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Meinag FE, Fatahi M, Vahedian V, Maroufi NF, Mosayyebi B, Ahmadi E, Rahmati M. Modulatory effects of miRNAs in doxorubicin resistance: A mechanistic view. Funct Integr Genomics 2024; 24:150. [PMID: 39222264 DOI: 10.1007/s10142-024-01431-x] [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: 11/26/2023] [Revised: 07/04/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024]
Abstract
MicroRNAs (miRNAs) are a group of small non-coding RNAs and play an important role in controlling vital biological processes, including cell cycle control, apoptosis, metabolism, and development and differentiation, which lead to various diseases such as neurological, metabolic disorders, and cancer. Chemotherapy consider as gold treatment approaches for cancer patients. However, chemotherapeutic is one of the main challenges in cancer management. Doxorubicin (DOX) is an anti-cancer drug that interferes with the growth and spread of cancer cells. DOX is used to treat various types of cancer, including breast, nervous tissue, bladder, stomach, ovary, thyroid, lung, bone, muscle, joint and soft tissue cancers. Also recently, miRNAs have been identified as master regulators of specific genes responsible for the mechanisms that initiate chemical resistance. miRNAs have a regulatory effect on chemotherapy resistance through the regulation of apoptosis process. Also, the effect of miRNAs p53 gene as a key tumor suppressor was confirmed via studies. miRNAs can affect main biological pathways include PI3K pathway. This review aimed to present the current understanding of the mechanisms and effects of miRNAs on apoptosis, p53 and PTEN/PI3K/Akt signaling pathway related to DOX resistance.
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Affiliation(s)
- Fatemeh Ebadi Meinag
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mina Fatahi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahid Vahedian
- Department of Hematology, Transfusion Medicine and Cellular Therapy/Cell Therapy Center (CTC-USP), Clinical Hospital and Cancer Institute (ICESP), Faculty of Medicine, University of Sao Paulo (FMUSP-HC), Sao Paulo, Brazil
- Department of Clinical Medicine, Division of Medical Investigation Laboratory (LIM/31), Pathogenesis and Targeted Therapy in Onco-Immuno-Hematology and Immuno-Oncology, Clinical Hospital, Faculty of Medicine, University of Sao Paulo (FMUSP-HC), Sao Paulo, Brazil
- Comprehensive Center for Translational and Precision Oncology (CTO), SP State Cancer Institute (ICESP), Sao Paulo, Brazil
| | - Nazila Fathi Maroufi
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Bashir Mosayyebi
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elham Ahmadi
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Rahmati
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Yu X, Zhang Y, Luo F, Zhou Q, Zhu L. The role of microRNAs in the gastric cancer tumor microenvironment. Mol Cancer 2024; 23:170. [PMID: 39164671 PMCID: PMC11334576 DOI: 10.1186/s12943-024-02084-x] [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: 06/25/2024] [Accepted: 08/13/2024] [Indexed: 08/22/2024] Open
Abstract
BACKGROUND Gastric cancer (GC) is one of the deadliest malignant tumors with unknown pathogenesis. Due to its treatment resistance, high recurrence rate, and lack of reliable early detection techniques, a majority of patients have a poor prognosis. Therefore, identifying new tumor biomarkers and therapeutic targets is essential. This review aims to provide fresh insights into enhancing the prognosis of patients with GC by summarizing the processes through which microRNAs (miRNAs) regulate the tumor microenvironment (TME) and highlighting their critical role in the TME. MAIN TEXT A comprehensive literature review was conducted by focusing on the interactions among tumor cells, extracellular matrix, blood vessels, cancer-associated fibroblasts, and immune cells within the GC TME. The role of noncoding RNAs, known as miRNAs, in modulating the TME through various signaling pathways, cytokines, growth factors, and exosomes was specifically examined. Tumor formation, metastasis, and therapy in GC are significantly influenced by interactions within the TME. miRNAs regulate tumor progression by modulating these interactions through multiple signaling pathways, cytokines, growth factors, and exosomes. Dysregulation of miRNAs affects critical cellular processes such as cell proliferation, differentiation, angiogenesis, metastasis, and treatment resistance, contributing to the pathogenesis of GC. CONCLUSIONS miRNAs play a crucial role in the regulation of the GC TME, influencing tumor progression and patient prognosis. By understanding the mechanisms through which miRNAs control the TME, potential biomarkers and therapeutic targets can be identified to improve the prognosis of patients with GC.
