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1
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Liu H, Wang L. MicroRNA-34a negatively regulates Netrin1 and mediates MEK/ERK pathway to regulate chemosensitivity of gastric cancer cells. Discov Oncol 2024; 15:563. [PMID: 39404782 PMCID: PMC11480279 DOI: 10.1007/s12672-024-01451-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 10/11/2024] [Indexed: 10/19/2024] Open
Abstract
OBJECTIVE To explore the mechanism of action of MicroRNAs-34a (miR-34a) and Eurite growth guiding factor 1 (Netrin1) in cisplatin resistance in gastric cancer (GC), providing new clues for overcoming tumor resistance and optimizing anti-tumor therapy for GC. METHODS The Cancer Genome Atlas (TCGA), Differentially Expressed MicroRNAs (miRNAs) in human cancers (dbDEMC), and Starbase online databases were used to analyze the correlation between miR-34a and Netrin-1 and prognosis in GC, and to predict and verify the targeted binding of miR-34a to Netrin-1. The experimental methods including Cell transfection, real-time polymerase chain reaction (RT-PCR), Cell-Counting-Kit-8 (CCK8) assay, flow cytometry, wound scratch assay, transwell assay, and western blotting were used to investigate the effects of miR-34a and Netrin1 on chemotherapy resistance and biological characteristics in cisplatin-resistant GC cells (HGC27/DDP), and to analyze the molecular mechanism of cisplatin resistance. RESULTS miR-34a expression was downregulated in gastric cancer clinical samples and cisplatin-resistant cells, while Netrin1 was upregulated, and was related to overall survival (OS). Upregulation of miR-34a can significantly reduce the IC50 value of cisplatin(0.65 vs 1.6 ng/mL) and Multidrug Resistance 1 (MDR-1) protein level, inhibit the proliferation activity, reduce the expression levels of proliferating cell nuclear antigen (PCNA) and ki-67 protein, and induce the increase of apoptosis rate and the enhancement of cycle arrest. Upregulation of miR-34a can also significantly reduce the expression level of Matrix metalloproteinase 9 (MMP9) protein, promote the expression of E-cadherin protein, reduce the wound healing rate and invasion number to inhibit migration and invasion ability in drug-resistant gastric cancer cells. Moreover, overexpression of Netrin1 on the basis of upregulation of miR-34a can weaken the above changes caused by upregulation of miR-34a. In addition, upregulation of miR-34a can significantly inhibit the Mitogen-activated protein kinase kinase (MEK) / Extracellular regulated protein kinases (ERK) pathway, while overexpression of Netrin1 can activate the MEK/ERK pathway, and inhibition of MEK/ERK pathway can effectively counteract the protein expression of Netrin1, and reverse changes in the expression of cisplatin IC50 and MDR-1 proteins caused by co-upregulation of miR-34a/Netrin1 in HGC27/DDP, as well as changes in proliferation, apoptosis, migration and invasion. In addition, upregulation of miR-34a can significantly inhibit the MEK/ERK pathway, while overexpression of Netrin1 can activate the MEK/ERK pathway. If the MEK/ERK pathway was inhibited, it can effectively counteract the protein overexpression of Netrin1, and reverse the changes in the expression of cisplatin IC50 and MDR-1 proteins in HGC27/DDP induced by co-upregulation of miR-34a / Netrin1, as well as changes in proliferation, apoptosis, migration and invasion. CONCLUSION miR-34a targets and negatively regulates Netrin1 to mediate the proliferation, apoptosis, apoptosis, migration, and invasion of drug-resistant gastric cancer cells via the MEK/ERK pathway, and change the chemosensitivity in GC cells. miR-34a/Netrin1/MEK/ERK axis may serve as a novel therapeutic target for chemoresistance in GC, it is of great significance for overcoming drug resistance and developing new therapeutic strategies for GC.
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Affiliation(s)
- Haiping Liu
- Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi University, 348 Dexiang Street, Xiangyang District, Jiamusi City, 154000, Heilongjiang Province, People's Republic of China
| | - Limin Wang
- Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi University, 348 Dexiang Street, Xiangyang District, Jiamusi City, 154000, Heilongjiang Province, People's Republic of China.
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2
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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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3
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Gao W, Zhou J, Morshedi M. MicroRNA-34 and gastrointestinal cancers: a player with big functions. Cancer Cell Int 2024; 24:163. [PMID: 38725047 PMCID: PMC11084024 DOI: 10.1186/s12935-024-03338-w] [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: 09/16/2023] [Accepted: 04/18/2024] [Indexed: 05/12/2024] Open
Abstract
It is commonly assumed that gastrointestinal cancer is the most common form of cancer across the globe and is the leading contributor to cancer-related death. The intricate mechanisms underlying the growth of GI cancers have been identified. It is worth mentioning that both non-coding RNAs (ncRNAs) and certain types of RNA, such as circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and microRNAs (miRNAs), can have considerable impact on the development of gastrointestinal (GI) cancers. As a tumour suppressor, in the group of short non-coding regulatory RNAs is miR-34a. miR-34a silences multiple proto-oncogenes at the post-transcriptional stage by targeting them, which inhibits all physiologically relevant cell proliferation pathways. However, it has been discovered that deregulation of miR-34a plays important roles in the growth of tumors and the development of cancer, including invasion, metastasis, and the tumor-associated epithelial-mesenchymal transition (EMT). Further understanding of miR-34a's molecular pathways in cancer is also necessary for the development of precise diagnoses and effective treatments. We outlined the most recent research on miR-34a functions in GI cancers in this review. Additionally, we emphasize the significance of exosomal miR-34 in gastrointestinal cancers.
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Affiliation(s)
- Wei Gao
- Department of Gastrointestinal and Hernia and Abdominal Wall Surgery, The First Hospital, China Medical University, Shenyang, 110001, China
| | - Jianping Zhou
- Department of Gastrointestinal and Hernia and Abdominal Wall Surgery, The First Hospital, China Medical University, Shenyang, 110001, China.
| | - Mohammadamin Morshedi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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Liu C, Li S, Tang Y. Mechanism of cisplatin resistance in gastric cancer and associated microRNAs. Cancer Chemother Pharmacol 2023; 92:329-340. [PMID: 37535106 DOI: 10.1007/s00280-023-04572-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 07/27/2023] [Indexed: 08/04/2023]
Abstract
Gastric cancer (GC) is a common malignant tumor with high morbidity and mortality rates that seriously affects human health worldwide. Although surgery is currently the preferred clinical treatment for GC, chemotherapy remains the first choice for perioperative treatment, adjuvant therapy, and palliative care for patients with advanced GC. Cisplatin (DDP) is an antineoplastic agent that has been used clinically for decades, and it is the first-line chemotherapy for many solid tumors. However, the therapeutic efficacy of DDP is often limited by resistance and the complexity of its resistance mechanisms, which involve multiple proteins and signaling pathways. It is well documented that a variety of microRNAs (miRNAs) differentially expressed in DDP-resistant GC cells play important roles in regulating or reversing DDP resistance via various pathways. In this review, we first provide an introduction to the cytotoxicity and major resistance mechanisms of DDP in GC and then discuss the role and mechanism of miRNAs in regulating the DDP resistance process in GC cells. This work demonstrates the potential of relevant miRNAs to become diagnostic and prognostic biomarkers for gastric cancer and targets of action to enhance chemosensitivity and provides directions for future research.
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Affiliation(s)
- Changqing Liu
- Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Cancer Research Institute of Hengyang Medical School, University of South China, 28 Changsheng Road, Hengyang, 421001, Hunan Province, People's Republic of China
| | - Shan Li
- Department of Pathology, People's Hospital of Shaoyang County, Hengyang, Hunan Province, People's Republic of China
| | - Yunlian Tang
- Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Cancer Research Institute of Hengyang Medical School, University of South China, 28 Changsheng Road, Hengyang, 421001, Hunan Province, People's Republic of China.
