi Zhu
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Orthopaedic Surgery, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - William Wagstaff
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Rex C. Haydon
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Hue H. Luu
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Sherwin Ho
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Michael J. Lee
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Jason Strelzow
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Russell R. Reid
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Laboratory of Craniofacial Suture Biology and Development, Department of Surgery Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Tong-Chuan He
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Laboratory of Craniofacial Suture Biology and Development, Department of Surgery Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
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Chien TL, Wu YC, Lee HL, Sung WW, Yu CY, Chang YC, Lin CC, Wang CC, Tsai MC. PNU-74654 Induces Cell Cycle Arrest and Inhibits EMT Progression in Pancreatic Cancer. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1531. [PMID: 37763649 PMCID: PMC10532988 DOI: 10.3390/medicina59091531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 08/17/2023] [Accepted: 08/18/2023] [Indexed: 09/29/2023]
Abstract
Background and Objectives: PNU-74654, a Wnt/β-catenin pathway inhibitor, has an antiproliferative effect on many cancer types; however, its therapeutic role in pancreatic cancer (PC) has not yet been demonstrated. Here, the effects of PNU-74654 on proliferation and cell cycle phase distribution were studied in PC cell lines. Materials and Methods: The cancer-related molecular pathways regulated by PNU-74654 were determined by a proteome profiling oncology array and confirmed by western blotting. Results: The cell viability and proliferative ability of PC cells were decreased by PNU-74654 treatment. G1 arrest was observed, as indicated by the downregulation of cyclin E and cyclin-dependent kinase 2 (CDK2) and the upregulation of p27. PNU-74654 inhibited the epithelial-mesenchymal transition (EMT), as determined by an increase in E-cadherin and decreases in N-cadherin, ZEB1, and hypoxia-inducible factor-1 alpha (HIF-1α). PNU-74654 also suppressed cytoplasmic and nuclear β-catenin and impaired the NF-κB pathway. Conclusions: These results demonstrate that PNU-74654 modulates G1/S regulatory proteins and inhibits the EMT, thereby suppressing PC cell proliferation, migration, and invasion. The synergistic effect of PNU-74654 and chemotherapy or the exclusive use of PNU-74654 may be therapeutic options for PC and require further investigation.
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Affiliation(s)
- Tai-Long Chien
- Department of Gastroenterology, Antai Medical Care Corporation Antai Tian-Sheng Memorial Hospital, Pingtung 928, Taiwan
| | - Yao-Cheng Wu
- School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
| | - Hsiang-Lin Lee
- School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Department of Surgery, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Wen-Wei Sung
- School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Department of Urology, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Chia-Ying Yu
- School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Department of Urology, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Ya-Chuan Chang
- School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Department of Urology, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Chun-Che Lin
- School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Chi-Chih Wang
- School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Ming-Chang Tsai
- School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung 402, Taiwan
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Identification and Validation of Potentially Clinically Relevant CpG Regions within the Class 2 Tumor Suppressor Gene SFRP1 in Pancreatic Cancer. Cancers (Basel) 2023; 15:cancers15030683. [PMID: 36765639 PMCID: PMC9913221 DOI: 10.3390/cancers15030683] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/18/2023] [Accepted: 01/20/2023] [Indexed: 01/25/2023] Open
Abstract
In pancreatic cancer treatment, tumor stage-dependent chemotherapies are used to prolong overall survival. By measuring DNA promoter hypermethylation in the plasma of patients with stage IV pancreatic cancer, it was recently shown that promoter DNA methylation of the tumor suppressor gene SFRP1 has a high value for predicting failure of drug treatment with gemcitabine. In this study, we therefore aimed to identify as precisely as possible the region in the SFRP1 promoter that is frequently hypermethylated in pancreatic cancer tissue. First, we used the TCGA data set to define CpG-rich regions flanking the SFRP1 transcription start site that were significantly more methylated in pancreatic cancer compared to normal pancreatic acinar tissue. A core CpG island was identified that exhibited abundant tumor DNA methylation and anti-correlation of SFRP1 mRNA expression. To validate our in silico results, we performed bisulfide conversion followed by DNA pyrosequencing of 28 matched formalin-fixed, paraffin-embedded (FFPE) pancreatic cancer cases and six pancreatic cancer cell lines. A defined block of seven CpG sites within the core CpG island was identified, which confirmed our in silico results by showing significantly higher SFRP1 methylation in pancreatic cancer specimens than in normal pancreatic tissue. By selecting this core CpG island, we were able to determine a median overall survival benefit for the low SFRP1 methylation group compared to the high SFRP1 methylation group (702 versus 517 days, p = 0.01) in the TCGA pancreatic cancer cohort. We propose a compact pyrosequencing assay that can be used in the future to further investigate the prognostic value of SFRP1 promoter hypermethylation in predicting pancreatic cancer chemoresistance. Therefore, instead of DNA analysis from blood (liquid biopsy), DNA easily extractable from cancer tissue blocks (FFPE material) could be used.
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Abstract
C-Myc overexpression is a common finding in pancreatic cancer and predicts the aggressive behavior of cancer cells. It binds to the promoter of different genes, thereby regulating their transcription. C-Myc is downstream of KRAS and interacts with several oncogenic and proliferative pathways in pancreatic cancer. C-Myc enhances aerobic glycolysis in cancer cells and regulates glutamate biosynthesis from glutamine. It provides enough energy for cancer cells' metabolism and sufficient substrate for the synthesis of organic molecules. C-Myc overexpression is associated with chemoresistance, intra-tumor angiogenesis, epithelial-mesenchymal transition (EMT), and metastasis in pancreatic cancer. Despite its title, c-Myc is not "undruggable" and recent studies unveiled that it can be targeted, directly or indirectly. Small molecules that accelerate c-Myc ubiquitination and degradation have been effective in preclinical studies. Small molecules that hinder c-Myc-MAX heterodimerization or c-Myc/MAX/DNA complex formation can functionally inhibit c-Myc. In addition, c-Myc can be targeted through transcriptional, post-transcriptional, and translational modifications.
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Affiliation(s)
- Moein Ala
- School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran
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10
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Pancreatic Cancer: Beyond Brca Mutations. J Pers Med 2022; 12:jpm12122076. [PMID: 36556296 PMCID: PMC9787452 DOI: 10.3390/jpm12122076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 12/12/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Pancreatic cancer is the fourth-leading cause of cancer-related deaths worldwide. The outcomes in patients with pancreatic cancer remain unsatisfactory. In the current review, we summarize the genetic and epigenetic architecture of metastatic pancreatic cancer beyond the BRCA mutations, focusing on the genetic alterations and the molecular pathology in pancreatic cancer. This review focuses on the molecular targets for the treatment of pancreatic cancer, with a correlation to future treatments. The potential approach addressed in this review may lead to the identification of a subset of patients with specific biological behaviors and treatment responses.
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Mathebela P, Damane BP, Mulaudzi TV, Mkhize-Khwitshana ZL, Gaudji GR, Dlamini Z. Influence of the Microbiome Metagenomics and Epigenomics on Gastric Cancer. Int J Mol Sci 2022; 23:13750. [PMID: 36430229 PMCID: PMC9693604 DOI: 10.3390/ijms232213750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/01/2022] [Accepted: 11/04/2022] [Indexed: 11/11/2022] Open
Abstract
Gastric cancer (GC) is one of the major causes of cancer deaths worldwide. The disease is seldomly detected early and this limits treatment options. Because of its heterogeneous and complex nature, the disease remains poorly understood. The literature supports the contribution of the gut microbiome in the carcinogenesis and chemoresistance of GC. Drug resistance is the major challenge in GC therapy, occurring as a result of rewired metabolism. Metabolic rewiring stems from recurring genetic and epigenetic factors affecting cell development. The gut microbiome consists of pathogens such as H. pylori, which can foster both epigenetic alterations and mutagenesis on the host genome. Most of the bacteria implicated in GC development are Gram-negative, which makes it challenging to eradicate the disease. Gram-negative bacterium co-infections with viruses such as EBV are known as risk factors for GC. In this review, we discuss the role of microbiome-induced GC carcinogenesis. The disease risk factors associated with the presence of microorganisms and microbial dysbiosis are also discussed. In doing so, we aim to emphasize the critical role of the microbiome on cancer pathological phenotypes, and how microbiomics could serve as a potential breakthrough in determining effective GC therapeutic targets. Additionally, consideration of microbial dysbiosis in the GC classification system might aid in diagnosis and treatment decision-making, taking the specific pathogen/s involved into account.
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Affiliation(s)
- Precious Mathebela
- Department of Surgery, Steve Biko Academic Hospital, University of Pretoria, Hatfield 0028, South Africa
| | - Botle Precious Damane
- Department of Surgery, Steve Biko Academic Hospital, University of Pretoria, Hatfield 0028, South Africa
| | - Thanyani Victor Mulaudzi
- Department of Surgery, Steve Biko Academic Hospital, University of Pretoria, Hatfield 0028, South Africa
| | - Zilungile Lynette Mkhize-Khwitshana
- School of Medicine, University of Kwa-Zulu Natal, Durban, KwaZulu-Natal 4013, South Africa
- SAMRC Research Capacity Development Division, South African Medical Research Council, Tygerberg, Cape Town 7501, South Africa
| | - Guy Roger Gaudji
- Department of Urology, Level 7, Bridge C, Steve Biko Academic Hospital, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Arcadia 0007, South Africa
| | - Zodwa Dlamini
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfield 0028, South Africa
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12
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Kumar A, Singh AK, Singh H, Thareja S, Kumar P. Regulation of thymidylate synthase: an approach to overcome 5-FU resistance in colorectal cancer. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 40:3. [PMID: 36308643 DOI: 10.1007/s12032-022-01864-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Accepted: 09/29/2022] [Indexed: 01/17/2023]
Abstract
Thymidylate synthase is the rate-limiting enzyme required for DNA synthesis and overexpression of this enzyme causes resistance to cancer cells. Long treatments with 5-FU cause resistance to Thymidylate synthase targeting drugs. We have also compiled different mechanisms of drug resistance including autophagy and apoptosis, drug detoxification and ABC transporters, drug efflux, signaling pathways (AKT/PI3K, RAS-MAPK, WNT/β catenin, mTOR, NFKB, and Notch1 and FOXM1) and different genes associated with resistance in colorectal cancer. We can overcome 5-FU resistance in cancer cells by regulating thymidylate synthase by natural products (Coptidis rhizoma), HDAC inhibitors, mTOR inhibitors, Folate antagonists, and several other drugs which have been used in combination with TS inhibitors. This review is a compilation of different approaches reported for the regulation of thymidylate synthase to overcome resistance in colorectal cancer cells.
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Affiliation(s)
- Adarsh Kumar
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda, 151401, India
| | - Ankit Kumar Singh
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda, 151401, India
| | - Harshwardhan Singh
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda, 151401, India
| | - Suresh Thareja
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda, 151401, India
| | - Pradeep Kumar
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda, 151401, India.
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13
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Palazzolo S, Canzonieri V, Rizzolio F. The history of small extracellular vesicles and their implication in cancer drug resistance. Front Oncol 2022; 12:948843. [PMID: 36091133 PMCID: PMC9451101 DOI: 10.3389/fonc.2022.948843] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 07/06/2022] [Indexed: 12/01/2022] Open
Abstract
Small extracellular vesicles (EVs) in the last 20 years are demonstrated to possess promising properties as potential new drug delivery systems, biomarkers, and therapeutic targets. Moreover, EVs are described to be involved in the most important steps of tumor development and progression including drug resistance. The acquired or intrinsic capacity of cancer cells to resist chemotherapies is one of the greatest obstacles to overcome to improve the prognosis of many patients. EVs are involved in this mechanism by exporting the drugs outside the cells and transferring the drug efflux pumps and miRNAs in recipient cells, in turn inducing drug resistance. In this mini-review, the main mechanisms by which EVs are involved in drug resistance are described, giving a rapid and clear overview of the field to the readers.