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Affiliation(s)
- Xianzhe Yu
- Department of Medical Oncology, West China Hospital, Sichuan University, Sichuan Province, Cancer Center, Chengdu, 610041, People's Republic of China
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Sichuan Province, Chengdu, 610041, People's Republic of China
- Department of Gastrointestinal Surgery, Chengdu Second People's Hospital, Sichuan Province, No. 10 Qinyun Nan Street, Chengdu, 610041, People's Republic of China
| | - Yin Zhang
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China
- Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
- Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Fengming Luo
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Qinghua Zhou
- Department of Medical Oncology, West China Hospital, Sichuan University, Sichuan Province, Cancer Center, Chengdu, 610041, People's Republic of China.
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Sichuan Province, Chengdu, 610041, People's Republic of China.
| | - Lingling Zhu
- Department of Medical Oncology, West China Hospital, Sichuan University, Sichuan Province, Cancer Center, Chengdu, 610041, People's Republic of China.
- Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Sichuan Province, Chengdu, 610041, People's Republic of China.
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Mattioli R, Ilari A, Colotti B, Mosca L, Fazi F, Colotti G. Doxorubicin and other anthracyclines in cancers: Activity, chemoresistance and its overcoming. Mol Aspects Med 2023; 93:101205. [PMID: 37515939 DOI: 10.1016/j.mam.2023.101205] [Citation(s) in RCA: 89] [Impact Index Per Article: 44.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 07/15/2023] [Accepted: 07/17/2023] [Indexed: 07/31/2023]
Abstract
Anthracyclines have been important and effective treatments against a number of cancers since their discovery. However, their use in therapy has been complicated by severe side effects and toxicity that occur during or after treatment, including cardiotoxicity. The mode of action of anthracyclines is complex, with several mechanisms proposed. It is possible that their high toxicity is due to the large set of processes involved in anthracycline action. The development of resistance is a major barrier to successful treatment when using anthracyclines. This resistance is based on a series of mechanisms that have been studied and addressed in recent years. This work provides an overview of the anthracyclines used in cancer therapy. It discusses their mechanisms of activity, toxicity, and chemoresistance, as well as the approaches used to improve their activity, decrease their toxicity, and overcome resistance.
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Affiliation(s)
- Roberto Mattioli
- Dept. Biochemical Sciences A. Rossi Fanelli, Sapienza University of Rome, Rome, Italy
| | - Andrea Ilari
- Institute of Molecular Biology and Pathology, Italian National Research Council IBPM-CNR, Rome, Italy
| | - Beatrice Colotti
- Dept. Biochemical Sciences A. Rossi Fanelli, Sapienza University of Rome, Rome, Italy
| | - Luciana Mosca
- Dept. Biochemical Sciences A. Rossi Fanelli, Sapienza University of Rome, Rome, Italy
| | - Francesco Fazi
- Department of Anatomical, Histological, Forensic & Orthopaedic Sciences, Section of Histology and Medical Embryology, Sapienza University of Rome, Rome, Italy
| | - Gianni Colotti
- Institute of Molecular Biology and Pathology, Italian National Research Council IBPM-CNR, Rome, Italy.
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Fathi D, Elballal MS, Elesawy AE, Abulsoud AI, Elshafei A, Elsakka EG, Ismail A, El-Mahdy HA, Elrebehy MA, Doghish AS. An emphasis on the interaction of signaling pathways highlights the role of miRNAs in the etiology and treatment resistance of gastric cancer. Life Sci 2023; 322:121667. [PMID: 37023952 DOI: 10.1016/j.lfs.2023.121667] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/01/2023] [Accepted: 04/03/2023] [Indexed: 04/07/2023]
Abstract
Gastric cancer (GC) is 4th in incidence and mortality rates globally. Several genetic and epigenetic factors, including microRNAs (miRNAs), affect its initiation and progression. miRNAs are short chains of nucleic acids that can regulate several cellular processes by controlling their gene expression. So, dysregulation of miRNAs expressions is associated with GC initiation, progression, invasion capacity, apoptosis evasions, angiogenesis, promotion and EMT enhancement. Of important pathways in GC and controlled by miRNAs are Wnt/β-catenin signaling, HMGA2/mTOR/P-gp, PI3K/AKT/c-Myc, VEGFR and TGFb signaling. Hence, this review was conducted to review an updated view of the role of miRNAs in GC pathogenesis and their modulatory effects on responses to different GC treatment modalities.