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5
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Yue Y, Lin X, Qiu X, Yang L, Wang R. The Molecular Roles and Clinical Implications of Non-Coding RNAs in Gastric Cancer. Front Cell Dev Biol 2021; 9:802745. [PMID: 34966746 PMCID: PMC8711095 DOI: 10.3389/fcell.2021.802745] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 11/29/2021] [Indexed: 01/19/2023] Open
Abstract
Gastric cancer (GC) is one of the most common malignancies in the world. It is also the fifth most common cancer in China. In recent years, a large number of studies have proved that non-coding RNAs (ncRNAs) can regulate cell proliferation, invasion, metastasis, apoptosis, and angiogenesis. NcRNAs also influence the therapeutic resistance of gastric cancer. NcRNAs mainly consist of miRNAs, lncRNAs and circRNAs. In this paper, we summarized ncRNAs as biomarkers and therapeutic targets for gastric cancer, and also reviewed their role in clinical trials and diagnosis. We sum up different ncRNAs and related moleculars and signaling pathway in gastric cancer, like Bcl-2, PTEN, Wnt signaling. In addition, the potential clinical application of ncRNAs in overcoming chemotherapy and radiotherapy resistance in GC in the future were also focused on.
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Affiliation(s)
- Yanping Yue
- Department of Medical Oncology, Affiliated Cancer Hospital, Nantong University, Nantong, China
| | - Xinrong Lin
- Department of Medical Oncology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Xinyue Qiu
- Department of Medical Oncology, Affiliated Cancer Hospital, Nantong University, Nantong, China
| | - Lei Yang
- Department of Medical Oncology, Affiliated Cancer Hospital, Nantong University, Nantong, China
| | - Rui Wang
- Department of Medical Oncology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China
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6
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Dashti F, Mirazimi SMA, Rabiei N, Fathazam R, Rabiei N, Piroozmand H, Vosough M, Rahimian N, Hamblin MR, Mirzaei H. The role of non-coding RNAs in chemotherapy for gastrointestinal cancers. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 26:892-926. [PMID: 34760336 PMCID: PMC8551789 DOI: 10.1016/j.omtn.2021.10.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gastrointestinal (GI) cancers, including colorectal, gastric, hepatic, esophageal, and pancreatic tumors, are responsible for large numbers of deaths around the world. Chemotherapy is the most common approach used to treat advanced GI cancer. However, chemoresistance has emerged as a critical challenge that prevents successful tumor elimination, leading to metastasis and recurrence. Chemoresistance mechanisms are complex, and many factors and pathways are involved. Among these factors, non-coding RNAs (ncRNAs) are critical regulators of GI tumor development and subsequently can induce resistance to chemotherapy. This occurs because ncRNAs can target multiple signaling pathways, affect downstream genes, and modulate proliferation, apoptosis, tumor cell migration, and autophagy. ncRNAs can also induce cancer stem cell features and affect the epithelial-mesenchymal transition. Thus, ncRNAs could possibly act as new targets in chemotherapy combinations to treat GI cancer and to predict treatment response.
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Affiliation(s)
- Fatemeh Dashti
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Seyed Mohammad Ali Mirazimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Nikta Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Fathazam
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negin Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Haleh Piroozmand
- Faculty of Veterinary Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
- Radiation Biology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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7
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Hussein RM, Al-Dalain SM. Betaine downregulates microRNA 34a expression via a p53-dependent manner in cisplatin-induced nephrotoxicity in rats. J Biochem Mol Toxicol 2021; 35:e22856. [PMID: 34318554 DOI: 10.1002/jbt.22856] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 05/25/2021] [Accepted: 07/14/2021] [Indexed: 01/20/2023]
Abstract
Cisplatin-induced nephrotoxicity limits its wide application as a chemotherapeutic drug. Betaine is a natural trimethylglycine compound involved in several biological reactions. In this study, the protective effect of betaine against cisplatin-induced nephrotoxicity through modulating the expression of microRNA 34a (miRNA 34a), p53, apoptosis, and inflammation was investigated. Adult Wistar rats were divided into normal group (received vehicle); betaine group (received 250 mg betaine/kg BW/day via oral gavage from Day 1 to Day 25); cisplatin group (received a single intraperitoneal dose of cisplatin at 5 mg/kg BW on Day 21) and betaine + cisplatin group (received the same doses of betaine and cisplatin). The results demonstrated that the cisplatin group exhibited severe kidney tissue damage and an increase in blood creatinine and urea levels. Furthermore, the cisplatin group showed a significant upregulation of miRNA 34a and higher levels of phospho-p53, caspase 3, cytochrome c, NFk B, and IL-1β compared to the normal group. Remarkably, the betaine + cisplatin group showed significantly decreased blood creatinine and urea concentrations, decreased levels of miRNA 34a, phospho-p53, caspase 3, cytochrome c, NFk B, and IL-1β as well as improved kidney tissue integrity compared to the cisplatin group. In conclusion, cisplatin-induced nephrotoxicity in rats was associated with upregulation of miRNA 34a expression, apoptosis, and inflammation in p53-dependent manner. These effects were reversed by betaine administration that ultimately improved the kidney function and tissue integrity.
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Affiliation(s)
- Rasha M Hussein
- Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Mutah University, Al-Karak, Jordan.,Department of Biochemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Saed M Al-Dalain
- Department of Pharmacology, Faculty of Medicine, Mutah University, Al-Karak, Jordan
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8
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Zangouei AS, Moghbeli M. MicroRNAs as the critical regulators of cisplatin resistance in gastric tumor cells. Genes Environ 2021; 43:21. [PMID: 34099061 PMCID: PMC8182944 DOI: 10.1186/s41021-021-00192-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 05/24/2021] [Indexed: 12/13/2022] Open
Abstract
Combined chemotherapeutic treatment is the method of choice for advanced and metastatic gastric tumors. However, resistance to chemotherapeutic agents is one of the main challenges for the efficient gastric cancer (GC) treatment. Cisplatin (CDDP) is used as an important regimen of chemotherapy for GC which induces cytotoxicity by interfering with DNA replication in cancer cells and inducing their apoptosis. Majority of patients experience cisplatin-resistance which is correlated with tumor metastasis and relapse. Moreover, prolonged and high-dose cisplatin administrations cause serious side effects such as nephrotoxicity, ototoxicity, and anemia. Since, there is a high rate of recurrence after CDDP treatment in GC patients; it is required to clarify the molecular mechanisms associated with CDDP resistance to introduce novel therapeutic methods. There are various cell and molecular processes associated with multidrug resistance (MDR) including drug efflux, detoxification, DNA repair ability, apoptosis alteration, signaling pathways, and epithelial-mesenchymal transition (EMT). MicroRNAs are a class of endogenous non-coding RNAs involved in chemo resistance of GC cells through regulation of all of the MDR mechanisms. In present review we have summarized all of the miRNAs associated with cisplatin resistance based on their target genes and molecular mechanisms in gastric tumor cells. This review paves the way of introducing a miRNA-based panel of prognostic markers to improve the efficacy of chemotherapy and clinical outcomes in GC patients. It was observed that miRNAs are mainly involved in cisplatin response of gastric tumor cells via regulation of signaling pathways, autophagy, and apoptosis.
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Affiliation(s)
- Amir Sadra Zangouei
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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9
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Li S, Wei X, He J, Cao Q, Du D, Zhan X, Zeng Y, Yuan S, Sun L. The comprehensive landscape of miR-34a in cancer research. Cancer Metastasis Rev 2021; 40:925-948. [PMID: 33959850 DOI: 10.1007/s10555-021-09973-3] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 04/29/2021] [Indexed: 12/12/2022]
Abstract
MicroRNA-34 (miR-34) plays central roles in human diseases, especially cancers. Inactivation of miR-34 is detected in cancer cell lines and tumor tissues versus normal controls, implying its potential tumor-suppressive effect. Clinically, miR-34 has been identified as promising prognostic indicators for various cancers. In fact, members of the miR-34 family, especially miR-34a, have been convincingly proved to affect almost the whole cancer progression process. Here, a total of 512 (miR-34a, 10/21), 85 (miR-34b, 10/16), and 114 (miR-34c, 10/14) putative targets of miR-34a/b/c are predicted by at least ten miRNA databases, respectively. These targets are further analyzed in gene ontology (GO), KEGG pathway, and the Reactome pathway dataset. The results suggest their involvement in the regulation of signal transduction, macromolecule metabolism, and protein modification. Also, the targets are implicated in critical signaling pathways, such as MAPK, Notch, Wnt, PI3K/AKT, p53, and Ras, as well as apoptosis, cell cycle, and EMT-related pathways. Moreover, the upstream regulators of miR-34a, mainly including transcription factors (TFs), lncRNAs, and DNA methylation, will be summarized. Meanwhile, the potential TF upstream of miR-34a/b/c will be predicted by PROMO, JASPAR, Animal TFDB 3.0, and GeneCard databases. Notably, miR-34a is an attractive target for certain cancers. In fact, miR-34a-based systemic delivery combined with chemotherapy or radiotherapy can more effectively control tumor progression. Collectively, this review will provide a panorama for miR-34a in cancer research.