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Affiliation(s)
- Stefano Palazzolo
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) Istituto di ricovero e cura a carattere scientifico (IRCCS), Aviano, Italy
| | - Vincenzo Canzonieri
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) Istituto di ricovero e cura a carattere scientifico (IRCCS), Aviano, Italy
| | - Flavio Rizzolio
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) Istituto di ricovero e cura a carattere scientifico (IRCCS), Aviano, Italy
- Department of Molecular Science and Nanosystems, Ca’ Foscary University, Venice, Italy
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14
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Selenium and tellurium in the development of novel small molecules and nanoparticles as cancer multidrug resistance reversal agents. Drug Resist Updat 2022; 63:100844. [DOI: 10.1016/j.drup.2022.100844] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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15
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Yan R, Fan X, Xiao Z, Liu H, Huang X, Liu J, Zhang S, Yao J, An G, Ge Y. Inhibition of DCLK1 sensitizes resistant lung adenocarcinomas to EGFR-TKI through suppression of Wnt/β-Catenin activity and cancer stemness. Cancer Lett 2022; 531:83-97. [DOI: 10.1016/j.canlet.2022.01.030] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 01/24/2022] [Accepted: 01/24/2022] [Indexed: 12/19/2022]
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16
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Chen L, Xu Z, Li Q, Feng Q, Zheng C, Du Y, Yuan R, Peng X. USP28 facilitates pancreatic cancer progression through activation of Wnt/β-catenin pathway via stabilising FOXM1. Cell Death Dis 2021; 12:887. [PMID: 34584067 PMCID: PMC8478945 DOI: 10.1038/s41419-021-04163-z] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 08/21/2021] [Accepted: 09/08/2021] [Indexed: 11/09/2022]
Abstract
Ubiquitination is an important post-translational modification that can be reversed by a family of enzymes called deubiquitinating enzymes (DUBs). Ubiquitin-specific protease 28 (USP28), a member of the DUBs family, functions as a potential tumour promoter in various cancers. However, the biological function and clinical significance of USP28 in pancreatic cancer (PC) are still unclear. Here, we showed that PC tumours had higher USP28 expression compared with that of normal pancreatic tissues, and high USP28 level was significantly correlated with malignant phenotype and shorter survival in patients with PC. Overexpression of USP28 accelerated PC cell growth, whereas USP28 knockdown impaired PC cell growth both in vitro and in vivo. Further, we found that USP28 promoted PC cell growth by facilitating cell cycle progression and inhibiting apoptosis. Mechanistically, USP28 deubiquitinated and stabilised FOXM1, a critical mediator of Wnt/β-catenin signalling. USP28-mediated stabilisation of FOXM1 significantly promoted nucleus β-catenin trans-activation, which in turn led to the activation of the Wnt/β-catenin pathway. Finally, restoration of FOXM1 expression abolished the anti-tumour effects of USP28-silencing. Thus, USP28 contributes to PC pathogenesis through enhancing the FOXM1-mediated Wnt/β-catenin signalling, and could be a potential diagnostic and therapeutic target for PC cases.
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Affiliation(s)
- Leifeng Chen
- Department of General Surgery, the Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Zheng Xu
- Department of General Surgery, the Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China
| | - Qing Li
- Department of Pathology, the Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China
| | - Qian Feng
- Department of General Surgery, the Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China
| | - Cihua Zheng
- Department of General Surgery, the Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China
| | - Yunyan Du
- Department of Medical, Jiangxi Provincial People's Hospital of Nanchang University, Nanchang, 330006, China.
| | - Rongfa Yuan
- Department of General Surgery, the Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China.
| | - Xiaogang Peng
- Jiangxi Province Key Laboratory of Molecular Medicine, the Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China.
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Lu Y, Tian M, Liu J, Wang K. LINC00511 facilitates Temozolomide resistance of glioblastoma cells via sponging miR-126-5p and activating Wnt/β-catenin signaling. J Biochem Mol Toxicol 2021; 35:e22848. [PMID: 34328678 DOI: 10.1002/jbt.22848] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 06/02/2021] [Accepted: 07/12/2021] [Indexed: 12/13/2022]
Abstract
Temozolomide (TMZ) is the first-line chemotherapy drug for glioblastoma (GBM) but acquired TMZ resistance is frequently observed. Thus, a TMZ resistant GBM cell line U87-R was established to search for potential long noncoding RNAs (lncRNAs) used in TMZ resistance. In our study, LINC00511 was identified as a TMZ resistance-associated lncRNA in U87-R cells by transcriptome RNA sequencing. The potential functions of LINC00511 were evaluated by quantitative real-time polymerase chain reaction, cell viability assay, colony formation assay, western blot, soft agar assay, flow cytometry, tumor xenograft model, immunofluorescence, sphere formation assay, fluorescent in situ hybridization, luciferase reporter assay, and RNA pull-down assay. We found that LINC00511 was upregulated in U87-R cells and GBM samples, and correlated with poor prognosis of GBM patients. Silencing LINC00511 impaired TMZ tolerance of U87-R cells, while LINC00511 overexpression increased TMZ resistance of sensitive GBM cells. Wnt/β-catenin signaling was activated in U87-R cells, and inhibiting Wnt/β-catenin signaling enhanced TMZ sensitivity. Furthermore, LINC00511 was mainly distributed in the cytoplasm of GBM cells and regulated Wnt/β-catenin activation by acting as a molecular sponge for miR-126-5p. Multiple genes of Wnt/β-catenin signaling such as DVL3, WISP1, and WISP2 were targeted by miR-126-5p. MiR-126-5p restoration impaired TMZ resistance of GBM cells. In conclusion, our results provided a novel insight into acquired TMZ resistance of GBM cells and suggested LINC00511 as a potential biomarker or therapeutic target for GBM patients.
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Affiliation(s)
- Yan Lu
- Department of Neurology, Xinxiang Central Hospital, Xinxiang, Henan province, China
| | - Meng Tian
- Department of Critical Care Medicine, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, China
| | - Jiongbo Liu
- Department of Neurology, The Second People's Hospital of Xinxiang, Xinxiang, Henan province, China
| | - Kuanhong Wang
- Department of Neurology, Xinxiang Central Hospital, Xinxiang, Henan province, China
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Deng Y, Cai S, Shen J, Peng H. Tetraspanins: Novel Molecular Regulators of Gastric Cancer. Front Oncol 2021; 11:702510. [PMID: 34222025 PMCID: PMC8250138 DOI: 10.3389/fonc.2021.702510] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 06/07/2021] [Indexed: 12/11/2022] Open
Abstract
Gastric cancer is the fourth and fifth most common cancer worldwide in men and women, respectively. However, patients with an advanced stage of gastric cancer still have a poor prognosis and low overall survival rate. The tetraspanins belong to a protein superfamily with four hydrophobic transmembrane domains and 33 mammalian tetraspanins are ubiquitously distributed in various cells and tissues. They interact with other membrane proteins to form tetraspanin-enriched microdomains and serve a variety of functions including cell adhesion, invasion, motility, cell fusion, virus infection, and signal transduction. In this review, we summarize multiple utilities of tetraspanins in the progression of gastric cancer and the underlying molecular mechanisms. In general, the expression of TSPAN8, CD151, TSPAN1, and TSPAN4 is increased in gastric cancer tissues and enhance the proliferation and invasion of gastric cancer cells, while CD81, CD82, TSPAN5, TSPAN9, and TSPAN21 are downregulated and suppress gastric cancer cell growth. In terms of cell motility regulation, CD9, CD63 and CD82 are metastasis suppressors and the expression level is inversely associated with lymph node metastasis. We also review the clinicopathological significance of tetraspanins in gastric cancer including therapeutic targets, the development of drug resistance and prognosis prediction. Finally, we discuss the potential clinical value and current limitations of tetraspanins in gastric cancer treatments, and provide some guidance for future research.
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Affiliation(s)
- Yue Deng
- Department of Human Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sicheng Cai
- Department of Human Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian Shen
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huiming Peng
- Department of Human Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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19
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Xiong J, Jiang P, Zhong L, Wang Y. The Novel Tumor Suppressor Gene ZNF24 Induces THCA Cells Senescence by Regulating Wnt Signaling Pathway, Resulting in Inhibition of THCA Tumorigenesis and Invasion. Front Oncol 2021; 11:646511. [PMID: 34136386 PMCID: PMC8201406 DOI: 10.3389/fonc.2021.646511] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Accepted: 04/16/2021] [Indexed: 11/25/2022] Open
Abstract
OBJECT Clinically, the effective treatment options available to thyroid cancer (THCA) patients are very limited. Elucidating the features of tumor suppressor genes (TSGs) and the corresponding signal transduction cascade may provide clues for the development of new strategies for targeted therapy of THCA. Therefore, this paper aims to explore the mechanism of ZNF24 underlying promoting THCA cell senescence at molecular level. METHODS We performed RT-PCR and Western Blotting for evaluating associated RNA and protein expression. CCK8, colony forming, wound healing and Transwell chamber assays were conducted to examine THCA cell proliferation, invasion and migration. β-galactosidase staining assay was performed to detect THCA cells senescence. The size and volume of xenotransplanted tumors in nude mice are calculated to asses ZNF24 effect in vivo. RESULTS Ectopic expression of ZNF24 significantly inhibited the cell viability, colony forming, migration and invasion abilities of THCA cell lines (K1/GLAG-66i and BCPAPi) (P < 0.05). ZNF24 induced BCPAPi cells senescence through regulating Wnt signaling pathway. ZNF24 inhibited Wnt signaling pathway activition by competitively binding β-catenin from LEF1/TCF1-β-catenin complex. In nude mice, both Ectopic expression of ZNF24 and 2,4-Da (the strong β-catenin/Tcf-4 inhibitor) treatment significantly decreased both the size and weight of xenotransplanted tumors when compared with control mice (P < 0.05). CONCLUSION Results obtained in vivo and in vitro reveal the role of ZNF24 in significantly suppressing THCA tumorigenesis and invasion by regulating Wnt signaling pathway.
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Affiliation(s)
- Juan Xiong
- School of Public Health, Health Science Center, Shenzhen University, Shenzhen, China
| | - Panpan Jiang
- School of Life and Marine Sciences, Shenzhen University, Shenzhen, China
- Shenzhen RealOmics (Biotech) Co., Ltd., Shenzhen, China
| | - Li Zhong
- School of Life and Marine Sciences, Shenzhen University, Shenzhen, China
| | - Youling Wang
- School of Life and Marine Sciences, Shenzhen University, Shenzhen, China
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20
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Fru PN, Nweke EE, Mthimkhulu N, Mvango S, Nel M, Pilcher LA, Balogun M. Anti-Cancer and Immunomodulatory Activity of a Polyethylene Glycol-Betulinic Acid Conjugate on Pancreatic Cancer Cells. Life (Basel) 2021; 11:462. [PMID: 34063891 PMCID: PMC8223974 DOI: 10.3390/life11060462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 04/28/2021] [Accepted: 05/04/2021] [Indexed: 12/09/2022] Open
Abstract
Drug delivery systems involving polymer therapeutics enhance drug potency by improved solubility and specificity and may assist in circumventing chemoresistance in pancreatic cancer (PC). We compared the effectiveness of the naturally occurring drug, betulinic acid (BA), alone and in a polymer conjugate construct of polyethylene glycol (PEG), (PEG-BA), on PC cells (MIA PaCa-2), a normal cell line (Vero) and on peripheral blood mononuclear cells (PBMCs). PEG-BA, was tested for its effect on cell death, immunomodulation and chemoresistance-linked signalling pathways. The conjugate was significantly more toxic to PC cells (p < 0.001, IC50 of 1.35 ± 0.11 µM) compared to BA (IC50 of 12.70 ± 0.34 µM), with a selectivity index (SI) of 7.28 compared to 1.4 in Vero cells. Cytotoxicity was confirmed by increased apoptotic cell death. PEG-BA inhibited the production of IL-6 by 4-5.5 fold compared to BA-treated cells. Furthermore, PEG-BA treatment of MIA PaCa-2 cells resulted in the dysregulation of crucial chemoresistance genes such as WNT3A, TXNRD1, SLC2A1 and GATA3. The dysregulation of chemoresistance-associated genes and the inhibition of cytokines such as IL-6 by the model polymer construct, PEG-BA, holds promise for further exploration in PC treatment.
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Affiliation(s)
- Pascaline Nanga Fru
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa; (E.E.N.); (N.M.); (M.N.)
| | - Ekene Emmanuel Nweke
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa; (E.E.N.); (N.M.); (M.N.)
| | - Nompumelelo Mthimkhulu
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa; (E.E.N.); (N.M.); (M.N.)
| | - Sindisiwe Mvango
- Biopolymer Modification and Therapeutics Laboratory, Chemicals Cluster, Council for Scientific and Industrial Research, Meiring Naude Road, Brummeria, Pretoria 0001, South Africa; (S.M.); (M.B.)