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Wei XC, Xia YR, Zhou P, Xue X, Ding S, Liu LJ, Zhu F. Hepatitis B core antigen modulates exosomal miR-135a to target vesicle-associated membrane protein 2 promoting chemoresistance in hepatocellular carcinoma. World J Gastroenterol 2021; 27:8302-8322. [PMID: 35068871 PMCID: PMC8717014 DOI: 10.3748/wjg.v27.i48.8302] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/22/2021] [Accepted: 11/11/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. The association of hepatitis B virus (HBV) infection with HCC is hitherto documented. Exosomal miRNAs contribute to cancer progression and chemoresistance. HBV X protein has been known to modulate miRNAs that facilitate cell proliferation and the process of hepatocarcinogenesis. However, there has been no report on hepatitis B core antigen (HBc) regulating exosomal miRNAs to induce drug resistance of HCC cells. AIM To elucidate the mechanism by which HBc promotes Doxorubicin hydrochloride (Dox) resistance in HCC. METHODS Exosomes were isolated by ultracentrifugation. The morphology and size of exosomes were evaluated by Dynamic Light Scattering (DLS) and transmission electron microscopy (TEM). The miRNAs differentially expressed in HCC were identified using The Cancer Genome Atlas (TCGA) database. The level of miR-135a-5p in patient tissue samples was detected by quantitative polymerase chain reaction. TargetScan and luciferase assay were used to predict and prove the target gene of miR-135a-5p. Finally, we identified the effects of miR-135a-5p on anti-apoptosis and the proliferation of HCC in the presence or absence of Dox using flow cytometry, Cell counting kit 8 (CCK-8) assay and western blot. RESULTS We found that HBc increased the expression of exosomal miR-135a-5p. Integrated analysis of bioinformatics and patient samples found that miR-135a-5p was increased in HCC tissues in comparison with paracancerous tissues. Bioinformatic analysis and in vitro validation identified vesicle-associated membrane protein 2 (VAMP2) as a novel target gene of miR-135a-5p. Functional assays showed that exosomal miR-135a-5p induced apoptosis protection, cell proliferation, and chemotherapy resistance in HCC. In addition, the rescue experiment demonstrated that VAMP2 reversed apoptosis protection, cell growth, and drug resistance by miR-135a-5p. Finally, HBc promoted HCC anti-apoptosis, proliferation, and drug resistance and prevented Dox-induced apoptosis via the miR-135a-5p/VAMP2 axis. CONCLUSION These data suggested that HBc upregulated the expression of exosomal miR-135a-5p and promoted anti-apoptosis, cell proliferation, and chemical resistance through miR-135a-5p/VAMP2. Thus, our work indicated an essential role of the miR-135a-5p/VAMP2 regulatory axis in chemotherapy resistance of HCC and a potential molecular therapeutic target for HCC.
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Affiliation(s)
- Xiao-Cui Wei
- State Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Ya-Ru Xia
- State Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Ping Zhou
- State Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Xing Xue
- State Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Shuang Ding
- State Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Li-Juan Liu
- State Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Fan Zhu
- State Key Laboratory of Virology, Hubei Province Key Laboratory of Allergy and Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
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Liu Y, Ao X, Ji G, Zhang Y, Yu W, Wang J. Mechanisms of Action And Clinical Implications of MicroRNAs in the Drug Resistance of Gastric Cancer. Front Oncol 2021; 11:768918. [PMID: 34912714 PMCID: PMC8667691 DOI: 10.3389/fonc.2021.768918] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/15/2021] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignant tumors of digestive systems worldwide, with high recurrence and mortality. Chemotherapy is still the standard treatment option for GC and can effectively improve the survival and life quality of GC patients. However, with the emergence of drug resistance, the clinical application of chemotherapeutic agents has been seriously restricted in GC patients. Although the mechanisms of drug resistance have been broadly investigated, they are still largely unknown. MicroRNAs (miRNAs) are a large group of small non-coding RNAs (ncRNAs) widely involved in the occurrence and progression of many cancer types, including GC. An increasing amount of evidence suggests that miRNAs may play crucial roles in the development of drug resistance by regulating some drug resistance-related proteins as well as gene expression. Some also exhibit great potential as novel biomarkers for predicting drug response to chemotherapy and therapeutic targets for GC patients. In this review, we systematically summarize recent advances in miRNAs and focus on their molecular mechanisms in the development of drug resistance in GC progression. We also highlight the potential of drug resistance-related miRNAs as biomarkers and therapeutic targets for GC patients.