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Affiliation(s)
- Sijing Li
- New Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, China
| | - Xiaohui Wei
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Jinyong He
- New Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, China
- China Cell-Gene Therapy Translational Medicine Research Center, Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
- School of Medicine, Sun Yat-sen University, Shenzhen, 518107, China
| | - Quanquan Cao
- MARBEC, Université Montpellier, UM-CNRS-IRD-IFREMER, cc 092, Place E. Bataillon, 34095, Montpellier Cedex 05, France
| | - Danyu Du
- New Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, China
| | - Xiaoman Zhan
- New Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, China
| | - Yuqi Zeng
- New Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, China
| | - Shengtao Yuan
- Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China.
| | - Li Sun
- New Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, China.
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Gu ML, Zhou XX, Ren MT, Shi KD, Yu MS, Jiao WR, Wang YM, Zhong WX, Ji F. Blockage of ETS homologous factor inhibits the proliferation and invasion of gastric cancer cells through the c-Met pathway. World J Gastroenterol 2020; 26:7497-7512. [PMID: 33384550 PMCID: PMC7754554 DOI: 10.3748/wjg.v26.i47.7497] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 10/13/2020] [Accepted: 11/02/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is one of the most common and deadliest types of cancer worldwide due to its delayed diagnosis and high metastatic frequency, but its exact pathogenesis has not been fully elucidated. ETS homologous factor (EHF) is an important member of the ETS family and contributes to the pathogenesis of multiple malignant tumors. To date, whether EHF participates in the development of GC via the c-Met signaling pathway remains unclear.
AIM To investigate the role and mechanism of EHF in the occurrence and development of GC.
METHODS The expression of EHF mRNA in GC tissues and cell lines was measured by quantitative PCR. Western blotting was performed to determine the protein expression of EHF, c-Met, and its downstream signal molecules. The EHF expression in GC tissues was further detected by immunohistochemical staining. To investigate the role of EHF in GC oncogenesis, small interfering RNA (siRNA) against EHF was transfected into GC cells. The cell proliferation of GC cells was determined by Cell Counting Kit-8 and colony formation assays. Flow cytometry was performed following Annexin V/propidium iodide (PI) to identify apoptotic cells and PI staining to analyze the cell cycle. Cell migration and invasion were assessed by transwell assays.
RESULTS The data showed that EHF was upregulated in GC tissues and cell lines in which increased expression of c-Met was also observed. Silencing of EHF by siRNA reduced the proliferation of GC cells. Inhibition of EHF induced significant apoptosis and cell cycle arrest in GC cells. Cell migration and invasion were significantly inhibited. EHF silencing led to c-Met downregulation and further blocked the Ras/c-Raf/extracellular signal-related kinase 1/2 (Erk1/2) pathway. Additionally, phosphatase and tensin homolog was upregulated and glycogen synthase kinase 3 beta was deactivated. Moreover, inactivation of signal transducer and activator of transcription 3 was detected following EHF inhibition, leading to inhibition of the epithelial-to-mesenchymal transition (EMT).
CONCLUSION These results suggest that EHF plays a key role in cell proliferation, invasion, apoptosis, the cell cycle and EMT via the c-Met pathway. Therefore, EHF may serve as an antineoplastic target for the diagnosis and treatment of GC.
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Affiliation(s)
- Meng-Li Gu
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Xin-Xin Zhou
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Meng-Ting Ren
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Ke-Da Shi
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Mo-Sang Yu
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Wen-Rui Jiao
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Ya-Mei Wang
- Department of Gastroenterology, The Fourth Affiliated Hospital, College of Medicine, Zhejiang University, Yiwu 322000, Zhejiang Province, China
| | - Wei-Xiang Zhong
- Department of Pathology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Feng Ji
- Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
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Pinelli S, Alinovi R, Corradi M, Poli D, Cavallo D, Pelosi G, Ampollini L, Goldoni M, Mozzoni P. A comparison between the effects of over-expression of miRNA-16 and miRNA-34a on cell cycle progression of mesothelioma cell lines and on their cisplatin sensitivity. Cancer Treat Res Commun 2020; 26:100276. [PMID: 33338854 DOI: 10.1016/j.ctarc.2020.100276] [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: 10/12/2020] [Revised: 11/26/2020] [Accepted: 12/09/2020] [Indexed: 11/17/2022]
Abstract
The prognosis of patients affected by malignant pleural mesothelioma (MPM) is presently poor and no therapeutic strategies have improved their survival yet. Introduction of miRNA mimics to restore their reduced or absent functionality in cancer cells is considered an important opportunity and a combination of miR's might be even more effective. In the present study, miR-16 and miR-34a were transfected, singularly and in combination, in MPM cell lines H2052 and H28, and their effects on cell proliferation and sensitivity to cisplatin are reported. Interestingly, the overexpression of both miRs, alone or combined, slows down the cell cycle progression, modulates the p53 and HMGB1 expression and increases the sensitivity of cells to cisplatin, producing a marked impairment of cell proliferation and strengthening the apoptotic effect of the drug. However, the co-overexpression of the two miRs results more effective only in the regulation of the cell cycle, but does not enhance the sensitivity of MPM cells to cisplatin. Consequently, although the potential of miR-16 and miR-34a is confirmed, we must conclude that their combination does not improve the response of MPM to chemotherapy.
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Affiliation(s)
- S Pinelli
- Department of Medicine and Surgery, University of Parma, via A. Gramsci 14, 43126 Parma, Italy.
| | - R Alinovi
- Department of Medicine and Surgery, University of Parma, via A. Gramsci 14, 43126 Parma, Italy.
| | - M Corradi
- Department of Medicine and Surgery, University of Parma, via A. Gramsci 14, 43126 Parma, Italy; University Hospital of Parma, Parma, Italy.
| | - D Poli
- INAIL Research, Department of Occupational and Environmental Medicine, Epidemiology and Hygiene Via Fontana Candida1, 00078 Monte Porzio Catone, Rome, Italy.
| | - D Cavallo
- INAIL Research, Department of Occupational and Environmental Medicine, Epidemiology and Hygiene Via Fontana Candida1, 00078 Monte Porzio Catone, Rome, Italy.
| | - G Pelosi
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parco Area delle Scienze 17/A, 43124 Parma, Italy.
| | - L Ampollini
- Department of Medicine and Surgery, University of Parma, via A. Gramsci 14, 43126 Parma, Italy; University Hospital of Parma, Parma, Italy.
| | - M Goldoni
- Department of Medicine and Surgery, University of Parma, via A. Gramsci 14, 43126 Parma, Italy.
| | - P Mozzoni
- Department of Medicine and Surgery, University of Parma, via A. Gramsci 14, 43126 Parma, Italy.