- Department of Chemistry, University of Pretoria, Pretoria 0002, South Africa;
| | - Marietha Nel
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa; (E.E.N.); (N.M.); (M.N.)
| | | | - Mohammed Balogun
- Biopolymer Modification and Therapeutics Laboratory, Chemicals Cluster, Council for Scientific and Industrial Research, Meiring Naude Road, Brummeria, Pretoria 0001, South Africa; (S.M.); (M.B.)
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Tang Y, Song G, Liu H, Yang S, Yu X, Shi L. Silencing of Long Non-Coding RNA HOTAIR Alleviates Epithelial-Mesenchymal Transition in Pancreatic Cancer via the Wnt/β-Catenin Signaling Pathway. Cancer Manag Res 2021; 13:3247-3257. [PMID: 33883938 PMCID: PMC8053715 DOI: 10.2147/cmar.s265578] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 12/18/2020] [Indexed: 12/20/2022] Open
Abstract
Purpose Pancreatic cancer (PC) is a malignancy with poor prognosis and controversial treatment options. Long non-coding RNA (lncRNA) is a significant factor in the development of PC. In the current study, the possible effects of HOTAIR on the epithelial-mesenchymal transition (EMT) of PC and the related mechanisms were investigated. Methods The PC models were induced by 10 mg/100 g dimethylbenzoanthracene (DMBA) in pancreas. Mice were injected with the HOTAIR mimic and HOTAIR shRNA to determine the role of HOTAIR in PC. Subsequently, the expression of HOTAIR in PC cells was assayed. To determine the mechanism of HOTAIR in PC, human PC cell line PANC-1, Miapaca-2 and human normal pancreatic ductal epithelial cell line HPDE6-C7 were transfected with the HOTAIR mimic, the shRNA against HOTAIR, the Wnt/b-catenin activator (LiCl), and the Wnt/b-catenin inhibitor (XAV939), respectively. Moreover, the expressions of the Wnt/β-catenin signaling pathway-related genes (β-catenin, cyclinD1, c-myc, LEF-1 and c-Jun) and the levels of the EMT markers (E-cadherin, N-cadherin and Vimentin) were determined. Finally, the cell biological processes were evaluated by functional experiments. Results HOTAIR was found to be highly expressed in the PC cells in mice. The expression of β-catenin, cyclinD1, c-myc, LEF-1 and c-Jun, N-cadherin and Vimentin was found to be decreased, while the expression of E-cadherin was found to be increased subsequent to the silencing of HOTAIR in human PC cell lines PANC-1 and Miapaca-2. Additionally, it was observed that the silencing of HOTAIR could inhibit the Wnt/β-catenin signaling pathway to alleviate EMT of tumor cells and inhibit the capacities of cell proliferation, migration, and invasion. Conclusion The key finding of the present study is that the silencing of HOTAIR could potentially inhibit EMT and growth of PC through the Wnt/β-catenin signaling pathway, providing a novel therapy for PC.
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Affiliation(s)
- Yinhua Tang
- Department of Gastroenterology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People's Republic of China
| | - Guang Song
- Department of Gastroenterology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People's Republic of China
| | - Hongcheng Liu
- Department of Gastroenterology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People's Republic of China
| | - Shuang Yang
- Department of Gastroenterology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People's Republic of China
| | - Xiaoyi Yu
- Department of Gastroenterology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People's Republic of China
| | - Lijun Shi
- Department of Gastroenterology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People's Republic of China
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22
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Conformation-Specific Inhibitory Anti-MMP-7 Monoclonal Antibody Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Chemotherapeutic Cell Kill. Cancers (Basel) 2021; 13:cancers13071679. [PMID: 33918254 PMCID: PMC8038143 DOI: 10.3390/cancers13071679] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 03/23/2021] [Accepted: 03/30/2021] [Indexed: 02/07/2023] Open
Abstract
Matrix metalloproteases (MMPs) undergo post-translational modifications including pro-domain shedding. The activated forms of these enzymes are effective drug targets, but generating potent biological inhibitors against them remains challenging. We report the generation of anti-MMP-7 inhibitory monoclonal antibody (GSM-192), using an alternating immunization strategy with an active site mimicry antigen and the activated enzyme. Our protocol yielded highly selective anti-MMP-7 monoclonal antibody, which specifically inhibits MMP-7's enzyme activity with high affinity (IC50 = 132 ± 10 nM). The atomic model of the MMP-7-GSM-192 Fab complex exhibited antibody binding to unique epitopes at the rim of the enzyme active site, sterically preventing entry of substrates into the catalytic cleft. In human PDAC biopsies, tissue staining with GSM-192 showed characteristic spatial distribution of activated MMP-7. Treatment with GSM-192 in vitro induced apoptosis via stabilization of cell surface Fas ligand and retarded cell migration. Co-treatment with GSM-192 and chemotherapeutics, gemcitabine and oxaliplatin elicited a synergistic effect. Our data illustrate the advantage of precisely targeting catalytic MMP-7 mediated disease specific activity.
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Liu X, Li Z, Wang Y. Advances in Targeted Therapy and Immunotherapy for Pancreatic Cancer. Adv Biol (Weinh) 2021; 5:e1900236. [PMID: 33729700 DOI: 10.1002/adbi.201900236] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 08/19/2020] [Indexed: 12/24/2022]
Abstract
Pancreatic cancer is a highly aggressive malignancy with an overall 5-year survival rate of <6% due to therapeutic resistance and late-stage diagnosis. These statistics have not changed despite 50 years of research and therapeutic development. Pancreatic cancer is predicted to become the second leading cause of cancer mortality by the year 2030. Currently, the treatment options for pancreatic cancer are limited. This disease is usually diagnosed at a late stage, which prevents curative surgical resection. Chemotherapy is the most frequently used approach for pancreatic cancer treatment and has limited effects. In many other cancer types, targeted therapy and immunotherapy have made great progress and have been shown to be very promising prospects; these treatments also provide hope for pancreatic cancer. The need for research on targeted therapy and immunotherapy is pressing due to the poor prognosis of pancreatic cancer, and in recent years, there have been some breakthroughs for targeted therapy and immunotherapy in pancreatic cancer. This review summarizes the current preclinical and clinical studies of targeted therapy and immunotherapy for pancreatic cancer and ends by describing the challenges and outlook.
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Affiliation(s)
- Xiaoxiao Liu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SINH - Changzheng Hospital Joint Center for Translational Medicine, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Zhang Li
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SINH - Changzheng Hospital Joint Center for Translational Medicine, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yuexiang Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SINH - Changzheng Hospital Joint Center for Translational Medicine, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
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Sinha S, Secreto CR, Boysen JC, Lesnick C, Wang Z, Ding W, Call TG, Kenderian SJ, Parikh SA, Warner SL, Bearss DJ, Ghosh AK, Kay NE. Upregulation of AXL and β-catenin in chronic lymphocytic leukemia cells cultured with bone marrow stroma cells is associated with enhanced drug resistance. Blood Cancer J 2021; 11:37. [PMID: 33602892 PMCID: PMC7893033 DOI: 10.1038/s41408-021-00426-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 01/22/2021] [Accepted: 01/28/2021] [Indexed: 11/12/2022] Open
Affiliation(s)
- Sutapa Sinha
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | | | | | | | - Zhiquan Wang
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - Wei Ding
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | | | | | | | | | | | - Asish K Ghosh
- Stephenson Cancer Center and Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Neil E Kay
- Division of Hematology, Mayo Clinic, Rochester, MN, USA.
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Thakur G, Kumar R, Kim SB, Lee SY, Lee SL, Rho GJ. Therapeutic Status and Available Strategies in Pancreatic Ductal Adenocarcinoma. Biomedicines 2021; 9:biomedicines9020178. [PMID: 33670230 PMCID: PMC7916947 DOI: 10.3390/biomedicines9020178] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 02/03/2021] [Accepted: 02/08/2021] [Indexed: 02/06/2023] Open
Abstract
One of the most severe and devastating cancer is pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC) is one of the major pancreatic exocrine cancer with a poor prognosis and growing prevalence. It is the most deadly disease, with an overall five-year survival rate of 6% to 10%. According to various reports, it has been demonstrated that pancreatic cancer stem cells (PCSCs) are the main factor responsible for the tumor development, proliferation, resistance to anti-cancer drugs, and recurrence of tumors after surgery. PCSCs have encouraged new therapeutic methods to be explored that can specifically target cancer cells. Furthermore, stem cells, especially mesenchymal stem cells (MSCs), are known as influential anti-cancer agents as they function through anti-inflammatory, paracrine, cytokines, and chemokine's action. The properties of MSCs, such as migration to the site of infection and host immune cell activation by its secretome, seem to control the microenvironment of the pancreatic tumor. MSCs secretome exhibits similar therapeutic advantages as a conventional cell-based therapy. Moreover, the potential for drug delivery could be enhanced by engineered MSCs to increase drug bioactivity and absorption at the tumor site. In this review, we have discussed available therapeutic strategies, treatment hurdles, and the role of different factors such as PCSCs, cysteine, GPCR, PKM2, signaling pathways, immunotherapy, and NK-based therapy in pancreatic cancer.
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Affiliation(s)
- Gitika Thakur
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Raj Kumar
- Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology, Waknaghat, Solan 173 234, Himachal Pradesh, India;
| | - Saet-Byul Kim
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Sang-Yeob Lee
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Sung-Lim Lee
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Gyu-Jin Rho
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
- Correspondence:
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Kim YE, Kim EK, Song MJ, Kim TY, Jang HH, Kang D. SILAC-Based Quantitative Proteomic Analysis of Oxaliplatin-Resistant Pancreatic Cancer Cells. Cancers (Basel) 2021; 13:cancers13040724. [PMID: 33578797 PMCID: PMC7916634 DOI: 10.3390/cancers13040724] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 02/07/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary Resistance to oxaliplatin remains a major challenge in pancreatic cancer therapy. However, molecular mechanisms underlying oxaliplatin resistance in pancreatic cancer is still unclear. The aim of this study was to identify global changes of proteins involved in oxaliplatin resistance in pancreatic cancer cells, thereby elucidating the multiple mechanisms of oxaliplatin resistance in pancreatic cancer. We presented the quantitative proteomic profiling of oxaliplatin-resistant pancreatic cancer cells via a stable isotope labelling by amino acids in cell culture (SILAC)-based shotgun proteomic approach. Multiple biological processes including DNA repair, cell cycle process, and type I interferon signaling pathway were enriched in oxaliplatin-resistant pancreatic cancer cells. Furthermore, we demonstrated that both Wntless homolog protein (WLS) and myristoylated alanine-rich C-kinase substrate (MARCKS) could participate in oxaliplatin resistance in pancreatic cancer cells. Abstract Oxaliplatin is a commonly used chemotherapeutic drug for the treatment of pancreatic cancer. Understanding the cellular mechanisms of oxaliplatin resistance is important for developing new strategies to overcome drug resistance in pancreatic cancer. In this study, we performed a stable isotope labelling by amino acids in cell culture (SILAC)-based quantitative proteomics analysis of oxaliplatin-resistant and sensitive pancreatic cancer PANC-1 cells. We identified 107 proteins whose expression levels changed (thresholds of 2-fold changes and p-value ≤ 0.05) between oxaliplatin-resistant and sensitive cells, which were involved in multiple biological processes, including DNA repair, cell cycle process, and type I interferon signaling pathway. Notably, myristoylated alanine-rich C-kinase substrate (MARCKS) and Wntless homolog protein (WLS) were upregulated in oxaliplatin-resistant cells compared to sensitive cells, as confirmed by qRT-PCR and Western blot analysis. We further demonstrated the activation of AKT and β-catenin signaling (downstream targets of MARCKS and WLS, respectively) in oxaliplatin-resistant PANC-1 cells. Additionally, we show that the siRNA-mediated suppression of both MARCKS and WLS enhanced oxaliplatin sensitivity in oxaliplatin-resistant PANC-1 cells. Taken together, our results provide insights into multiple mechanisms of oxaliplatin resistance in pancreatic cancer cells and reveal that MARCKS and WLS might be involved in the oxaliplatin resistance.