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Affiliation(s)
- Ying Liu
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China.,School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Xiang Ao
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Guoqiang Ji
- Clinical Laboratory, Linqu People's Hospital, Linqu, China
| | - Yuan Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Wanpeng Yu
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Jianxun Wang
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
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Torki Z, Ghavi D, Hashemi S, Rahmati Y, Rahmanpour D, Pornour M, Alivand MR. The related miRNAs involved in doxorubicin resistance or sensitivity of various cancers: an update. Cancer Chemother Pharmacol 2021; 88:771-793. [PMID: 34510251 DOI: 10.1007/s00280-021-04337-8] [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: 03/16/2021] [Accepted: 07/23/2021] [Indexed: 12/24/2022]
Abstract
Doxorubicin (DOX) is an effective chemotherapy agent against a wide variety of tumors. However, intrinsic or acquired resistance diminishes the sensitivity of cancer cells to DOX, which leads to a cancer relapse and treatment failure. Resolutions to this challenge includes identification of the molecular pathways underlying DOX sensitivity/resistance and the development of innovative techniques to boost DOX sensitivity. DOX is classified as a Topoisomerase II poison, which is cytotoxic to rapidly dividing tumor cells. Molecular mechanisms responsible for DOX resistance include effective DNA repair and resumption of cell proliferation, deregulated development of cancer stem cell and epithelial to mesenchymal transition, and modulation of programmed cell death. MicroRNAs (miRNAs) have been shown to potentiate the reversal of DOX resistance as they have gene-specific regulatory functions in DOX-responsive molecular pathways. Identifying the dysregulation patterns of miRNAs for specific tumors following treatment with DOX facilitates the development of novel combination therapies, such as nanoparticles harboring miRNA or miRNA inhibitors to eventually prevent DOX-induced chemoresistance. In this article, we summarize recent findings on the role of miRNAs underlying DOX sensitivity/resistance molecular pathways. Also, we provide latest strategies for utilizing deregulated miRNA patterns as biomarkers or miRNAs as tools to overcome chemoresistance and enhance patient's response to DOX treatment.
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Affiliation(s)
- Zahra Torki
- Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Davood Ghavi
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Solmaz Hashemi
- Department of Surgery, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yazdan Rahmati
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Dara Rahmanpour
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Pornour
- Department of Photo Healing and Regeneration, Medical Laser Research Center, Yara Institute, Academic Center for Education, Culture, and Research (ACECR), Tehran, Iran.
| | - Mohammad Reza Alivand
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Non-coding RNAs underlying chemoresistance in gastric cancer. Cell Oncol (Dordr) 2020; 43:961-988. [PMID: 32495294 DOI: 10.1007/s13402-020-00528-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 04/17/2020] [Accepted: 04/24/2020] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Gastric cancer (GC) is a major health issue in the Western world. Current clinical imperatives for this disease include the identification of more effective biomarkers to detect GC at early stages and enhance the prevention and treatment of metastatic and chemoresistant GC. The advent of non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs) and long-non coding RNAs (lncRNAs), has led to a better understanding of the mechanisms by which GC cells acquire features of therapy resistance. ncRNAs play critical roles in normal physiology, but their dysregulation has been detected in a variety of cancers, including GC. A subset of ncRNAs is GC-specific, implying their potential application as biomarkers and/or therapeutic targets. Hence, evaluating the specific functions of ncRNAs will help to expand novel treatment options for GC. CONCLUSIONS In this review, we summarize some of the well-known ncRNAs that play a role in the development and progression of GC. We also review the application of such ncRNAs in clinical diagnostics and trials as potential biomarkers. Obviously, a deeper understanding of the biology and function of ncRNAs underlying chemoresistance can broaden horizons toward the development of personalized therapy against GC.