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12
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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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13
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El Darsa H, El Sayed R, Abdel-Rahman O. MET Inhibitors for the Treatment of Gastric Cancer: What's Their Potential? J Exp Pharmacol 2020; 12:349-361. [PMID: 33116950 PMCID: PMC7547764 DOI: 10.2147/jep.s242958] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 09/09/2020] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer remains a disease with a dismal prognosis. Extensive efforts to find targetable disease drivers in gastric cancer were implemented to improve patient outcomes. Beyond anti-HER2 therapy, MET pathway seems to be culprit of cancer invasiveness with MET-overexpressing tumors having poorer prognosis. Tyrosine kinase inhibitors targeting the HGF/MET pathway were studied in MET-positive gastric cancer, but no substantial benefit was proven. Some patients responded in early phase trials but later developed resistance. Others failed to show any benefit at all. Etiologies of resistance may entail inappropriate patient selection with a lack of MET detection standardization, tumor alternative pathways, variable MET amplification, and genetic variation. Optimizing MET detection techniques and better understanding the MET pathway, as well as tumor bypass mechanisms, are an absolute need to devise means to overcome resistance using targeted therapy alone, or in combination with other synergistic agents to improve outcomes of patients with MET-positive GC.
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Affiliation(s)
- Haidar El Darsa
- Division of Medical Oncology, Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Rola El Sayed
- Division of Hematology-Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Omar Abdel-Rahman
- Division of Medical Oncology, Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada
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14
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Lu H, Zhang Q, Sun Y, Wu D, Liu L. LINC00689 induces gastric cancer progression via modulating the miR-338-3p/HOXA3 axis. J Gene Med 2020; 22:e3275. [PMID: 32926751 DOI: 10.1002/jgm.3275] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 08/08/2020] [Accepted: 08/29/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND LINC00689 acts one critical regulatory role in several tumors. However, the functional, regulatory mechanism and expression of LINC00689 remains unknown in gastric cancer. METHODS LINC00689 and miR-338-3p levels were determined using a quantitative reverse transcriptase-polymerase chain reaction analysis and an enzyme-linked immunoassay and a cell-counting kit-8 assay were utilized to detect interleukin (IL)-8, IL-6 and IL-1β expression and cell proliferation, respectively. RESULTS We found that LINC00689 and HOXA3 are overexpressed and miR-338-3p is decreased in gastric cancer cells. Compared to control specimens, LINC00689 is overexpressed in gastric cancer specimens and the level of LINC00689 was up-regulated in 32 cases (32/40; 80.0%) compared to control samples. LINC00689 increased cell growth, epithelial-mesenchymal transition (EMT) development and secretion of inflammatory factors in gastric cancer. Compared to control specimens, miR-338-3p expression was decreased in gastric cancer specimens and a Pearson's correlation assay revealed that miR-338-3p was negatively correlated with LINC00689 expression in gastric cancer specimens. HOXA3 was identified as one target gene of miR-338-3p and Ectopic expression of LINC00689 suppressed miR-338-3p and enhanced HOXA3 expression in HGC-27 cells. LINC00689 enhanced cell growth, EMT development and secretion of inflammatory factors by promoting HOXA3. CONCLUSIONS LINC00689 may present a potential future target for gastric cancer treatment.
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Affiliation(s)
- Hui Lu
- Department of Medical Oncology, The First People's Hospital of Zhengzhou, ZhengZhou, China
| | - Qian Zhang
- Department of Medical Oncology, The First People's Hospital of Zhengzhou, ZhengZhou, China
| | - Yaqiong Sun
- Department of Medical Oncology, The First People's Hospital of Zhengzhou, ZhengZhou, China
| | - Dedong Wu
- Department of Medical Oncology, The First People's Hospital of Zhengzhou, ZhengZhou, China
| | - Liying Liu
- Department of Medical Oncology, The First People's Hospital of Zhengzhou, ZhengZhou, China
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15
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Luo S, Shen M, Chen H, Li W, Chen C. Long non‑coding RNA TP73‑AS1 accelerates the progression and cisplatin resistance of non‑small cell lung cancer by upregulating the expression of TRIM29 via competitively targeting microRNA‑34a‑5p. Mol Med Rep 2020; 22:3822-3832. [PMID: 32901838 PMCID: PMC7533438 DOI: 10.3892/mmr.2020.11473] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 05/29/2020] [Indexed: 12/22/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is a leading subtype of lung cancer, with high mortality rates. Recently, long non-coding RNAs (lncRNAs) have been associated with NSCLC. The present study aimed to examine the role of the TP73 antisense RNA 1 (TP73-AS1) lncRNA in NSCLC. TP73-AS1 and microRNA(miR)-34a-5p expression levels were measured using reverse transcription-quantitative PCR (RT-qPCR) and chromogenic in situ hybridization (CISH). Cell proliferation, apoptosis, migration and invasion was determined using Cell Counting Kit-8 (CCK-8), flow cytometry, Transwell and Matrigel assays, respectively. The median inhibitory concentration (IC50) value of cisplatin (cis-diamminedichloroplatinum; DDP) was assessed using a CCK-8 assay. The interaction between miR-34a-5p and TP73-AS1 or tripartite motif-containing 29 (TRIM29) was predicted using microRNA.org and Starbase, then verified using a dual-luciferase reporter assay. The expression of TRIM29 was quantified at the mRNA and protein level using RT-qPCR and western blot analysis, respectively. TP73-AS1 was significantly upregulated, while miR-34a-5p was downregulated in NSCLC tissues and cells. Functionally, TP73-AS1 knockdown inhibited proliferation, migration, invasion and DDP resistance, whilst inducing apoptosis in NSCLC cells. miR-34a-5p was identified as a target for TP73-AS1, and its inhibition reversed the effects of TP73-AS1 knockdown on NSCLC cells. In addition, TRIM29 was targeted by miR-34a-5p, and its overexpression reversed the effects of miR-34a-5p. Moreover, TP73-AS1 acted as a molecular sponge for miR-34a-5p, increasing the expression of TRIM29. In conclusion, TP73-AS1 contributed to proliferation, migration and DDP resistance but inhibited apoptosis of NSCLC cells by upregulating TRIM29 and sponging miR-34a-5p.
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Affiliation(s)
- Shunxiang Luo
- Department of Oncology, The First People's Hospital of Tianmen, Tianmen, Hubei 431700, P.R. China
| | - Ming Shen
- Department of Oncology, The First People's Hospital of Tianmen, Tianmen, Hubei 431700, P.R. China
| | - Hui Chen
- Department of Oncology, The First People's Hospital of Tianmen, Tianmen, Hubei 431700, P.R. China
| | - Weiwei Li
- Department of Oncology, The First People's Hospital of Tianmen, Tianmen, Hubei 431700, P.R. China
| | - Cong Chen
- Department of Oncology, The First People's Hospital of Tianmen, Tianmen, Hubei 431700, P.R. China
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16
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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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17
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Ahadi A. Dysregulation of miRNAs as a signature for diagnosis and prognosis of gastric cancer and their involvement in the mechanism underlying gastric carcinogenesis and progression. IUBMB Life 2020; 72:884-898. [DOI: 10.1002/iub.2259] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Accepted: 02/08/2020] [Indexed: 02/06/2023]
Affiliation(s)
- Alireza Ahadi
- Department of Medical Genetics, School of MedicineShahid Beheshti University of Medical Sciences Tehran Iran
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18
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Kong J, Wang W. A Systemic Review on the Regulatory Roles of miR-34a in Gastrointestinal Cancer. Onco Targets Ther 2020; 13:2855-2872. [PMID: 32308419 PMCID: PMC7138617 DOI: 10.2147/ott.s234549] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 12/22/2019] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs) are a class of endogenous non-coding single-stranded small-molecule RNAs that regulate gene expression by repressing target messenger RNA (mRNA) translation or degrading mRNA. miR-34a is one of the most important miRNAs participating in various physiological and pathological processes. miR-34a is abnormally expressed in a variety of tumors. The roles of miR-34a in gastrointestinal cancer (GIC) draw lots of attention. Numerous studies have demonstrated that dysregulated miR-34a is closely related to the proliferation, differentiation, migration, and invasion of tumor cells, as well as the diagnosis, prognosis, treatment, and chemo-resistance of tumors. Thus, we systematically reviewed the abnormal expression and regulatory roles of miR-34a in GICs including esophageal cancer (EC), gastric cancer (GC), colorectal cancer (CRC), hepatocellular carcinoma (HCC), pancreatic cancer (PC), and gallbladder cancer (GBC). It may provide a profile of versatile roles of miR-34a in GICs.