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Affiliation(s)
- Young Eun Kim
- Center for Bioanalysis, Division of Chemical and Medical Metrology, Korea Research Institute of Standards and Science, Daejeon 34113, Korea;
- School of Earth Sciences and Environmental Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Korea;
| | - Eun-Kyung Kim
- Department of Biochemistry, College of Medicine, Gachon University, Incheon 21999, Korea; (E.-K.K.); (M.-J.S.)
| | - Min-Jeong Song
- Department of Biochemistry, College of Medicine, Gachon University, Incheon 21999, Korea; (E.-K.K.); (M.-J.S.)
| | - Tae-Young Kim
- School of Earth Sciences and Environmental Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Korea;
| | - Ho Hee Jang
- Department of Biochemistry, College of Medicine, Gachon University, Incheon 21999, Korea; (E.-K.K.); (M.-J.S.)
- Correspondence: (H.H.J.); (D.K.)
| | - Dukjin Kang
- Center for Bioanalysis, Division of Chemical and Medical Metrology, Korea Research Institute of Standards and Science, Daejeon 34113, Korea;
- Correspondence: (H.H.J.); (D.K.)
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Spirina LV, Avgustinovich AV, Afanas'ev SG, Cheremisina OV, Volkov MY, Choynzonov EL, Gorbunov AK, Usynin EA. Molecular Mechanism of Resistance to Chemotherapy in Gastric Cancers, the Role of Autophagy. Curr Drug Targets 2021; 21:713-721. [PMID: 31775598 DOI: 10.2174/1389450120666191127113854] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 11/11/2019] [Accepted: 11/21/2019] [Indexed: 12/13/2022]
Abstract
Gastric cancer (GC) is biologically and genetically heterogeneous with complex carcinogenesis at the molecular level. Despite the application of multiple approaches in the GC treatment, its 5-year survival is poor. A major limitation of anti-cancer drugs application is intrinsic or acquired resistance, especially to chemotherapeutical agents. It is known that the effectiveness of chemotherapy remains debatable and varies according to the molecular type of GC. Chemotherapy has an established role in the management of GC. Perioperative chemotherapy or postoperative chemotherapy is applied for localized ones. Most of the advanced GC patients have a poor response to treatment and unfavorable outcomes with standard therapies. Resistance substantially limits the depth and duration of clinical responses to targeted anticancer therapies. Through the use of complementary experimental approaches, investigators have revealed that cancer cells can achieve resistance through adaptation or selection driven by specific genetic, epigenetic, or microenvironmental alterations. Ultimately, these diverse alterations often lead to the activation of MAPK, AKT/mTOR, and Wnt/β-catenin signaling pathways that, when co-opted, enable cancer cells to survive drug treatments. We have summarized the mechanisms of resistance development to cisplatin, 5-fluorouracil, and multidrug resistance in the GC management. The complexity of molecular targets and components of signaling cascades altered in the resistance development results in the absence of significant benefits in GC treatment, and its efficacy remains low. The universal process responsible for the failure in the multimodal approach in GC treatment is autophagy. Its dual role in oncogenesis is the most unexplored issue. We have discussed the possible mechanism of autophagy regulation upon the action of endogenous factors and drugs. The experimental data obtained in the cultured GC cells need further verification. To overcome the cancer resistance and to prevent autophagy as the main reason of ineffective treatment, it is suggested the concept of the direct influence of autophagy molecular markers followed by the standard chemotherapy. Dozen of studies have focused on finding the rationale for the benefits of such complex therapy. The perspectives in the molecular-based management of GC are associated with the development of molecular markers predicting the protective autophagy initiation and search for novel targets of effective anticancer therapy.
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Affiliation(s)
- Liudmila V Spirina
- Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 5 Koopertivny street, Tomsk, 634050, Russian Federation.,Siberian State Medical University, 2, Moskovsky trakt, Tomsk, 634050, Russian Federation
| | - Alexandra V Avgustinovich
- Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 5 Koopertivny street, Tomsk, 634050, Russian Federation
| | - Sergey G Afanas'ev
- Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 5 Koopertivny street, Tomsk, 634050, Russian Federation
| | - Olga V Cheremisina
- Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 5 Koopertivny street, Tomsk, 634050, Russian Federation
| | - Maxim Yu Volkov
- Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 5 Koopertivny street, Tomsk, 634050, Russian Federation
| | - Evgeny L Choynzonov
- Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 5 Koopertivny street, Tomsk, 634050, Russian Federation.,Siberian State Medical University, 2, Moskovsky trakt, Tomsk, 634050, Russian Federation
| | - Alexey K Gorbunov
- Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 5 Koopertivny street, Tomsk, 634050, Russian Federation
| | - Evgeny A Usynin
- Cancer Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, 5 Koopertivny street, Tomsk, 634050, Russian Federation.,Siberian State Medical University, 2, Moskovsky trakt, Tomsk, 634050, Russian Federation
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Hua YQ, Zhang K, Sheng J, Ning ZY, Li Y, Shi WD, Liu LM. Fam83D promotes tumorigenesis and gemcitabine resistance of pancreatic adenocarcinoma through the Wnt/β-catenin pathway. Life Sci 2021; 287:119205. [PMID: 33571515 DOI: 10.1016/j.lfs.2021.119205] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/29/2021] [Accepted: 02/05/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Elevated expression of family with sequence similarity 83 member D (Fam83D) has been found in various cancers; however, its role in pancreatic adenocarcinoma (PDAC) remains unclear. The current study was designed to elucidate the roles of Fam83D in pancreatic cancer. METHOD The level of Fam83D was detected in PDAC tissues and adjacent no-tumorous tissues. Effects of Fam83D on proliferation, glycolysis and gemcitabine (GEM) sensitivity of pancreatic cancer cells were examined. RESULTS Fam83D was overexpressed in PDAC and associated with clinical stage, metastatic status and survival rates of PDAC patients. Function study showed that Fam83D knockdown (KD) caused inhibited proliferation, suppressed mitochondrial respiration capacity, reduced aerobic glycolysis, and down-regulation of nuclear β-catenin, proto-oncogene C-Myc, and lactate dehydrogenase A (LDHA). Fam83D KD enhanced the sensitivity of PDAC cells to GEM in vitro and in vivo. On the contrary, Fam83D overexpression displayed reverse effects on PDAC cells. Moreover, the Wnt/β-catenin inhibitor abolished the effects of Fam83D overexpression in PDAC cells. CONCLUSIONS the current data suggest that enhanced Fam83D expression contributes to PDAC progression and the development of chemoresistance through the Wnt/β-catenin signaling.
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Affiliation(s)
- Yong-Qiang Hua
- Minimally Invasive Treatment Center, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai 200032, PR China; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong An Road, Shanghai 200032, PR China
| | - Ke Zhang
- Minimally Invasive Treatment Center, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai 200032, PR China; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong An Road, Shanghai 200032, PR China
| | - Jie Sheng
- Minimally Invasive Treatment Center, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai 200032, PR China; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong An Road, Shanghai 200032, PR China
| | - Zhou-Yu Ning
- Minimally Invasive Treatment Center, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai 200032, PR China; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong An Road, Shanghai 200032, PR China
| | - Ye Li
- Minimally Invasive Treatment Center, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai 200032, PR China; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong An Road, Shanghai 200032, PR China
| | - Wei-Dong Shi
- Minimally Invasive Treatment Center, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai 200032, PR China
| | - Lu-Ming Liu
- Minimally Invasive Treatment Center, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai 200032, PR China; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong An Road, Shanghai 200032, PR China.
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Ning MY, Cheng ZL, Zhao J. MicroRNA-448 targets SATB1 to reverse the cisplatin resistance in lung cancer via mediating Wnt/β-catenin signalling pathway. J Biochem 2021; 168:41-51. [PMID: 32525527 DOI: 10.1093/jb/mvaa024] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Accepted: 02/06/2020] [Indexed: 12/12/2022] Open
Abstract
This study aims to examine whether miR-448 reverses the cisplatin (DDP) resistance in lung cancer by modulating SATB1. QRT-PCR and immunohistochemistry were used to examine the miR-448 and SATB1 expressions in DDP-sensitive and -resistant lung cancer patients. A microarray was used to investigate the cytoplasmic/nucleic ratio (C/N ratios) of genes in A549 cells targeted by miR-448, followed by Dual-luciferase reporter gene assay. A549/DDP cells were transfected with miR-448 mimics/inhibitors with or without SATB1 siRNA followed by MTT assay, Edu staining, flow cytometry, qRT-PCR and western blotting. MiR-448 was lower but SATB1 was increased in DDP-resistant patients and A549/DDP cells. And the patients showed low miR-448 expression or SATB1 positive expression had poor prognosis. SATB1, as a target gene with higher C/N ratios (>1), was found negatively regulated by miR-448. Besides, miR-448 inhibitors increased resistance index of A549/DDP cells, promoted cell proliferation, increased cell distribution in S phrase, declined cell apoptosis and activated Wnt/β-catenin pathway. However, SATB1 siRNA could reverse the above effect caused by miR-448 inhibitors. MiR-448 targeting SATB1 to counteract the DDP resistance of lung cancer cells via Wnt/β-catenin pathway.
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Affiliation(s)
- Mei-Ying Ning
- Department of Pharmacy, Cangzhou Central Hospital, No.16 Xinhua West Road, Yunhe District, Cangzhou 061001, China
| | - Zhao-Lin Cheng
- Department of Pharmacy, Cangzhou People's Hospital, No.7 Qingchi Road, Xinhua District, Cangzhou 061000, China
| | - Jing Zhao
- Department of Pharmacy, Cangzhou Central Hospital, No.16 Xinhua West Road, Yunhe District, Cangzhou 061001, China
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Wang Q, Liao J, He Z, Su Y, Lin D, Xu L, Xu H, Lin J. LHX6 Affects Erlotinib Resistance and Migration of EGFR-Mutant Non-Small-Cell Lung Cancer HCC827 Cells Through Suppressing Wnt/β-Catenin Signaling. Onco Targets Ther 2020; 13:10983-10994. [PMID: 33149613 PMCID: PMC7605383 DOI: 10.2147/ott.s258896] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Accepted: 10/08/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND miR-214 has been reported to contribute to erlotinib resistance in non-small-cell lung cancer (NSCLC) through targeting LHX6; however, the molecular mechanisms underlying the involvement of LHX6 in mediating the resistance to EGFR-TKIs in erlotinib-resistant NSCLC HCC827 (HCC827/ER) cells remain unknown. This study aimed to investigate the mechanisms responsible for the contribution of LHX6 to EGFR-TKIs resistance in HCC827/ER cells. MATERIALS AND METHODS HCC827/ER cells were generated by erlotinib treatment at a dose-escalation scheme. LHX6 knockout or overexpression was modeled in HCC827 and HCC827/ER cells, and then erlotinib IC50 values were measured. The cell migration ability was evaluated using a transwell migration assay, and the TCF/LEF luciferase activity was assessed with a TCF/LEF reporter luciferase assay. LHX6, β-catenin and Cyclin D1 expression was quantified using qPCR and Western blotting assays. In addition, the LHX6 expression was detected in lung cancer and peri-cancer specimens using immunohistochemical staining, and the associations of LHX expression with the clinicopathological characteristics of lung cancer were evaluated. RESULTS Lower LHX6 expression was detected in HCC827/ER cells than in HCC827 cells (P < 0.0001), while higher β-catenin expression was seen in HCC827/ER cells than in HCC827 cells (P < 0.001). LHX6 knockout increased erlotinib resistance and cell migration ability in HCC827 cells, and LHX6 overexpression inhibited erlotinib resistance and cell migration ability in HCC827/ER cells. In addition, LHX6 mediated erlotinib resistance and cell migration ability in HCC827/ER cells via the Wnt/β-catenin pathway. Immunohistochemical staining showed lower LHX6 expression in lung cancer specimens relative to peri-cancer specimens, and there were no associations of LHX6 expression with pathologic stage, gender, age or tumor size in lung cancer patients (P > 0.05). CONCLUSION LHX6 down-regulation may induce EGFR-TKIs resistance and increase the migration ability of HCC827/ER cells via activation of the Wnt/β-catenin pathway.