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Ghafouri-Fard S, Vafaee R, Shoorei H, Taheri M. MicroRNAs in gastric cancer: Biomarkers and therapeutic targets. Gene 2020; 757:144937. [PMID: 32640300 DOI: 10.1016/j.gene.2020.144937] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 06/09/2020] [Accepted: 07/01/2020] [Indexed: 02/07/2023]
Abstract
MicroRNAs (miRNAs) are a group of non-coding RNAs that have critical roles in regulation of expression of genes. They can inhibit or decrease expression of target genes mostly via interaction with 3' untranslated region of their targets. Their crucial roles in the regulation of expression of tumor suppressor genes and oncogenes have potentiated them as contributors in tumorigenesis. Moreover, their stability in body fluids has enhanced their potential as cancer biomarkers. In the present review article, we describe the role of miRNAs in the pathogenesis of gastric cancer and advances in application of miRNAs as biomarkers and therapeutic targets in this kind of malignancy.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reza Vafaee
- Proteomics Research Center, Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Shoorei
- Department of Anatomical Sciences, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Mohammad Taheri
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Wei L, Sun J, Zhang N, Zheng Y, Wang X, Lv L, Liu J, Xu Y, Shen Y, Yang M. Noncoding RNAs in gastric cancer: implications for drug resistance. Mol Cancer 2020; 19:62. [PMID: 32192494 PMCID: PMC7081551 DOI: 10.1186/s12943-020-01185-7] [Citation(s) in RCA: 331] [Impact Index Per Article: 66.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Accepted: 03/12/2020] [Indexed: 12/18/2022] Open
Abstract
Gastric cancer is the fourth most common malignancy and the third leading cause of cancer-related deaths worldwide. Advanced gastric cancer patients can notably benefit from chemotherapy including adriamycin, platinum drugs, 5-fluorouracil, vincristine, and paclitaxel as well as targeted therapy drugs. Nevertheless, primary drug resistance or acquisition drug resistance eventually lead to treatment failure and poor outcomes of the gastric cancer patients. The detailed mechanisms involved in gastric cancer drug resistance have been revealed. Interestingly, different noncoding RNAs (ncRNAs), such as microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), are critically involved in gastric cancer development. Multiple lines of evidences demonstrated that ncRNAs play a vital role in gastric cancer resistance to chemotherapy reagents and targeted therapy drugs. In this review, we systematically summarized the emerging role and detailed molecular mechanisms of ncRNAs impact drug resistance of gastric cancer. Additionally, we propose the potential clinical implications of ncRNAs as novel therapeutic targets and prognostic biomarkers for gastric cancer.
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Affiliation(s)
- Ling Wei
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Jujie Sun
- Department of Pathology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Nasha Zhang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Yan Zheng
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Xingwu Wang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Liyan Lv
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Jiandong Liu
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Yeyang Xu
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Yue Shen
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China
| | - Ming Yang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong Province, China.
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Luo YJ, Huang QM, Ren Y, Liu ZL, Xu CF, Wang H, Xiao JW. Non-coding RNA in drug resistance of gastric cancer. World J Gastrointest Oncol 2019; 11:957-970. [PMID: 31798777 PMCID: PMC6883183 DOI: 10.4251/wjgo.v11.i11.957] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 09/21/2019] [Accepted: 10/03/2019] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer (GC) is the third leading cause of cancer-related mortality worldwide. The poorly prognosis and survival of GC are due to diagnose in an advanced, non-curable stage and with a limited response to chemotherapy. The acquisition of drug resistance accounts for the majority of therapy failure of chemotherapy in GC patients. Although the mechanisms of anticancer drug resistance have been broadly studied, the regulation of these mechanisms has not been completely understood. Accumulating evidence has recently highlighted the role of non-coding RNAs (ncRNAs), including long non-coding RNAs and microRNAs, in the development and maintenance of drug resistance due to their regulatory features in specific genes involved in the chemoresistant phenotype of GC. We review the literature on ncRNAs in drug resistance of GC. This review summarizes the current knowledge about the ncRNAs’ characteristics, their regulation of the genes involved in chemoresistance and their potential as targeted therapies for personalized treatment in resistant GC.
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Affiliation(s)
- Ya-Jun Luo
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China
| | - Qing-Mei Huang
- Department of Oncology, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Yan Ren
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Zi-Lin Liu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Cheng-Fei Xu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Hao Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Jiang-Wei Xiao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
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12
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Chen C, Tang X, Liu Y, Zhu J, Liu J. Induction/reversal of drug resistance in gastric cancer by non-coding RNAs (Review). Int J Oncol 2019; 54:1511-1524. [PMID: 30896792 PMCID: PMC6438417 DOI: 10.3892/ijo.2019.4751] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 02/21/2019] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer (GC) is one of the most prevalent and malignant types of cancer worldwide. In China, it is the second most common type of cancer and the malignancy with the highest incidence and mortality rate. Chemotherapy for GC is not always effective due to the development of drug resistance. Drug resistance, which is frequently observed in GC, undermines the success rate of chemotherapy and the survival of patients with GC. The dysregulation of non‑coding RNAs (ncRNAs), primarily microRNAs (miRNAs or miRs) and long non‑coding RNAs (lncRNAs), is involved in the development of GC drug resistance via numerous mechanisms. These mechanisms contribute to the involvement of a large and complex network of ncRNAs in drug resistance. In this review, we focus on and summarize the latest research on the specific mechanisms of action of miRNAs and lncRNAs that modulate drug resistance in GC. In addition, we discuss future prospects and clinical applications of ncRNAs as potential targeted therapies against the chemoresistance of GC.