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Affiliation(s)
- Jiehong Kong
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People's Republic of China
| | - Weipeng Wang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People's Republic of China
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19
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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: 324] [Impact Index Per Article: 64.8] [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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20
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Zhan H, Tu S, Zhang F, Shao A, Lin J. MicroRNAs and Long Non-coding RNAs in c-Met-Regulated Cancers. Front Cell Dev Biol 2020; 8:145. [PMID: 32219093 PMCID: PMC7078111 DOI: 10.3389/fcell.2020.00145] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 02/21/2020] [Indexed: 12/16/2022] Open
Abstract
MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are components of many signaling pathways associated with tumor aggressiveness and cancer metastasis. Some lncRNAs are classified as competitive endogenous RNAs (ceRNAs) that bind to specific miRNAs to prevent interaction with target mRNAs. Studies have shown that the hepatocyte growth factor/mesenchymal-epithelial transition factor (HGF/c-Met) pathway is involved in physiological and pathological processes such as cell growth, angiogenesis, and embryogenesis. Overexpression of c-Met can lead to sustained activation of downstream signals, resulting in carcinogenesis, metastasis, and resistance to targeted therapies. In this review, we evaluated the effects of anti-oncogenic and oncogenic non-coding RNAs (ncRNAs) on c-Met, and the interactions among lncRNAs, miRNAs, and c-Met in cancer using clinical and tissue chromatin immunoprecipition (ChIP) analysis data. We summarized current knowledge of the mechanisms and effects of the lncRNAs/miR-34a/c-Met axis in various tumor types, and evaluated the potential therapeutic value of lncRNAs and/or miRNAs targeted to c-Met on drug-resistance. Furthermore, we discussed the functions of lncRNAs and miRNAs in c-Met-related carcinogenesis and potential therapeutic strategies.
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Affiliation(s)
- Hong Zhan
- Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Sheng Tu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Feng Zhang
- School of Medicine, Zhejiang University Hangzhou, Hangzhou, China
| | - Anwen Shao
- Department of Neurosurgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jun Lin
- Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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21
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Naghizadeh S, Mohammadi A, Duijf PHG, Baradaran B, Safarzadeh E, Cho WCS, Mansoori B. The role of miR-34 in cancer drug resistance. J Cell Physiol 2020; 235:6424-6440. [PMID: 32064620 DOI: 10.1002/jcp.29640] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 01/31/2020] [Indexed: 12/25/2022]
Abstract
Resistance to conventional chemotherapy remains a major cause of cancer relapse and cancer-related deaths. Therefore, there is an urgent need to overcome resistance barriers. To improve cancer treatment approaches, it is critical to elucidate the basic mechanisms underlying drug resistance. Increasingly, the mechanisms involving micro-RNAs (miRNAs) are studied because miRNAs are also considered practical therapeutic options due to high degrees of specificity, efficacy, and accuracy, as well as their ability to target multiple genes at the same time. Years of research have firmly established miR-34 as a key tumor suppressor miRNA whose target genes are involved in drug resistance mechanisms. Indeed, numerous articles show that low levels of circulating miR-34 or tumor-specific miR-34 expression are associated with poor response to chemotherapy. In addition, elevation of inherently low miR-34 levels in resistant cancer cells effectively restores sensitivity to chemotherapeutic agents. Here, we review this literature, also highlighting some contradictory observations. In addition, we discuss the potential utility of miR-34 expression as a predictive biomarker for chemotherapeutic drug response. Although caution needs to be exercised, miR-34 is emerging as a biomarker that could improve cancer precision medicine.
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Affiliation(s)
- Sanaz Naghizadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Mohammadi
- Department of Cancer and Inflammation Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Pascal H G Duijf
- University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Australia.,Institute of Health and Biomedical Innovation, Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elham Safarzadeh
- Department of Microbiology and Immunology, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | | | - Behzad Mansoori
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Cancer and Inflammation Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
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22
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Liu X, Sun R, Chen J, Liu L, Cui X, Shen S, Cui G, Ren Z, Yu Z. Crosstalk Mechanisms Between HGF/c-Met Axis and ncRNAs in Malignancy. Front Cell Dev Biol 2020; 8:23. [PMID: 32083078 PMCID: PMC7004951 DOI: 10.3389/fcell.2020.00023] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 01/13/2020] [Indexed: 12/24/2022] Open
Abstract
Several lines of evidence have confirmed the magnitude of crosstalk between HGF/c-Met axis (hepatocyte growth factor and its high-affinity receptor c-mesenchymal-epithelial transition factor) and non-coding RNAs (ncRNAs) in tumorigenesis. Through activating canonical or non-canonical signaling pathways, the HGF/c-Met axis mediates a range of oncogenic processes such as cell proliferation, invasion, apoptosis, and angiogenesis and is increasingly becoming a promising target for cancer therapy. Meanwhile, ncRNAs are a cluster of functional RNA molecules that perform their biological roles at the RNA level and are essential regulators of gene expression. The expression of ncRNAs is cell/tissue/tumor-specific, which makes them excellent candidates for cancer research. Many studies have revealed that ncRNAs play a crucial role in cancer initiation and progression by regulating different downstream genes or signal transduction pathways, including HGF/c-Met axis. In this review, we discuss the regulatory association between ncRNAs and the HGF/c-Met axis by providing a comprehensive understanding of their potential mechanisms and roles in cancer development. These findings could reveal their possible clinical applications as biomarkers for therapeutic interventions.
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Affiliation(s)
- Xin Liu
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ranran Sun
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jianan Chen
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Liwen Liu
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xichun Cui
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shen Shen
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Guangying Cui
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhigang Ren
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zujiang Yu
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Key Laboratory of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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23
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Cao Y, Liu Y, Shang L, Wei W, Shen Y, Gu Q, Xie X, Dong W, Lin Y, Yue Y, Wang F, Gu W. Decitabine and all-trans retinoic acid synergistically exhibit cytotoxicity against elderly AML patients via miR-34a/MYCN axis. Biomed Pharmacother 2020; 125:109878. [PMID: 32006898 DOI: 10.1016/j.biopha.2020.109878] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 01/15/2020] [Accepted: 01/17/2020] [Indexed: 12/16/2022] Open
Abstract
This study aimed to investigate the efficacy and mechanism of decitabine (DAC) and all-trans retinoic acid (ATRA) in elderly acute myeloid leukemia (AML) patients and cultured cells. Our clinical trial enrolled 36 elderly patients who were judged ineligible for conventional chemotherapy, receiving DAC and ATRA regimen (DAC 20 mg/m2 days 1-5; ATRA 20 mg/m2 days 4-28 in the first cycle and days 1-28 in the subsequent cycle). Treated with a median of 3 cycles (range 1-6), 44.4 % of patients achieved complete remission (CR), 11.1 % achieved CR with incomplete peripheral count recovery (CRi) and 13.9 % achieved partial remission (PR). The median overall survival (OS) was 12.1 months; the 1-year and 2-year OS rates were 49.6 % and 17.2 %. In addition, our in vitro studies indicated that the antineoplastic activities of DAC and ATRA mutually reinforced, which induced growth inhibition, cell cycle arrest and apoptosis of AML cells. Meanwhile, we found DAC and ATRA inhibited DNMT1, activated miR-34a via promoter hypomethylation, down-regulated its target MYCN and thus exerted a synergistic antineoplastic effect. In conclusion, DAC plus ATRA regimen might be effective and well-tolerated for elderly patients partially through modulating miR-34a/MYCN axis.