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Affiliation(s)
- Qiang Wang
- Department of Thoracic Medical Oncology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou350014, People’s Republic of China
| | - Jinrong Liao
- Department of Radiobiology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou350014, People’s Republic of China
| | - Zhiyong He
- Department of Thoracic Medical Oncology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou350014, People’s Republic of China
- Fujian Provincial Key Laboratory of Translation Cancer Medicine, Fuzhou350014, People’s Republic of China
| | - Ying Su
- Department of Radiobiology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou350014, People’s Republic of China
| | - Dong Lin
- Department of Thoracic Medical Oncology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou350014, People’s Republic of China
| | - Ling Xu
- Department of Thoracic Medical Oncology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou350014, People’s Republic of China
| | - Haipeng Xu
- Department of Thoracic Medical Oncology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou350014, People’s Republic of China
| | - Jinghui Lin
- Department of Thoracic Medical Oncology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou350014, People’s Republic of China
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Cir-ITCH inhibits gastric cancer migration, invasion and proliferation by regulating the Wnt/β-catenin pathway. Sci Rep 2020; 10:17443. [PMID: 33060778 PMCID: PMC7566509 DOI: 10.1038/s41598-020-74452-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 10/01/2020] [Indexed: 02/06/2023] Open
Abstract
Circular RNAs (circRNAs) are differentially expressed in various tumours, but the expression and regulatory mechanisms of circular RNA ITCH (cir-ITCH) in gastric cancer remain unclear. For this reason, in the present study, we assessed the expression of cir-ITCH and the associated regulatory mechanism of cir-ITCH in gastric cancer. Through RTq-PCR assays, we observed that cir-ITCH expression was attenuated in gastric cancer cell lines and tissues, with cir-ITCH expression in gastric cancer tissues with lymph node metastasis being considerably lower than that observed in gastric cancer tissues without lymph node metastasis. In addition, we demonstrated that cir-ITCH or linear ITCH may be a useful marker for gastric cancer prognosis by Kaplan–Meier survival analysis. We also showed that cir-ITCH overexpression could increase linear ITCH expression through miR-17 via RNA immunoprecipitation (RIP) and luciferase reporter assays. Moreover, in vivo and in vitro experimental results showed that cir-ITCH can act as a tumour suppressor to prevent gastric cancer tumourgenesis by sponging miR-17. The Wnt/β-catenin pathway plays a crucial role during the carcinogenesis of cancers, and we observed that cir-ITCH could negatively regulate Wnt/β-catenin signalling, which could be restored by miR-17. In summary, cir-ITCH was shown to prevent gastric cancer tumourgenesis through the Wnt/β-catenin signalling pathway by sequestering miR-17.
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Xu Y, Wu G, Zhang J, Li J, Ruan N, Zhang J, Zhang Z, Chen Y, Zhang Q, Xia Q. TRIM33 Overexpression Inhibits the Progression of Clear Cell Renal Cell Carcinoma In Vivo and In Vitro. BIOMED RESEARCH INTERNATIONAL 2020; 2020:8409239. [PMID: 32908919 PMCID: PMC7468622 DOI: 10.1155/2020/8409239] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 07/29/2020] [Accepted: 08/03/2020] [Indexed: 12/24/2022]
Abstract
PURPOSE To evaluate the expression of tripartite motif-containing 33 (TRIM33) in ccRCC tissues and explore the biological effect of TRIM33 on the progress of ccRCC. METHOD The Cancer Genome Atlas (TCGA) database was used to examine the mRNA expression levels of TRIM33 in ccRCC tissues and its clinical relevance. Immunohistochemistry (IHC) was performed to evaluate its expression in ccRCC tissues obtained from our hospital. The correlation between TRIM33 expression and clinicopathological features of the patients was also investigated. The effects of TRIM33 on the proliferation of ccRCC cells were examined using the CCK-8 and colony formation assays. The effects of TRIM33 on the migration and invasion of ccRCC cells were explored through wound healing and transwell assays, along with the use of Wnt signaling pathway agonists in rescue experiments. Western blotting was used to explore the potential mechanism of TRIM33 in renal cancer cells. A xenograft model was used to explore the effect of TRIM33 on tumor growth. RESULT Bioinformatics analysis showed that TRIM33 mRNA expression in ccRCC tissues was downregulated, and low TRIM33 expression was related to poor prognosis in ccRCC patients. In agreement with this, low TRIM33 expression was detected in human ccRCC tissues. TRIM33 expression levels were correlated with clinical characteristics, including tumor size and Furman's grade. Furthermore, TRIM33 overexpression inhibited proliferation, migration, and invasion of 786-O and ACHN cell lines. The rescue experiment showed that the originally inhibited migration and invasion capabilities were restored. TRIM33 overexpression reduced the expression levels of β-catenin, cyclin D1, and c-myc, and inhibited tumor growth in ccRCC cells in vivo. CONCLUSION TRIM33 exhibits an abnormally low expression in human ccRCC tissues. TRIM33 may serve as a potential therapeutic target and prognostic marker for ccRCC.
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Affiliation(s)
- Yingkun Xu
- Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
| | - Guangzhen Wu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, China
| | - Jiayao Zhang
- Liver Transplantation Center and Hepatobiliary Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
| | - Jianyi Li
- Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
| | - Ningke Ruan
- The Nursing College of Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Jianfeng Zhang
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110122, China
| | - Zhiyu Zhang
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, China
| | - Yougen Chen
- Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China
| | - Qi Zhang
- Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China
| | - Qinghua Xia
- Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China
- Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China
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Vaghari-Tabari M, Majidinia M, Moein S, Qujeq D, Asemi Z, Alemi F, Mohamadzadeh R, Targhazeh N, Safa A, Yousefi B. MicroRNAs and colorectal cancer chemoresistance: New solution for old problem. Life Sci 2020; 259:118255. [PMID: 32818543 DOI: 10.1016/j.lfs.2020.118255] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Revised: 08/01/2020] [Accepted: 08/09/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the most common gastrointestinal malignancies with a significant mortality rate. Despite the great advances in cancer treatment in the last few decades, effective treatment of CRC is still under challenge. One of the main problems associated with CRC treatment is the resistance of cancer cells to chemotherapy drugs. METHODS Many studies have been carried out to identify CRC chemoresistance mechanisms, and shed light on the role of ATP-binding cassette transporters (ABC transporters), enzymes as thymidylate synthase, some signaling pathways, and cancer stem cells (CSC) in chemoresistance and failed CRC chemotherapies. Other studies have also been recently carried out to find solutions to overcome chemoresistance. Some of these studies have identified the role of miRNAs in chemoresistance of the CRC cells and the effective use of these micro-molecules to CRC treatment. RESULTS Considering the results of these studies, more focus on miRNAs likely leads to a proper solution to overcome CRC chemoresistance. CONCLUSION The current study has reviewed the related literature while discussing the efficacy of miRNAs as potential clinical tools for overcoming CRC chemoresistance and reviewing the most important chemoresistance mechanisms in CRC cells.
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Affiliation(s)
- Mostafa Vaghari-Tabari
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Soheila Moein
- Department of Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran; Medicinal Plants Processing Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Durdi Qujeq
- Cellular and Molecular Biology Research Center (CMBRC), Health Research Institute, Babol University of Medical Sciences, Babol, Iran; Department of Clinical Biochemistry, Babol University of Medical Sciences, Babol, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Forough Alemi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ramin Mohamadzadeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nilofar Targhazeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amin Safa
- Institute of Research and Development, Duy Tan University, Da Nang, Vietnam; Faculty of Medicine, Zabol University of Medical Sciences, Zabol, Iran.
| | - Bahman Yousefi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Taherkhani F, Hosseini KM, Zebardast S, Chegini KG, Gheibi N. Anti proliferative and apoptotic effects on pancreatic cancer cell lines indicate new roles for ANGPTL8 (Betatrophin). Genet Mol Biol 2020; 43:e20190196. [PMID: 32745158 PMCID: PMC7416753 DOI: 10.1590/1678-4685-gmb-2019-0196] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Accepted: 05/31/2020] [Indexed: 11/25/2022] Open
Abstract
Despite considerable advances, the treatment of pancreatic cancer (PC) still
requires much effort. Unusual regulation of the Wnt and apoptotic signaling
pathways is widespread in cancer incidence. For instance, the
WIF1 (Wnt inhibitory factor 1) gene is down-regulated in
many cancers. The purpose of this study was to determine the effects of
recombinant Betatrophin, a recently discovered hormone, on MiaPaca-II and
Panc-1 pancreatic cell lines. Various concentrations of
Betatrophin were added to MiaPaca-II and Panc-1 pancreatic cell
lines during periods of 24 , 48, and 72 h. The MTT assay was applied to
investigate cell proliferation after treatment. The rate of apoptotic cells was
assessed using double-staining flow cytometry, and the expression levels of the
WIF1 gene and Bcl2 protein was observed by real-time PCR
and western blotting, respectively. The findings of this study suggest that
Betatrophin has an anti-proliferative effect on both MiaPaca-II and Panc-1 cell
lines, in line with the up-regulation of WIF1 as a tumor
suppressor gene. Moreover, the induction of apoptosis by ANGPTL8 occurred by the
down-regulation of Bcl2. Thus, Betatrophin can be proposed as a potential
therapeutic drug for treating pancreatic cancer.
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Affiliation(s)
| | | | - Sanaz Zebardast
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Koorosh Goodarzvand Chegini
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Nematollah Gheibi
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran
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Tong C, Qu K, Wang G, Liu R, Duan B, Wang X, Liu C. Knockdown of DNA-binding protein A enhances the chemotherapy sensitivity of colorectal cancer via suppressing the Wnt/β-catenin/Chk1 pathway. Cell Biol Int 2020; 44:2075-2085. [PMID: 32652867 DOI: 10.1002/cbin.11416] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 06/18/2020] [Accepted: 07/05/2020] [Indexed: 11/07/2022]
Abstract
DNA-binding protein A (dbpA) is reported to be upregulated in many cancers and associated with tumor progress. The present study aimed to investigate the role of dbpA in 5-fluorouracil (5-FU)-resistant and oxaliplatin (L-OHP)-resistant colorectal cancer (CRC) cells. We found that 5-FU and L-OPH treatment promoted the expression of dbpA. Enhanced dbpA promoted the drug resistance of SW620 cells to 5-FU and L-OHP. DbpA knockdown inhibited cell proliferation, induced cell apoptosis, and cell cycle arrested in SW620/5-FU and SW620/L-OHP cells. Besides, dbpA short hairpin RNA (shRNA) enhanced the cytotoxicity of 5-FU and L-OHP to SW620/5-FU and SW620/L-OHP cells. Meanwhile, dbpA shRNA inhibited the activation of the Wnt/β-catenin pathway that induced by 5-FU stimulation in SW620/5-FU cells. Activation of the Wnt/β-catenin pathway or overexpression of checkpoint kinase 1 (Chk1) abrogated the promoting effect of dbpA downregulation on 5-FU sensitivity of CRC cells. Importantly, downregulation of dbpA suppressed tumor growth and promoted CRC cells sensitivity to 5-FU in vivo. Our study indicated that the knockdown of dbpA enhanced the sensitivity of CRC cells to 5-FU via Wnt/β-catenin/Chk1 pathway, and DbpA may be a potential therapeutic target to sensitize drug resistance CRC to 5-FU and L-OHP.
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Affiliation(s)
- Cong Tong
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,First Department of General Surgery, Shaanxi Provincial People's Hospital/The Third Affiliated Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Kai Qu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Guorong Wang
- First Department of General Surgery, Shaanxi Provincial People's Hospital/The Third Affiliated Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Ruiting Liu
- First Department of General Surgery, Shaanxi Provincial People's Hospital/The Third Affiliated Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Baojun Duan
- Department of Oncology, Shaanxi Provincial People's Hospital/The Third Affiliated Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Xiaoqiang Wang
- First Department of General Surgery, Shaanxi Provincial People's Hospital/The Third Affiliated Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Chang Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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Ashrafizadeh M, Zarrabi A, Hushmandi K, Hashemi F, Hashemi F, Samarghandian S, Najafi M. MicroRNAs in cancer therapy: Their involvement in oxaliplatin sensitivity/resistance of cancer cells with a focus on colorectal cancer. Life Sci 2020; 256:117973. [PMID: 32569779 DOI: 10.1016/j.lfs.2020.117973] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 06/06/2020] [Accepted: 06/10/2020] [Indexed: 02/08/2023]
Abstract
The resistance of cancer cells into chemotherapy has restricted the efficiency of anti-tumor drugs. Oxaliplatin (OX) being an anti-tumor agent/drug is extensively used in the treatment of various cancer diseases. However, its frequent application has led to chemoresistance. As a consequence, studies have focused in finding underlying molecular pathways involved in OX resistance. MicroRNAs (miRs) are short endogenous non-coding RNAs that are able to regulate vital biological mechanisms such as cell proliferation and cell growth. The abnormal expression of miRs occurs in pathological events, particularly cancer. In the present review, we describe the involvement of miRs in OX resistance and sensitivity. The miRs are able to induce the oncogene factors and mechanisms, resulting in stimulation OX chemoresistance. Also, onco-suppressor miRs can enhance the sensitivity of cancer cells into OX chemotherapy and trigger apoptosis and cell cycle arrest, leading to reduced viability and progression of cancer cells. MiRs can also enhance the efficacy of OX chemotherapy. It is worth mentioning that miRs affect various down-stream targets in OX resistance/sensitivity such as STAT3, TGF-β, ATG4B, FOXO1, LATS2, NF-κB and so on. By identification of these miRs and their upstream and down-stream mediators, further studies can focus on targeting them to sensitize cancer cells into OX chemotherapy and induce apoptotic cell death.