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Affiliation(s)
- Chao Chen
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Xiaohuan Tang
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Yuanda Liu
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Jiaming Zhu
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Jingjing Liu
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
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13
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Zhao X, Sun Z, Li H, Jiang F, Zhou J, Zhang L. MiR-135a-5p modulates biological functions of thyroid carcinoma cells via targeting VCAN 3'-UTR. Cancer Biomark 2018; 20:207-216. [PMID: 28869452 DOI: 10.3233/cbm-170566] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Thyroid carcinoma is one of the most frequent malignant tumors of the endocrine system, which accounts for nearly 1% population in newly diagnosed carcinoma worldwide and the incidence has an increasing tendency in recent years. To explore whether miR-135a-5p could affect the proliferation, invasion and migration of thyroid carcinoma cells by targeting VCAN. The expression levels of miR-135a-5p and VCAN were detected in human thyroid carcinoma tissues and cells, para-carcinoma tissues, as well as human normal thyroid cells using RT-qPCR and Western blot. In addition, dual-luciferase reporter gene assay, MTT assay, colony formation assay, wound healing assay, Transwell assay, flow cytometry analysis and in vivo tumorigenesis assay were also conducted. The results demonstrated that miR-135a-5p was down-regulated while VCAN was up-regulated both in thyroid carcinoma tissues and cells. Furthermore, the up-regulation of miR-135a-5p inhibited cell proliferation, invasion and migration of thyroid carcinoma. Dual-luciferase reporter gene assay provided evidence indicating that miR-135a-5p targeted VCAN in thyroid carcinoma. MiR-135a-5p could inhibit cell proliferation, invasion and migration of thyroid carcinoma by targeting VCAN. MiR-135a-5p and VCAN might emerge as a target for the treatment of thyroid carcinoma.
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Affiliation(s)
- Xue Zhao
- Department of Laboratory Medicine, People's Hospital of Weifang, Weifang 266001, Shandong, China
| | - Zhigui Sun
- Department of Internal Medicine, People's Hospital of Rizhao, Rizhao 276800, Shandong, China
| | - Hui Li
- Department of Internal Medicine, People's Hospital of Zhangqiu, Zhangqiu 250200, Shandong, China
| | - Feng Jiang
- Department of Imaging, People's Hospital of Zhangqiu, Zhangqiu 250200, Shandong, China
| | - Jing Zhou
- Department of Oncological Radiotherapy, The Affiliated Hospital of Qingdao University, Qingdao 266071, Shandong, China
| | - Linghua Zhang
- Department of Emergency Surgery, Qingdao Hiser Medical Center, Qingdao 266001, Shandong, China
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14
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Parks JC, McCallie BR, Patton AL, Al-Safi ZA, Polotsky AJ, Griffin DK, Schoolcraft WB, Katz-Jaffe MG. The impact of infertility diagnosis on embryo-endometrial dialogue. Reproduction 2018; 155:543-552. [PMID: 29636406 DOI: 10.1530/rep-17-0566] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Accepted: 04/10/2018] [Indexed: 12/24/2022]
Abstract
Initial stages of implantation involve bi-directional molecular crosstalk between the blastocyst and endometrium. This study investigated an association between infertility etiologies, specifically advanced maternal age (AMA) and endometriosis, on the embryo-endometrial molecular dialogue prior to implantation. Co-culture experiments were performed with endometrial epithelial cells (EEC) and cryopreserved day 5 blastocysts (n = 41 ≥ Grade 3BB) donated from patients presenting with AMA or endometriosis, compared to fertile donor oocyte controls. Extracellular vesicles isolated from co-culture supernatant were analyzed for miRNA expression and revealed significant alterations correlating to AMA or endometriosis. Specifically, AMA resulted in 16 miRNAs with increased expression (P ≤ 0.05) and strong evidence for negative regulation toward 206 target genes. VEGFA, a known activator of cell adhesion, displayed decreased expression (P ≤ 0.05), validating negative regulation by 4 of these increased miRNAs: miR-126; 150; 29a; 29b (P ≤ 0.05). In endometriosis patients, a total of 10 significantly altered miRNAs displayed increased expression compared to controls (miR-7b; 9; 24; 34b; 106a; 191; 200b; 200c; 342-3p; 484) (P ≤ 0.05), targeting 1014 strong evidence-based genes. Three target genes of miR-106a (CDKN1A, E2F1 and RUNX1) were independently validated. Functional annotation analysis of miRNA-target genes revealed enriched pathways for both infertility etiologies, including disrupted cell cycle regulation and proliferation (P ≤ 0.05). These extracellular vesicle-bound secreted miRNAs are key transcriptional regulators in embryo-endometrial dialogue and may be prospective biomarkers of implantation success. One of the limitations of this study is that it was a stimulated, in vitro model and therefore may not accurately reflect the in-vivo environment.