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Affiliation(s)
- Yang Cao
- Department of Hematology, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Jiangsu Province, 213003, PR China
| | - Yue Liu
- Department of Hematology, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Jiangsu Province, 213003, PR China
| | - Limei Shang
- Department of Hematology, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Jiangsu Province, 213003, PR China
| | - Wei Wei
- Department of Hematology, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Jiangsu Province, 213003, PR China
| | - Yangling Shen
- Department of Hematology, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Jiangsu Province, 213003, PR China
| | - Quan Gu
- Department of Hematology, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Jiangsu Province, 213003, PR China
| | - Xiaobao Xie
- Department of Hematology, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Jiangsu Province, 213003, PR China
| | - Weimin Dong
- Department of Hematology, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Jiangsu Province, 213003, PR China
| | - Yan Lin
- Department of Hematology, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Jiangsu Province, 213003, PR China
| | - Yanhua Yue
- Department of Hematology, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Jiangsu Province, 213003, PR China
| | - Fei Wang
- Department of Hematology, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Jiangsu Province, 213003, PR China
| | - Weiying Gu
- Department of Hematology, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Jiangsu Province, 213003, PR China.
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24
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Zhao X, Hu GF, Shi YF, Xu W. Research Progress in microRNA-Based Therapy for Gastric Cancer. Onco Targets Ther 2019; 12:11393-11411. [PMID: 31920330 PMCID: PMC6935305 DOI: 10.2147/ott.s221354] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Accepted: 12/10/2019] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer (GC) is one of the leading causes of tumor-related mortality. In addition to surgery and endoscopic resection, systemic therapy remains the main treatment option for GC, especially for advanced-stage disease and for cases not suitable for surgical therapy. Hence, improving the efficacy of systemic therapy is still an urgent problem to overcome. In the past decade, the essential roles of microRNAs (miRNAs) in tumor treatment have been increasingly recognized. In particular, miRNAs were recently shown to reverse the resistance to chemotherapy drugs such as 5-fluorouracil, cisplatin, and doxorubicin. Synthesized nanoparticles loaded with mimics or inhibitors of miRNAs can directly target tumor cells to suppress their growth. Moreover, exosomes may serve as promising safe carriers for mimics or inhibitors of miRNAs to treat GC. Some miRNAs have also been shown to play roles in the mechanism of action of other anti-tumor drugs. Therefore, in this review, we highlight the research progress on microRNA-based therapy in GC and discuss the challenges and prospects associated with this strategy. We believe that microRNA-based therapy has the potential to offer a clinical benefit to GC patients, and this review would contribute to and motivate further research to promote this field toward this ultimate goal.
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Affiliation(s)
- Xu Zhao
- Department of Hepatology, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
| | - Gao-Feng Hu
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People's Republic of China.,Department of Clinical Laboratory, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
| | - Yan-Fen Shi
- Department of Pathology, China-Japan Friendship Hospital, Beijing 100029, People's Republic of China
| | - Wei Xu
- Department of Clinical Laboratory, The First Hospital of Jilin University, Changchun 130021, People's Republic of China
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25
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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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26
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Wu J, Sun B, Zhang S, Zhang J, Tong J, Nie J, Li J. Effects of radon on miR-34a-induced apoptosis in human bronchial epithelial BEAS-2B cells. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2019; 82:913-919. [PMID: 31496443 DOI: 10.1080/15287394.2019.1665350] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Radon exposure is known to be the second most frequent cause followed by tobacco exposure for lung cancer development. In lung cancer development, microRNAs (miRNAs) play an important role in regulating various target genes associated with this disease. It is well-established that apoptosis is involved in the elimination of cancer cells. However, the mechanisms underlying chronic radon exposure induced miRNAs regulation attributed to result in carcinogenesis and subsequent activation of apoptosis is not completely understood. The aim of this study was thus to examine chronic low level radon exposure on lung miRNAs as a model for carcinogenesis induction and subsequent activation of apoptosis using human bronchial epithelial BEAS-2B cells. Quantitative real-time PCR (qRT-PCR) and flow cytometry were used to determine the miR-34a gene expression and apoptotic rate in BEAS-2B cells. Data demonstrated that chronic radon exposure up-regulated the expressions of miR-34a and enhanced cellular apoptosis in a time-dependent manner. Western blot analysis demonstrated that overexpression of the gene miR-34a enhanced apoptotic rate and elevated proapoptotic Bax protein expression accompanied by decreased protein expressions of antiapoptotic Bcl-2 and PARP-1. It is noteworthy that the apoptotic rate was elevated in BEAS-2B cells transfected with mi-R34a mimic but reduced in mi-R34a inhibitor-transfected cells. Evidence thus indicates that chronic exposure to radon produced up-regulation of miR-34a gene which subsequently enhanced apoptosis in BEAS-2B cells. The observed consequences following chronic radon exposure leading to carcinogenesis appear to involve activation of miR-34a gene.
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Affiliation(s)
- Jing Wu
- School of Public Health, Medical College of Soochow University , Suzhou , JS , People's Republic of China
| | - Bin Sun
- School of Public Health, Medical College of Soochow University , Suzhou , JS , People's Republic of China
| | - Shuyu Zhang
- School of Radiation Medicine and Protection, Medical College of Soochow University , Suzhou , JS , People's Republic of China
| | - Jie Zhang
- School of Public Health, Medical College of Soochow University , Suzhou , JS , People's Republic of China
| | - Jian Tong
- School of Public Health, Medical College of Soochow University , Suzhou , JS , People's Republic of China
| | - Jihua Nie
- School of Public Health, Medical College of Soochow University , Suzhou , JS , People's Republic of China
| | - Jianxiang Li
- School of Public Health, Medical College of Soochow University , Suzhou , JS , People's Republic of China
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27
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Yao Z, Zhang Y, Xu D, Zhou X, Peng P, Pan Z, Xiao N, Yao J, Li Z. Research Progress on Long Non-Coding RNA and Radiotherapy. Med Sci Monit 2019; 25:5757-5770. [PMID: 31375656 PMCID: PMC6690404 DOI: 10.12659/msm.915647] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Long non-coding RNAs (lncRNAs), a group of non-protein-coding RNAs longer than 200 nucleotides, are involved in multiple biological and pathological processes, such as proliferation, apoptosis, migration, invasion, angiogenesis, and immune escape. Many studies have shown that lncRNAs participate in the complex network of cancer and play vital roles as oncogenes or tumor-suppressor genes in a variety of cancers. Moreover, recent research has shown that abnormal expression of lncRNAs in malignant tumor cells before and after radiotherapy may participate in the progression of cancers and affect the radiation sensitivity of malignant tumor cells mediated by specific signaling pathways or cell cycle regulation. In this review, we summarize the published studies on lncRNAs in radiotherapy regarding the biological function and mechanism of human cancers, including esophageal cancer, pancreatic cancers, nasopharyngeal carcinoma, hepatocellular carcinoma, cervical cancer, colorectal cancer, and gastric cancer.