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Affiliation(s)
- Milad Ashrafizadeh
- Department of Basic Science, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla 34956, Istanbul, Turkey; Center of Excellence for Functional Surfaces and Interfaces (EFSUN), Faculty of Engineering and Natural Sciences, Sabanci University, Tuzla, Istanbul 34956, Turkey
| | | | - Farid Hashemi
- DVM. Graduated, Young Researcher and Elite Club, Kazerun Branch, Islamic Azad University, Kazeroon, Iran
| | - Fardin Hashemi
- Student Research Committee, Department of Physiotherapy, Faculty of Rehabilitation, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Saeed Samarghandian
- Healthy Ageing Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Masoud Najafi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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Zhou Y, Hua Z, Zhu Y, Wang L, Chen F, Shan T, Zhou Y, Dai T. Upregulation of ARHGAP30 attenuates pancreatic cancer progression by inactivating the β-catenin pathway. Cancer Cell Int 2020; 20:225. [PMID: 32536813 PMCID: PMC7288688 DOI: 10.1186/s12935-020-01288-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Accepted: 05/22/2020] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Pancreatic cancer is a highly malignant gastrointestinal cancer that can widely metastasize during the early stage of disease, and it is associated with one of the worst prognoses among cancers. In this study, we aimed to investigate the function of Rho GTPase-activating protein 30 (ARHGAP30) in pancreatic cancer cells and thus propose a novel therapy for pancreatic cancer. METHODS ARHGAP30 expression in tumor tissues from patients with pancreatic cancer as well as cell lines was detected using immunohistochemistry (IHC), real-time polymerase chain reaction, and western blotting. Cell proliferation, transwell, and apoptosis assays were performed and the levels of related proteins were determined after ARHGAP30 knockdown or overexpression. Additionally, in vivo experiments were performed on nude mice. RESULTS ARHGAP30 expression was found to be significantly increased in tumor tissues from patients with pancreatic cancer as well as in pancreatic cancer cell lines. IHC and prognostic analyses indicated that patients with high ARHGAP30 expression had a good prognosis. ARHGAP30 overexpression significantly decreased pancreatic cancer cell proliferation and metastasis; promoted apoptosis; reduced β-catenin, B-cell lymphoma 2 (Bcl-2), matrix metalloproteinase-2 (MMP2), and MMP9 expression; and increased Bcl-2-associated X protein (Bax) and cleaved caspase-3 expression. ARHGAP30 knockdown elicited the opposite effects. The effects of ARHGAP30 knockdown were potently attenuated by the β-catenin inhibitor XAV939. ARHGAP30 knockdown-induced RHOA activity was potently attenuated by the RHOA inhibitor CCG1423. In vivo, ARHGAP30 overexpression significantly inhibited lung metastasis in nude mice and increased the survival of mice with lung metastases. CONCLUSIONS Our findings indicate that ARHGAP30 may function as a tumor suppressor in pancreatic cancer progression by regulating the expression of related genes and the β-catenin pathway.
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Affiliation(s)
- Yongping Zhou
- Department of Hepatobiliary Surgery, Wuxi Second Hospital, Nanjing Medical University, No. 68 Zhongshan Road, Wuxi, 214000 People’s Republic of China
| | - Zhiyuan Hua
- Department of Hepatobiliary Surgery, Wuxi Second Hospital, Nanjing Medical University, No. 68 Zhongshan Road, Wuxi, 214000 People’s Republic of China
| | - Ye Zhu
- Department of Hepatobiliary Surgery, Wuxi Second Hospital, Nanjing Medical University, No. 68 Zhongshan Road, Wuxi, 214000 People’s Republic of China
| | - Liying Wang
- Department of Hepatobiliary Surgery, Wuxi Second Hospital, Nanjing Medical University, No. 68 Zhongshan Road, Wuxi, 214000 People’s Republic of China
| | - Fangming Chen
- Department of Imaging, Wuxi Second Hospital, Nanjing Medical University, Wuxi, 214000 People’s Republic of China
| | - Ting Shan
- Department of General Surgery, Wuxi Second Hospital, Nanjing Medical University, No. 68 Zhongshan Road, Wuxi, 214000 People’s Republic of China
| | - Yunhai Zhou
- Department of General Surgery, Wuxi Second Hospital, Nanjing Medical University, No. 68 Zhongshan Road, Wuxi, 214000 People’s Republic of China
| | - Tu Dai
- Department of Hepatobiliary Surgery, Wuxi Second Hospital, Nanjing Medical University, No. 68 Zhongshan Road, Wuxi, 214000 People’s Republic of China
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Liu L, Zhu H, Liao Y, Wu W, Liu L, Liu L, Wu Y, Sun F, Lin HW. Inhibition of Wnt/β-catenin pathway reverses multi-drug resistance and EMT in Oct4 +/Nanog + NSCLC cells. Biomed Pharmacother 2020; 127:110225. [PMID: 32428834 DOI: 10.1016/j.biopha.2020.110225] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 04/28/2020] [Accepted: 04/30/2020] [Indexed: 12/17/2022] Open
Abstract
Cancer drug resistance and epithelial-mesenchymal transition (EMT), a critical process of cancer invasion and metastasis, have recently been associated with the existence of cancer stem cells (CSCs). However, there are no appropriate CSC-markers of non-small cell lung cancer (NSCLC)-associated drug resistance and EMT. It is unknown if and how the drug-resistant and EMT phenotypes in NSCLC cells link to specific stemness-related pathways. Here, we found a significant elevated expression of both Oct4 and Nanog in gefitinib-resistant NSCLC cells, which displayed multi-drug resistance (MDR) properties and exhibited EMT phenotype. Ectopic co-expression of Oct4/Nanog empowered NSCLC cells with cancer stem cell properties, including self-renewal, drug resistance, EMT and high tumorigenic capacity. Following molecular mechanism investigation indicated Oct4/Nanog-regulated drug resistance and EMT change through Wnt/β-catenin signaling activation. Moreover, silencing β-catenin abrogated Oct4/Nanog-mediated MDR and EMT process in NSCLC cells. Our findings propose Wnt/β-catenin pathway as a promising therapeutic target for the treatment of progression and metastasis of NSCLC with CSC-like signatures and epithelial-mesenchymal transition phenotype.
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Affiliation(s)
- Liyun Liu
- Research Center for Marine Drugs, State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai 200127, People's Republic of China
| | - Hongrui Zhu
- School of Life Sciences and Biopharmaceutical Sciences, Shenyang Pharmaceutical University, Liaoning 110016, People's Republic of China
| | - Yahui Liao
- Institute for Marine Biosystem and Neurosciences, Shanghai Ocean University, Shanghai 201306, People's Republic of China
| | - Wei Wu
- Research Center for Marine Drugs, State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai 200127, People's Republic of China
| | - Lei Liu
- Research Center for Marine Drugs, State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai 200127, People's Republic of China
| | - Li Liu
- Research Center for Marine Drugs, State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai 200127, People's Republic of China
| | - Ying Wu
- Research Center for Marine Drugs, State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai 200127, People's Republic of China
| | - Fan Sun
- Research Center for Marine Drugs, State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai 200127, People's Republic of China.
| | - Hou-Wen Lin
- Research Center for Marine Drugs, State Key Laboratory of Oncogenes and Related Genes, Department of Pharmacy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai 200127, People's Republic of China.
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Lin Q, He Y, Wang X, Zhang Y, Hu M, Guo W, He Y, Zhang T, Lai L, Sun Z, Yi Z, Liu M, Chen Y. Targeting Pyruvate Carboxylase by a Small Molecule Suppresses Breast Cancer Progression. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2020; 7:1903483. [PMID: 32382484 PMCID: PMC7201266 DOI: 10.1002/advs.201903483] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 02/14/2020] [Accepted: 02/24/2020] [Indexed: 05/29/2023]
Abstract
Rapid metabolism differentiates cancer cells from normal cells and relies on anaplerotic pathways. However, the mechanisms of anaplerosis-associated enzymes are rarely understood. The lack of potent and selective antimetabolism drugs restrains further clinical investigations. A small molecule ZY-444 ((N 4-((5-(4-(benzyloxy)phenyl)-2-thiophenyl)methyl)-N 2-isobutyl-2,4-pyrimidinediamine) is discovered to inhibit cancer cell proliferation specifically, having potent efficacies against tumor growth, metastasis, and recurrence. ZY-444 binds to cellular pyruvate carboxylase (PC), a key anaplerotic enzyme of the tricarboxylic acid cycle, and inactivates its catalytic activity. PC inhibition suppresses breast cancer growth and metastasis through inhibiting the Wnt/β-catenin/Snail signaling pathway. Lower PC expression in patient tumors is correlated with significant survival benefits. Comparative profiles of PC expression in cancer versus normal tissues implicate the tumor selectivity of ZY-444. Overall, ZY-444 holds promise therapeutically as an anti-cancer metabolism agent.
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Affiliation(s)
- Qingxiang Lin
- East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational MedicineShanghai Key Laboratory of Regulatory BiologyInstitute of Biomedical Sciences and School of Life SciencesEast China Normal UniversityShanghai200241P. R. China
| | - Yuan He
- East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational MedicineShanghai Key Laboratory of Regulatory BiologyInstitute of Biomedical Sciences and School of Life SciencesEast China Normal UniversityShanghai200241P. R. China
- Joint Center for Translational MedicineSouthern Medical University Affiliated Fengxian HospitalShanghai201499P. R. China
| | - Xue Wang
- East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational MedicineShanghai Key Laboratory of Regulatory BiologyInstitute of Biomedical Sciences and School of Life SciencesEast China Normal UniversityShanghai200241P. R. China
| | - Yong Zhang
- East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational MedicineShanghai Key Laboratory of Regulatory BiologyInstitute of Biomedical Sciences and School of Life SciencesEast China Normal UniversityShanghai200241P. R. China
| | - Meichun Hu
- East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational MedicineShanghai Key Laboratory of Regulatory BiologyInstitute of Biomedical Sciences and School of Life SciencesEast China Normal UniversityShanghai200241P. R. China
| | - Weikai Guo
- East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational MedicineShanghai Key Laboratory of Regulatory BiologyInstitute of Biomedical Sciences and School of Life SciencesEast China Normal UniversityShanghai200241P. R. China
| | - Yundong He
- East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational MedicineShanghai Key Laboratory of Regulatory BiologyInstitute of Biomedical Sciences and School of Life SciencesEast China Normal UniversityShanghai200241P. R. China
| | - Tao Zhang
- East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational MedicineShanghai Key Laboratory of Regulatory BiologyInstitute of Biomedical Sciences and School of Life SciencesEast China Normal UniversityShanghai200241P. R. China
| | - Li Lai
- East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational MedicineShanghai Key Laboratory of Regulatory BiologyInstitute of Biomedical Sciences and School of Life SciencesEast China Normal UniversityShanghai200241P. R. China
| | - Zhenliang Sun
- Joint Center for Translational MedicineSouthern Medical University Affiliated Fengxian HospitalShanghai201499P. R. China
| | - Zhengfang Yi
- East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational MedicineShanghai Key Laboratory of Regulatory BiologyInstitute of Biomedical Sciences and School of Life SciencesEast China Normal UniversityShanghai200241P. R. China
- Joint Center for Translational MedicineSouthern Medical University Affiliated Fengxian HospitalShanghai201499P. R. China
| | - Mingyao Liu
- East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational MedicineShanghai Key Laboratory of Regulatory BiologyInstitute of Biomedical Sciences and School of Life SciencesEast China Normal UniversityShanghai200241P. R. China
| | - Yihua Chen
- East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational MedicineShanghai Key Laboratory of Regulatory BiologyInstitute of Biomedical Sciences and School of Life SciencesEast China Normal UniversityShanghai200241P. R. China
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Solanki A, King D, Thibault G, Wang L, Gibbs SL. Quantification of fluorophore distribution and therapeutic response in matched in vivo and ex vivo pancreatic cancer model systems. PLoS One 2020; 15:e0229407. [PMID: 32097436 PMCID: PMC7041865 DOI: 10.1371/journal.pone.0229407] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 02/05/2020] [Indexed: 12/18/2022] Open
Abstract
Therapeutic resistance plagues cancer outcomes, challenging treatment particularly in aggressive disease. A unique method to decipher drug interactions with their targets and inform therapy is to employ fluorescence-based screening tools; however, to implement productive screening assays, adequate model systems must be developed. Patient-derived pancreatic cancer models (e.g., cell culture, patient-derived xenograft mouse models, and organoids) have been traditionally utilized to predict personalized therapeutic response. However, cost, long read out times and the inability to fully recapitulate the tumor microenvironment have rendered most models incompatible with clinical decision making for pancreatic ductal adenocarcinoma (PDAC) patients. Tumor explant cultures, where patient tissue can be kept viable for up to weeks, have garnered interest as a platform for delivering personalized therapeutic prediction on a clinically relevant timeline. To fully explore this ex vivo platform, a series of studies were completed to quantitatively compare in vivo models with tumor explants, examining gemcitabine therapeutic efficacy, small molecule uptake and drug-target engagement using a novel fluorescently-labeled gemcitabine conjugate. This initial work shows promise for patient-specific therapeutic selection, where tumor explant drug distribution and response recapitulated the in vivo behavior and could provide a valuable platform for understanding mechanisms of therapeutic response and resistance.