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Affiliation(s)
- Jason C Parks
- Colorado Center for Reproductive MedicineLone Tree, Colorado, USA .,University of KentCanterbury, UK
| | - Blair R McCallie
- Colorado Center for Reproductive MedicineLone Tree, Colorado, USA.,University of KentCanterbury, UK
| | - Alyssa L Patton
- Colorado Center for Reproductive MedicineLone Tree, Colorado, USA
| | - Zain A Al-Safi
- Department of Obstetrics and GynecologyUniversity of Colorado School of Medicine, Aurora, Colorado, USA
| | - Alex J Polotsky
- Department of Obstetrics and GynecologyUniversity of Colorado School of Medicine, Aurora, Colorado, USA
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Yang W, Ma J, Zhou W, Cao B, Zhou X, Yang Z, Zhang H, Zhao Q, Fan D, Hong L. Molecular mechanisms and theranostic potential of miRNAs in drug resistance of gastric cancer. Expert Opin Ther Targets 2017; 21:1063-1075. [PMID: 28994330 DOI: 10.1080/14728222.2017.1389900] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Systemic chemotherapy is a curative approach to inhibit gastric cancer cells proliferation. Despite the great progress in anti-cancer treatment achieved during the last decades, drug resistance and treatment refractoriness still extensively persists. Recently, accumulating studies have highlighted the role of miRNAs in drug resistance of gastric cancers by modulating some drug resistance-related proteins and genes expression. Pre-clinical reports indicate that miRNAs might serve as ideal biomarkers and potential targets, thus holding great promise for developing targeted therapy and personalized treatment for the patients with gastric cancer. Areas covered: This review provide a comprehensive overview of the current advances of miRNAs and molecular mechanisms underlying miRNA-mediated drug resistance in gastric cancer. We particularly focus on the potential values of drug resistance-related miRNAs as biomarkers and novel targets in gastric cancer therapy and envisage the future research developments of these miRNAs and challenges in translating the new findings into clinical applications. Expert opinion: Although the concrete mechanisms of miRNAs in drug resistance of gastric cancer have not been fully clarified, miRNA may be a promising theranostic approach. Further studies are still needed to facilitate the clinical applications of miRNAs in drug resistant gastric cancer.
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Affiliation(s)
- Wanli Yang
- a State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases , Fourth Military Medical University , Xi'an , China
| | - Jiaojiao Ma
- a State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases , Fourth Military Medical University , Xi'an , China
| | - Wei Zhou
- a State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases , Fourth Military Medical University , Xi'an , China
| | - Bo Cao
- b The First Brigade of Student , Fourth Military Medical University , Xi'an , China
| | - Xin Zhou
- b The First Brigade of Student , Fourth Military Medical University , Xi'an , China
| | - Zhiping Yang
- a State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases , Fourth Military Medical University , Xi'an , China
| | - Hongwei Zhang
- c Department of Digestive Surgery, Xijing Hospital , Fourth Military Medical University , Xi'an , China
| | - Qingchuan Zhao
- c Department of Digestive Surgery, Xijing Hospital , Fourth Military Medical University , Xi'an , China
| | | | - Liu Hong
- a State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases , Fourth Military Medical University , Xi'an , China
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Chakraborty C, Doss CGP, Sarin R, Hsu MJ, Agoramoorthy G. Can the chemotherapeutic agents perform anticancer activity through miRNA expression regulation? Proposing a new hypothesis [corrected]. PROTOPLASMA 2015; 252:1603-1610. [PMID: 25698235 DOI: 10.1007/s00709-015-0776-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Accepted: 02/03/2015] [Indexed: 06/04/2023]
Abstract
In the recent advancement of cancer therapy, mortality of the immortal cancer cells begins to decline, and it shows great promise for the chemotherapy regimen supported by targeted therapy. In this post-genomic era boosted by the discovery of microRNA (miRNA), it has been understood that miRNA regulates gene expression at the post-transcriptional level. On the other hand, some studies have also indicated that miRNA expression level has changed during the treatment of chemotherapy. Data based on various previous studies, we propose that the chemotherapeutic agents modulate miRNA expression that might perform anticancerous activities through cellular changes such as DNA repair, cell cycle arrest, or apoptosis.