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Affiliation(s)
- Zhifeng Yao
- Department of Radiotherapy, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China (mainland).,Department of Oncology, The Second Clinical Medical School of Nanjing Medical University, Nanjing, Jiangsu, China (mainland)
| | - Yiwen Zhang
- Department of Nursing, The Affiliated Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, China (mainland)
| | - Danghui Xu
- Department of Medical Imaging, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing, Jiangsu, China (mainland)
| | - Xuejun Zhou
- Department of Medical Imaging, The Affiliated Hospital of Nantong University, Nantong, Jiangsu, China (mainland)
| | - Peng Peng
- Department of Nursing, Nanjing Health Higher Vocational and Technical College, Nanjing, Jiangsu, China (mainland)
| | - Zhiyao Pan
- Department of Basic Medicine, Zhejiang University Medical College, Hangzhou, Zhejiang, China (mainland)
| | - Nan Xiao
- Department of Medical Imaging, Nanjing Health Higher Vocational and Technical College, Nanjing, Jiangsu, China (mainland)
| | - Jianxin Yao
- Department of Medical Imaging, Nanjing Health Higher Vocational and Technical College, Nanjing, Jiangsu, China (mainland)
| | - Zhifeng Li
- Department of Medical Imaging, Nanjing Health Higher Vocational and Technical College, Nanjing, Jiangsu, China (mainland)
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28
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Dong S, Zhang X, Liu D. Overexpression of long noncoding RNA GAS5 suppresses tumorigenesis and development of gastric cancer by sponging miR-106a-5p through the Akt/mTOR pathway. Biol Open 2019; 8:bio.041343. [PMID: 31182630 PMCID: PMC6602335 DOI: 10.1242/bio.041343] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Long noncoding RNAs (lncRNAs) have emerged as important regulators of human cancers. LncRNA GAS5 (GAS5) is identified as a tumor suppressor involved in several cancers. However, the roles of GAS5 and the mechanisms responsible for its functions in gastric cancer (GC) have not been well documented. Herein, the decreased GAS5 and increased miRNA-106a-5p levels were observed in GC and cell lines. GAS5 level was significantly inversely correlated with miRNA-106a-5p level in GC tissues. Moreover, dual-luciferase reporter and qRT-PCR assays showed that GAS5 bound to miRNA-106a-5p and negatively regulated its expression in GC cells. Functional experiments showed that GAS5 overexpression suppressed GC cell proliferation, migration and invasion capabilities, and promoted apoptosis, while miRNA-106a-5p overexpression inverted the functional effects induced by GAS5 overexpression. In vivo, GAS5 overexpression inhibited tumor growth by negatively regulating miRNA-106a-5p expression. Mechanistic investigations revealed that GAS5 overexpression inactivated the Akt/mTOR pathway by suppressing miRNA-106a-5p expression in vitro and in vivo. Taken together, our findings conclude the GAS5 overexpression suppresses tumorigenesis and development of gastric cancer by sponging miR-106a-5p through the Akt/mTOR pathway. Summary: GAS5, a tumor suppressor, was confirmed to suppress tumorigenesis and development of gastric cancer by sponging miR-106a-5p through the Akt/mTOR pathway, which provides a novel regulatory axis of GC progression.
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Affiliation(s)
- Shuaijun Dong
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China.,Department of Gastrointestinal Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, People's Republic of China
| | - Xiefu Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China
| | - Dechun Liu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, People's Republic of China
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29
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Feng W, Su Z, Yin Q, Zong W, Shen X, Ju S. ncRNAs associated with drug resistance and the therapy of digestive system neoplasms. J Cell Physiol 2019; 234:19143-19157. [PMID: 30941775 DOI: 10.1002/jcp.28551] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 02/25/2019] [Accepted: 03/05/2019] [Indexed: 12/19/2022]
Abstract
Digestive system cancer remains a common cancer and the main cause of cancer-related death worldwide. Drug resistance is a major challenge in the therapy of digestive system cancer, and represents a primary obstacle in the treatment of cancer by restricting the efficiency of both traditional chemotherapy and biological therapies. Existing studies indicate that noncoding RNAs play an important role in the evolution and progression of drug resistance in digestive system cancer, mainly by modulating drug transporter-related proteins, DNA damage repair, cell-cycle-related proteins, cell apoptosis-related proteins, drug target-related proteins, and the tumor microenvironment. In this review, we address the potential mechanisms of ncRNAs underlying drug resistance in digestive system tumors and discuss the possible application of ncRNAs against drug resistance in digestive system tumors.
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Affiliation(s)
- Wei Feng
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Zhangyao Su
- School of Medicine, Nantong University, Nantong, China
| | - Qingqing Yin
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Wei Zong
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Xianjuan Shen
- Clinical Medical Research Center, Affiliated Hospital of Nantong University, Nantong, China
| | - Shaoqing Ju
- Center of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
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30
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Wang M, Zhang R, Zhang S, Xu R, Yang Q. MicroRNA-574-3p regulates epithelial mesenchymal transition and cisplatin resistance via targeting ZEB1 in human gastric carcinoma cells. Gene 2019; 700:110-119. [PMID: 30917930 DOI: 10.1016/j.gene.2019.03.043] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 03/08/2019] [Accepted: 03/20/2019] [Indexed: 12/23/2022]
Abstract
MicroRNA-574-3p (miR-574-3p) has different roles in different cancer types. However, the exact regulation mechanism of miR-574-3p in gastric cancer (GC) progression remains unclear. Thus, we aimed to evaluate the role of miR-574-3p in GC metastasis. We investigated the mechanism via which miR-574-3p regulated cancer cell migration and invasion to determine the relationship between epithelial mesenchymal transition (EMT) and drug resistance. Our results indicated that human GC cell line SGC7901 cells were more sensitive to cisplatin (DDP), but SGC7901 cisplatin-resistant cells (SGC7901/DDP) were more resistant to DDP and had mesenchymal characteristics. In addition, miR-574-3p overexpression up-regulated E-cadherin expression, and concomitantly down-regulated the expression of vimentin. We also identified zinc finger E-box binding homeobox transcription factor 1 (ZEB1), a crucial EMT inducer gene, as a new target of miR-574-3p. In fact, miR-574-3p bound the 3' untranslated region (3'-UTR) of ZEB1, regulating expression of this transcription factor at both the mRNA and protein levels. Furthermore, miR-574-3p overexpression reduced the migratory and invasive properties of the SGC7901/DDP cells and inhibited cisplatin (DDP) resistance in vitro and in vivo. In conclusion, the results indicated that miR-574-3p inhibited the EMT and enhanced cisplatin sensitivity in GC cells by suppressing ZEB1. These results provide further evidence for the critical roles of miR-574-3p and ZEB1 in invasion and migration regulation characteristics of GC cells.
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Affiliation(s)
- Mingqi Wang
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun 130021, Jilin Province, China.
| | - Renwen Zhang
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun 130021, Jilin Province, China.
| | - Shu Zhang
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun 130021, Jilin Province, China.
| | - Rui Xu
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun 130021, Jilin Province, China.
| | - Qing Yang
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun 130021, Jilin Province, China.
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31
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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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32
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Chen L, Yuan D, Yang Y, Ren M. LincRNA-p21 enhances the sensitivity of radiotherapy for gastric cancer by targeting the β-catenin signaling pathway. J Cell Biochem 2018; 120:6178-6187. [PMID: 30484893 DOI: 10.1002/jcb.27905] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Accepted: 09/25/2018] [Indexed: 02/06/2023]
Abstract
Long noncoding RNAs (lncRNAs) are a large and diverse class of transcribed RNA molecules with a length of more than 200 nucleotides that modulate the gene expression at the posttranscriptional or transcriptional level. LncRNAs played crucial roles in many biological processes, such as cell proliferation, metastasis, and migraton. In this study, we evaluated the role of lincRNA-p21 in the gastric cancer (GC). We demonstrated that the expression level of lincRNA-p21 was downregulated in the GC tissues and cell lines. Moreover, ectopic expression of lincRNA-p21 suppressed the GC cell growth, cell cycle, and migration. Furthermore, we demonstrated that the X-ray increased the expression level of lincRNA-p21 in both the HCG-27 and SGC7901 cells and elevated expression of lincRNA-p21 increased the radiotherapy sensitivity of the GC cell. In addition, we showed that ectopic expression of lincRNA-p21 suppressed the β-catenin and c-myc expression. Overexpression of lincRNA-p21 inhibited the GC cell proliferation and increased the radiosensitivity of GC cells by regulating the β-catenin signaling pathway. These data suggested that lincRNA-p21 acted as a tumor suppressor gene in the development of GC.