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Affiliation(s)
- Allison Solanki
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Diana King
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Guillaume Thibault
- Center for Spatial Systems Biomedicine, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Lei Wang
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Summer L. Gibbs
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, Oregon, United States of America
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States of America
- Center for Spatial Systems Biomedicine, Oregon Health & Science University, Portland, Oregon, United States of America
- * E-mail:
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Zhao X, Jiang C, Xu R, Liu Q, Liu G, Zhang Y. TRIP6 enhances stemness property of breast cancer cells through activation of Wnt/β-catenin. Cancer Cell Int 2020; 20:51. [PMID: 32082081 PMCID: PMC7023708 DOI: 10.1186/s12935-020-1136-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 02/04/2020] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND The urgent problem in the treatment of breast cancer is the recurrence induced by breast cancer stem cells (CSCs). Understanding the role and molecular mechanism of specific molecules in breast cancer stem cells can provide a theoretical basis for better treatment. TRIP6 is an adapter protein which belongs to the zyxin family of LIM proteins and is important in regulating the functions of CSCs. The present study aims to investigate the effects and mechanism of TRIP6 in breast cancer. METHODS TRIP6 expression in breast cancer cells and tissues were detected by Real-Time PCR, western blot and immunohistochemistry (IHC). MTT assays, colony formation assays, Xenografted tumor model and mammosphere formation assays were performed to investigate the oncogenic functions of TRIP6 in the tumorigenic capability and the tumor-initiating cell-like phenotype of breast cancer cells in vitro and in vivo. Luciferase reporter, subcellular fractionation and immunofluorescence staining assays were performed to determine the underlying mechanism of TRIP6-mediated stemness of breast cancer cells. RESULTS TRIP6 expression was significantly upregulated in breast cancer, and was closely related to the clinicopathologic characteristics, poor overall survival (OS), relapse-free survival (RFS) and poor prognosis of breast cancer patients. Functional studies revealed that overexpression of TRIP6 significantly enhanced proliferative, tumorigenicity capability and the cancer stem cell-like properties of breast cancer in vitro and in vivo. On the contrary, silencing TRIP6 achieved the opposite results. Notably, we found that TRIP6 promoted Wnt/β-catenin signaling pathway in breast cancer to strengthen the tumor-initiating cell-like phenotype of breast cancer cells. CONCLUSIONS This study indicates that TRIP6 plays an important role in maintaining the stem cell-like characteristics of breast cancer cells, supporting the significance of TRIP6 as a novel potential prognostic biomarker and therapeutic target for diagnosis and treatment of breast cancer.
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Affiliation(s)
- Xiaohui Zhao
- GMU-Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, 511436 China
| | - Chao Jiang
- Department of Cancer Center, People’s Hospital of Baoan District, Shenzhen, 518101 China
| | - Rui Xu
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095 China
| | - Qingnan Liu
- GMU-Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, 511436 China
| | - Guanglin Liu
- Novartis Oncology (China) AG, Guangzhou, 510630 China
- The First Affiliation Hospital of Guangzhou Medical University, Guangzhou, 510120 China
| | - Yan Zhang
- Department of Medicine Oncology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655 Guangdong China
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Gupta PK, Dharanivasan G, Misra R, Gupta S, Verma RS. Nanomedicine in Cancer Stem Cell Therapy. Nanobiomedicine (Rij) 2020. [DOI: 10.1007/978-981-32-9898-9_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
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Li F, Dai L, Niu J. GPX2 silencing relieves epithelial-mesenchymal transition, invasion, and metastasis in pancreatic cancer by downregulating Wnt pathway. J Cell Physiol 2019; 235:7780-7790. [PMID: 31774184 DOI: 10.1002/jcp.29391] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 09/27/2019] [Indexed: 12/13/2022]
Abstract
Glutathione peroxidase 2 (GPX2) participates in many cancers including pancreatic cancer (PC), and overexpression of GPX2 promotes tumor growth. Herein, we identified the role of GPX2 in epithelial-mesenchymal transformation (EMT), invasion, and metastasis in PC. Bioinformatics prediction was applied to select PC-related genes. The regulatory function of GPX2 in PC was explored by treatment with short hairpin RNA against GPX2 or LiCl (activator of wingless-type MMTV integration site [Wnt] pathway) in PC cells. GPX2 level in PC tissues, the levels of GPX2, β-catenin, Vimentin, Snail, epithelial-cadherin (E-cadherin), matrix metalloproteinase 2 (MMP2), MMP9, and Wnt2 in cells were determined. Subsequently, cell proliferation, invasion, and metastasis were assayed. Bioinformatics analysis revealed that GPX2 was involved in PC development mediated by the Wnt pathway. GPX2 was highly expressed in PC tissues. GPX2 silencing downregulated levels of β-catenin, Vimentin, Snail, MMP2, MMP9, and Wnt2 but upregulated levels of E-cadherin. It was confirmed that GPX2 silencing suppressed PC cell proliferation, metastasis, and invasion. Furthermore, the trend of EMT and invasion and metastasis of PC induced by the LiCl-activated Wnt pathway was reversed when the GPX2 was silenced. GPX2 silencing could inhibit the Wnt pathway, subsequently suppress PC development.
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Affiliation(s)
- Fuzhou Li
- Department of Imaging, Linyi People's Hospital, Linyi, China
| | - Lan Dai
- Department of Gynaecology and Obstetrics, Chinese Medicine Hospital of Linyi City, Linyi, China
| | - Jixiang Niu
- Department of General Surgery, Linyi People's Hospital, Linyi, China
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Mok L, Kim Y, Lee S, Choi S, Lee S, Jang JY, Park T. HisCoM-PAGE: Hierarchical Structural Component Models for Pathway Analysis of Gene Expression Data. Genes (Basel) 2019; 10:E931. [PMID: 31739607 PMCID: PMC6896173 DOI: 10.3390/genes10110931] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 11/06/2019] [Accepted: 11/07/2019] [Indexed: 01/10/2023] Open
Abstract
Although there have been several analyses for identifying cancer-associated pathways, based on gene expression data, most of these are based on single pathway analyses, and thus do not consider correlations between pathways. In this paper, we propose a hierarchical structural component model for pathway analysis of gene expression data (HisCoM-PAGE), which accounts for the hierarchical structure of genes and pathways, as well as the correlations among pathways. Specifically, HisCoM-PAGE focuses on the survival phenotype and identifies its associated pathways. Moreover, its application to real biological data analysis of pancreatic cancer data demonstrated that HisCoM-PAGE could successfully identify pathways associated with pancreatic cancer prognosis. Simulation studies comparing the performance of HisCoM-PAGE with other competing methods such as Gene Set Enrichment Analysis (GSEA), Global Test, and Wald-type Test showed HisCoM-PAGE to have the highest power to detect causal pathways in most simulation scenarios.
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Affiliation(s)
- Lydia Mok
- Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul 08826, Korea
| | - Yongkang Kim
- Department of Statistics, Seoul National University, Seoul 08826, Korea
| | - Sungyoung Lee
- Center for Precision Medicine, Seoul National University Hospital, Seoul 03080, Korea
| | - Sungkyoung Choi
- Department of Applied Mathematics, Hanyang University (ERICA), Ansan 15588, Korea
| | - Seungyeoun Lee
- Department of Mathematics and Statistics, Sejong University, Seoul 05006, Korea
| | - Jin-Young Jang
- Department of Surgery, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Taesung Park
- Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul 08826, Korea
- Department of Statistics, Seoul National University, Seoul 08826, Korea
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Yu C, Ding Z, Liang H, Zhang B, Chen X. The Roles of TIF1γ in Cancer. Front Oncol 2019; 9:979. [PMID: 31632911 PMCID: PMC6783507 DOI: 10.3389/fonc.2019.00979] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Accepted: 09/13/2019] [Indexed: 12/22/2022] Open
Abstract
Transcriptional intermediary factor 1 γ (TIF1γ), also known as TRIM33, RFG7, PTC7, or Ectodermin, is an E3 ubiquitin-ligase family member with a ring-box-coiled-coil region. It can regulate TGF-β/Smad signaling in two different ways in different cellular contexts. On one hand, TIF1γ can monoubiquitinate Smad4 to inhibit the formation of Smad2/3/4 nuclear complexes. On the other hand, TIF1γ can function as a cofactor of phosphorylated (p)-Smad2/3, competing with Smad4 to inhibit the formation of the Smad2/3/4 complex. In addition, TIF1γ has been reported to play a role in transcription elongation, cellular differentiation, embryonic development, and mitosis. As transforming growth factor-β (TGF-β) superfamily signaling plays an important role in the occurrence and development of cancer, and TIF1γ was reported to be involved in the regulation of TGF-β superfamily signaling, studies on TIF1γ during the last decade have focused on its role in the development of cancer. However, TIF1γ can function either as a tumor suppressor or promoter in different cellular contexts, yet there are few reviews focusing on the roles of TIF1γ in cancer. Hence, in this paper we systematically review and discuss the roles of TIF1γ in cancer. Firstly, we review the biological features, the regulatory mechanisms and the related signaling pathways of TIF1γ. Next, we illustrate the roles of TIF1γ in different tumors. We then provide a tentative hypothesis that explains the dual roles of TIF1 γ in cancer. Finally, we provide our viewpoint regarding the future developments of cancer research focusing on TIF1γ, especially in relation to the effects of TIF1γ on tumoral immunity.