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Affiliation(s)
- Chiranjib Chakraborty
- Department of Bio-informatics, School of Computer and Information Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India.
| | - C George Priya Doss
- Medical Biotechnology Division, School of Biosciences and Technology, VIT University, Vellore, India
| | - Renu Sarin
- Department of Chemistry, Galgotias College of Engineering and Technology, Greater Noida, Uttar Pradesh, India
| | - Minna J Hsu
- Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
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Yang Q, Zhang RW, Sui PC, He HT, Ding L. Dysregulation of non-coding RNAs in gastric cancer. World J Gastroenterol 2015; 21:10956-10981. [PMID: 26494954 PMCID: PMC4607897 DOI: 10.3748/wjg.v21.i39.10956] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Revised: 08/28/2015] [Accepted: 09/15/2015] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer (GC) is one of the most common cancers in the world and a significant threat to the health of patients, especially those from China and Japan. The prognosis for patients with late stage GC receiving the standard of care treatment, including surgery, chemotherapy and radiotherapy, remains poor. Developing novel treatment strategies, identifying new molecules for targeted therapy, and devising screening techniques to detect this cancer in its early stages are needed for GC patients. The discovery of non-coding RNAs (ncRNAs), primarily microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), helped to elucidate the mechanisms of tumorigenesis, diagnosis and treatment of GC. Recently, significant research has been conducted on non-coding RNAs and how the regulatory dysfunction of these RNAs impacts the tumorigenesis of GC. In this study, we review papers published in the last five years concerning the dysregulation of non-coding RNAs, especially miRNAs and lncRNAs, in GC. We summarize instances of aberrant expression of the ncRNAs in GC and their effect on survival-related events, including cell cycle regulation, AKT signaling, apoptosis and drug resistance. Additionally, we evaluate how ncRNA dysregulation affects the metastatic process, including the epithelial-mesenchymal transition, stem cells, transcription factor activity, and oncogene and tumor suppressor expression. Lastly, we determine how ncRNAs affect angiogenesis in the microenvironment of GC. We further discuss the use of ncRNAs as potential biomarkers for use in clinical screening, early diagnosis and prognosis of GC. At present, no ideal ncRNAs have been identified as targets for the treatment of GC.
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Ou Y, Zhai D, Wu N, Li X. Downregulation of miR-363 increases drug resistance in cisplatin-treated HepG2 by dysregulating Mcl-1. Gene 2015; 572:116-122. [PMID: 26143754 DOI: 10.1016/j.gene.2015.07.002] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2014] [Revised: 05/05/2015] [Accepted: 07/01/2015] [Indexed: 12/21/2022]
Abstract
Systemic therapy with cytotoxic agents provides marginal benefit in hepatocellular carcinoma (HCC) treatment especially for patients with advanced HCC. Cisplatin is one of the most active cytotoxic agents for HCC treatment. However, acquisition of cisplatin resistance is common, and one important underlying mechanism of such resistance is apoptosis-resistance. In this study, we found that miR-363 levels were significantly decreased in HCC patients treated with cisplatin-based chemotherapy. MiR-363 levels were also lower in cisplatin-resistant HepG2 (HepG2-R) cells than in HepG2 cells. Exogenous miR-363 significantly overcame cisplatin resistance in HepG2-R cells, whereas miR-363 knockdown increased the cell viability during cisplatin treatment. We further demonstrated that miR-363 directly targeted to Mcl-1 3'-UTR (3'-Untranslated Regions). Downregulation of miR-363 resulted in upregulation of Mcl-1 which is a key member of anti-apoptotic Bcl-2 family and increased drug resistance. We finally demonstrated that miR-363 decreased cisplatin resistance of HCC cell, partly by targeting Mcl-1. These data suggest that the combination of miR-363 and cisplatin may represent a novel approach in treatment for HCC, thus offering a new target for chemotherapy of HCC.
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Affiliation(s)
- Yangyang Ou
- Xiangya Hospital of Central-South University, Changsha, Hunan 410008, PR China
| | - Denggao Zhai
- Xiangya Hospital of Central-South University, Changsha, Hunan 410008, PR China
| | - Nan Wu
- Xiangya Hospital of Central-South University, Changsha, Hunan 410008, PR China
| | - Xiaoli Li
- Xiangya Hospital of Central-South University, Changsha, Hunan 410008, PR China.
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