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Affiliation(s)
| | | | | | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Jin C, Song P, Pang J. The CK2 inhibitor CX4945 reverses cisplatin resistance in the A549/DDP human lung adenocarcinoma cell line. Oncol Lett 2019; 18:3845-3856. [PMID: 31579410 DOI: 10.3892/ol.2019.10696] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 06/13/2019] [Indexed: 12/31/2022] Open
Abstract
Lung cancer negatively impacts global health, and the incidence of non-small cell lung cancer (NSCLC) is highest among all forms of lung cancer. Chemotherapy failure mainly occurs due to drug resistance; however, the associated molecular mechanism remains unclear. Casein kinase II (CK2), which plays important roles in the occurrence, development and metastasis of many tumours, regulates Wnt signaling by modulating β-catenin expression. In the present study the effects of the CK2 inhibitor, CX4945 on cisplatin [or cis-diamminedichloroplatinum (II); (DDP)]-resistant A549 cells (A549/DDP) were investigated to elucidate the underlying molecular mechanism. A549/DDP cells were divided into four groups (blank control, CX4945, cisplatin and CX4945+cisplatin). Cisplatin resistance was 5.16-fold greater in A549/DDP cells compared with that in A549 cells, with an optimal cisplatin concentration of 5 µg/ml. Moreover, levels of CK2, dishevelled-2 (DVL-2) phosphorylated (p) at Ser143 (p-DVL-2Ser143), and major Wnt-signaling proteins were significantly higher in A549/DDP cells compared with that in A549 cells (P<0.05), with these levels further increased following cisplatin treatment (P<0.05), whereas these levels significantly decreased in A549 cells after cisplatin treatment (P<0.05). Additionally, multidrug-resistance-associated protein 1 and lung resistance protein expression was significantly higher in A549/DDP cells compared with that in A549 cells (P<0.05), with these levels increasing further in A549/DDP (P<0.05) but not A549 cells upon cisplatin treatment (P>0.05). In addition, reduced expression of resistance proteins in A549/DDP cells was accompanied by a decline in the 50% growth inhibition after CX4945 pre-treatment. Furthermore, levels of p-DVL-2Ser143 and major Wnt-signaling proteins decreased significantly after treatment of A549/DDP cells with CX4945+cisplatin, whereas DVL-2 and p-DVL-2Thr224 levels remained unchanged. Additionally, significant elevations in apoptosis rates in the CX4945+cisplatin group relative to the control and cisplatin-only groups, was observed (P<0.001). These results suggested that inhibiting Wnt/β-catenin signaling with CX4945, which attenuates levels of drug-resistance-associated proteins and induces apoptosis, might reverse cisplatin resistance in NSCLC.
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Affiliation(s)
- Chengji Jin
- Respiratory Department, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China
| | - Ping Song
- Respiratory Department, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China
| | - Ji Pang
- Department of Physiology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
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Prabhakar K, Rodrίguez CI, Jayanthy AS, Mikheil DM, Bhasker AI, Perera RJ, Setaluri V. Role of miR-214 in regulation of β-catenin and the malignant phenotype of melanoma. Mol Carcinog 2019; 58:1974-1984. [PMID: 31338875 DOI: 10.1002/mc.23089] [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: 04/04/2019] [Revised: 07/05/2019] [Accepted: 07/10/2019] [Indexed: 12/15/2022]
Abstract
Wnt/β-catenin signaling plays an important role in melanocyte biology, especially in the early stages of melanocyte transformation and melanomagenesis. β-catenin, encoded by the gene CTNNB1, is an intracellular signal transducer of Wnt signaling and activates transcription of genes important for cell proliferation and survival. Wnt/β-catenin signaling is frequently activated in melanoma through oncogenic mutations of β-catenin and elevated β-catenin levels are positively correlated with melanoma aggressiveness. Molecular mechanisms that regulate β-catenin expression in melanoma are not fully understood. MicroRNA-214 is known to function as a tumor suppressor by targeting β-catenin in several types of cancer cells. Here, we investigated the regulation of β-catenin by miR-214 and its role in melanoma. We show that β-catenin mRNA levels are negatively correlated with miR-214 in melanoma. However, overexpression of miR-214 paradoxically increased β-catenin protein levels and promoted malignant properties of melanoma cells including resistance to mitogen-activated protein kinase inhibitors (MAPKi). RNA-seq analysis revealed that melanoma cells predominantly express a β-catenin mRNA isoform lacking miR-214 target site. Using matched miRNA and mRNA-seq and bioinformatics analysis, we identified novel miR-214 targets, ankyrin repeat domain 6 (ANKRD6) and C-terminal binding protein 1 (CTBP1), that are involved in negative regulation of Wnt signaling. Overexpression of miR-214 or knockdown of the novel miR-214 targets, ANKRD6 or CTBP1, increased melanoma cell proliferation, migration, and decreased sensitivity to MAPKi. Our data suggest that in melanoma cells β-catenin is not regulated by miR-214 and the functions of miR-214 in melanoma are mediated partly by regulating proteins involved in attenuation of Wnt/β-catenin signaling.
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Affiliation(s)
- Kirthana Prabhakar
- Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Carlos I Rodrίguez
- Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Ashika S Jayanthy
- Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Dareen M Mikheil
- Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Aishwarya Iyer Bhasker
- Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Ranjan J Perera
- Sanford-Burham Prebys Medical Discovery Institute, Orlando, Florida
| | - Vijayasaradhi Setaluri
- Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.,William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin
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Bahmad HF, Chamaa F, Assi S, Chalhoub RM, Abou-Antoun T, Abou-Kheir W. Cancer Stem Cells in Neuroblastoma: Expanding the Therapeutic Frontier. Front Mol Neurosci 2019; 12:131. [PMID: 31191243 PMCID: PMC6546065 DOI: 10.3389/fnmol.2019.00131] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 05/07/2019] [Indexed: 12/12/2022] Open
Abstract
Neuroblastoma (NB) is the most common extracranial solid tumor often diagnosed in childhood. Despite intense efforts to develop a successful treatment, current available therapies are still challenged by high rates of resistance, recurrence and progression, most notably in advanced cases and highly malignant tumors. Emerging evidence proposes that this might be due to a subpopulation of cancer stem cells (CSCs) or tumor-initiating cells (TICs) found in the bulk of the tumor. Therefore, the development of more targeted therapy is highly dependent on the identification of the molecular signatures and genetic aberrations characteristic to this subpopulation of cells. This review aims at providing an overview of the key molecular players involved in NB CSCs and focuses on the experimental evidence from NB cell lines, patient-derived xenografts and primary tumors. It also provides some novel approaches of targeting multiple drivers governing the stemness of CSCs to achieve better anti-tumor effects than the currently used therapeutic agents.
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Affiliation(s)
- Hisham F Bahmad
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Farah Chamaa
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Sahar Assi
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Reda M Chalhoub
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Tamara Abou-Antoun
- Department of Pharmaceutical Sciences, School of Pharmacy, Lebanese American University, Byblos, Lebanon
| | - Wassim Abou-Kheir
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
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Viscarra T, Buchegger K, Jofre I, Riquelme I, Zanella L, Abanto M, Parker AC, Piccolo SR, Roa JC, Ili C, Brebi P. Functional and transcriptomic characterization of carboplatin-resistant A2780 ovarian cancer cell line. Biol Res 2019; 52:13. [PMID: 30894224 PMCID: PMC6427839 DOI: 10.1186/s40659-019-0220-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 02/27/2019] [Indexed: 02/07/2023] Open
Abstract
Background Ovarian cancer is a significant cancer-related cause of death in women worldwide. The most used chemotherapeutic regimen is based on carboplatin (CBDCA). However, CBDCA resistance is the main obstacle to a better prognosis. An in vitro drug-resistant cell model would help in the understanding of molecular mechanisms underlying this drug-resistance phenomenon. The aim of this study was to characterize cellular and molecular changes of induced CBDCA-resistant ovarian cancer cell line A2780. Methods The cell selection strategy used in this study was a dose-per-pulse method using a concentration of 100 μM for 2 h. Once 20 cycles of exposure to the drug were completed, the cell cultures showed a resistant phenotype. Then, the ovarian cancer cell line A2780 was grown with 100 μM of CBDCA (CBDCA-resistant cells) or without CBDCA (parental cells). After, a drug sensitivity assay, morphological analyses, cell death assays and a RNA-seq analysis were performed in CBDCA-resistant A2780 cells. Results Microscopy on both parental and CBDCA-resistant A2780 cells showed similar characteristics in morphology and F-actin distribution within cells. In cell-death assays, parental A2780 cells showed a significant increase in phosphatidylserine translocation and caspase-3/7 cleavage compared to CBDCA-resistant A2780 cells (P < 0.05 and P < 0.005, respectively). Cell viability in parental A2780 cells was significantly decreased compared to CBDCA-resistant A2780 cells (P < 0.0005). The RNA-seq analysis showed 156 differentially expressed genes (DEGs) associated mainly to molecular functions. Conclusion CBDCA-resistant A2780 ovarian cancer cells is a reliable model of CBDCA resistance that shows several DEGs involved in molecular functions such as transmembrane activity, protein binding to cell surface receptor and catalytic activity. Also, we found that the Wnt/β-catenin and integrin signaling pathway are the main metabolic pathway dysregulated in CBDCA-resistant A2780 cells. Electronic supplementary material The online version of this article (10.1186/s40659-019-0220-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Tamara Viscarra
- Laboratorio de Patología Molecular, Centro de Excelencia en Medicina Traslacional-Scientific and Technological Bioresource Nucleus (CEMT-BIOREN), Universidad de La Frontera, Avenida Alemania #0478, 3th Floor, Temuco, Chile
| | - Kurt Buchegger
- Laboratorio de Patología Molecular, Centro de Excelencia en Medicina Traslacional-Scientific and Technological Bioresource Nucleus (CEMT-BIOREN), Universidad de La Frontera, Avenida Alemania #0478, 3th Floor, Temuco, Chile
| | - Ignacio Jofre
- Laboratory of Neurosciences and Biological Peptides, Center of Biotechnology in Reproduction (CEBIOR-BIOREN), Department of Preclinical Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco, Chile
| | - Ismael Riquelme
- Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Temuco, Chile
| | - Louise Zanella
- Laboratorio de Patología Molecular, Centro de Excelencia en Medicina Traslacional-Scientific and Technological Bioresource Nucleus (CEMT-BIOREN), Universidad de La Frontera, Avenida Alemania #0478, 3th Floor, Temuco, Chile
| | - Michel Abanto
- Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Casilla 54-D, Temuco, Chile
| | - Alyssa C Parker
- Department of Biology, Brigham Young University, Provo, UT, USA
| | | | - Juan Carlos Roa
- Department of Pathology, UC Centre for Investigational Oncology (CITO), Advanced Centre for Chronic Diseases (ACCDis), The Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago de Chile, Chile
| | - Carmen Ili
- Laboratorio de Patología Molecular, Centro de Excelencia en Medicina Traslacional-Scientific and Technological Bioresource Nucleus (CEMT-BIOREN), Universidad de La Frontera, Avenida Alemania #0478, 3th Floor, Temuco, Chile.
| | - Priscilla Brebi
- Laboratorio de Patología Molecular, Centro de Excelencia en Medicina Traslacional-Scientific and Technological Bioresource Nucleus (CEMT-BIOREN), Universidad de La Frontera, Avenida Alemania #0478, 3th Floor, Temuco, Chile.
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MicroRNA-137 reduces stemness features of pancreatic cancer cells by targeting KLF12. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:126. [PMID: 30866999 PMCID: PMC6416947 DOI: 10.1186/s13046-019-1105-3] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Accepted: 02/13/2019] [Indexed: 02/07/2023]
Abstract
Background Cancer stem cells (CSCs) play an important role in the development of pancreatic cancer. We previously showed that the microRNA miR-137 is downregulated in clinical samples of pancreatic cancer, and its expression negatively regulates the proliferation and invasiveness of pancreatic cancer cells. Methods The stemness features of pancreatic cancer cells was detected by flow cytometry, immunofluorescence and sphere formation assay. Xenograft mouse models were used to assess the role of miR-137 in stemness features of pancreatic cancer cells in vivo. Dual-luciferase reporter assays were used to determine how miR-137 regulates KLF12. Bioinformatics and Chromatin immunoprecipitation analysis of KLF12 recruitment to the DVL2 promoters. Involvement of the Wnt/β-catenin pathways was investigated by western blot and Immunohistochemistry. Results miR-137 inhibits pancreatic cancer cell stemness in vitro and vivo. KLF12 as miR-137 target inhibits CSC phenotype in pancreatic cancer cells. Suppression of KLF12 by miR-137 inhibits Wnt/β-catenin signalling. KLF12 expression correlates with DVL2 and canonical Wnt pathway in clinical pancreatic cancer. Conclusion Our results suggest that miR-137 reduces stemness features of pancreatic cancer cells by Targeting KLF12-associated Wnt/β-catenin pathways and may identify new diagnostic and therapeutic targets in pancreatic cancer. Electronic supplementary material The online version of this article (10.1186/s13046-019-1105-3) contains supplementary material, which is available to authorized users.
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