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Affiliation(s)
- Lijun Chen
- Department of Radiotherapy, Xinxiang Central Hospital, Henan, China
| | - Dongfang Yuan
- Department of Radiotherapy, Xinxiang Central Hospital, Henan, China
| | - Yichen Yang
- Queen Mary School, Nanchang University, Nanchang, China
| | - Minzhu Ren
- Department of Radiotherapy, Xinxiang Central Hospital, Henan, China
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33
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Liu H, Deng H, Zhao Y, Li C, Liang Y. LncRNA XIST/miR-34a axis modulates the cell proliferation and tumor growth of thyroid cancer through MET-PI3K-AKT signaling. J Exp Clin Cancer Res 2018; 37:279. [PMID: 30463570 PMCID: PMC6249781 DOI: 10.1186/s13046-018-0950-9] [Citation(s) in RCA: 235] [Impact Index Per Article: 33.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 11/06/2018] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Thyroid cancer is one of the most prevalent malignancies in endocrine system. Further understanding and revealing the molecular mechanism underlying thyroid cancer are indispensable for the development of effective diagnosis and treatments. In the present study, we attempted to provide novel basis for targeted therapy for thyroid cancer from the aspect of lncRNA-miRNA-mRNA interaction. METHODS The expression and cellular function of XIST (X-inactive specific transcript) was determined. miRNAs which may be direct targets of XIST were screened for from online GEO database and miR-34a was selected. Next, the predicted binding between XIST and miR-34a, and the dynamic effect of XIST and miR-34a on downstream MET (hepatocyte growth factor receptor)-PI3K (phosphoinositide 3-kinase)-AKT (α-serine/threonine-protein kinase) signaling was evaluated. RESULTS XIST was significantly up-regulated in thyroid cancer tissues and cell lines; XIST knockdown suppressed the cell proliferation in vivo and the tumor growth in vitro. Based on online database and online tool prediction results, miR-34a was underexpressed in thyroid cancer and might be a direct target of XIST. Herein, we confirmed the negative interaction between XIST and miR-34a; moreover, XIST knockdown could reduce the protein levels of MET, a downstream target of miR-34a, and the phosphorylation of PI3K and AKT. In thyroid cancer tissues, MET mRNA and protein levels of MET were up-regulated; MET was positively correlated with XIST while negatively correlated with miR-34a, further confirming that XIST serves as a ceRNA for miR-34a through sponging miR-34a, competing with MET for miR-34a binding, and finally modulating thyroid cancer cell proliferation and tumor growth. CONCLUSION In the present study, we provided novel experimental basis for targeted therapy for thyroid cancer from the aspect of lncRNA-miRNA-mRNA interaction.
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Affiliation(s)
- Hua Liu
- Nuclear Medicine Department, Xiangya Hospital, Central South University, Changsha, Hunan People’s Republic of China
| | - Haoyu Deng
- Nuclear Medicine Department, Xiangya Hospital, Central South University, Changsha, Hunan People’s Republic of China
| | - Yajie Zhao
- Nuclear Medicine Department, Xiangya Hospital, Central South University, Changsha, Hunan People’s Republic of China
| | - Can Li
- Nuclear Medicine Department, Xiangya Hospital, Central South University, Changsha, Hunan People’s Republic of China
| | - Yu Liang
- Oncology Department, Xiangya Hospital, Central South University, Changsha, No. 87 Xiangya Road, Changsha, Hunan 410008 People’s Republic of China
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Kashyap D, Tuli HS, Garg VK, Goel N, Bishayee A. Oncogenic and Tumor-Suppressive Roles of MicroRNAs with Special Reference to Apoptosis: Molecular Mechanisms and Therapeutic Potential. Mol Diagn Ther 2018; 22:179-201. [PMID: 29388067 DOI: 10.1007/s40291-018-0316-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
MicroRNAs (miRNAs) are the non-coding class of minute RNA molecules that negatively control post-transcriptional regulation of various functional genes. These miRNAs are transcribed from the loci present in the introns of functional or protein-coding genes, exons of non-coding genes, or even in the 3'-untranslated region (3'-UTR). They have potential to modulate the stability or translational efficiency of a variety of target RNA [messenger RNA (mRNA)]. The regulatory function of miRNAs has been elucidated in several pathological conditions, including neurological (Alzheimer's disease and Parkinson's disease) and cardiovascular conditions, along with cancer. Importantly, miRNA identification in cancer progression and invasion has evolved as an incipient era in cancer treatment. Several studies have shown the influence of miRNAs on various cancer processes, including apoptosis, invasion, metastasis and angiogenesis. In particular, apoptosis induction in tumor cells through miRNA has been extensively studied. The biphasic mode (up- and down-regulation) of miRNA expression in apoptosis and other cancer processes has already been determined. The findings of these studies could be utilized to develop potential therapeutic strategies for the management of various cancers. The present review critically describes the oncogenic and tumor suppressor role of miRNAs in apoptosis and other cancer processes, therapy resistance, and use of their presence in the body fluids as biomarkers.
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Affiliation(s)
- Dharambir Kashyap
- Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, Punjab, India
| | - Hardeep Singh Tuli
- Department of Biotechnology, Maharishi Markandeshwar University, Mullana-Ambala, 133207, Haryana, India.
| | - Vivek Kumar Garg
- Department of Biochemistry, Government Medical College and Hospital, Chandigarh, 160030, Punjab, India
| | - Neelam Goel
- Department of Information Technology, University Institute of Engineering and Technology, Panjab University, Chandigarh, 160014, Punjab, India
| | - Anupam Bishayee
- Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, Miami, FL, 33169, USA.
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Corrà F, Agnoletto C, Minotti L, Baldassari F, Volinia S. The Network of Non-coding RNAs in Cancer Drug Resistance. Front Oncol 2018; 8:327. [PMID: 30211115 PMCID: PMC6123370 DOI: 10.3389/fonc.2018.00327] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 07/31/2018] [Indexed: 12/12/2022] Open
Abstract
Non-coding RNAs (ncRNAs) have been implicated in most cellular functions. The disruption of their function through somatic mutations, genomic imprinting, transcriptional and post-transcriptional regulation, plays an ever-increasing role in cancer development. ncRNAs, including notorious microRNAs, have been thus proposed to function as tumor suppressors or oncogenes, often in a context-dependent fashion. In parallel, ncRNAs with altered expression in cancer have been reported to exert a key role in determining drug sensitivity or restoring drug responsiveness in resistant cells. Acquisition of resistance to anti-cancer drugs is a major hindrance to effective chemotherapy and is one of the most important causes of relapse and mortality in cancer patients. For these reasons, non-coding RNAs have become recent focuses as prognostic agents and modifiers of chemo-sensitivity. This review starts with a brief outline of the role of most studied non-coding RNAs in cancer and then highlights the modulation of cancer drug resistance via known ncRNAs based mechanisms. We identified from literature 388 ncRNA-drugs interactions and analyzed them using an unsupervised approach. Essentially, we performed a network analysis of the non-coding RNAs with direct relations with cancer drugs. Within such a machine-learning framework we detected the most representative ncRNAs-drug associations and groups. We finally discussed the higher integration of the drug-ncRNA clusters with the goal of disentangling effectors from downstream effects and further clarify the involvement of ncRNAs in the cellular mechanisms underlying resistance to cancer treatments.
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Affiliation(s)
- Fabio Corrà
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Chiara Agnoletto
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Linda Minotti
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Federica Baldassari
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Stefano Volinia
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
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Huang Y, Zou Y, Lin L, Ma X, Chen H. Identification of serum miR-34a as a potential biomarker in acute myeloid leukemia. Cancer Biomark 2018; 22:799-805. [DOI: 10.3233/cbm-181381] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Wang H, Qin R, Guan A, Yao Y, Huang Y, Jia H, Huang W, Gao J. HOTAIR enhanced paclitaxel and doxorubicin resistance in gastric cancer cells partly through inhibiting miR-217 expression. J Cell Biochem 2018; 119:7226-7234. [PMID: 29856087 DOI: 10.1002/jcb.26901] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 03/28/2018] [Indexed: 12/31/2022]
Abstract
Drug resistance is a big obstacle for clinical anti-tumor treatment outcome. However, the role of HOTAIR in drug resistance in gastric cancer (GC) remains unknown. In this study, we showed that overexpression of HOTAIR enhanced paclitaxel and doxorubicin resistance in GC cells. Furthermore, the expression of HOTAIR was upregulated in GC tissues and higher expression of HOTAIR was associated with late stage. In addition, we showed that miR-217 expression was lower in GC tissues compared with the paired non-tumour tissues and downregulated expression of miR-217 was correlated with late stage. Interestingly, the expression of miR-217 was negatively correlated with HOTAIR expression in GC tissues. Ectopic expression of HOTAIR increased GC cell proliferation, cell cycle, and migration. Elevated expression of HOTAIR suppressed miR-217 expression and enhanced GPC5 and PTPN14 expression. Furthermore, we demonstrated that overexpression of miR-217 suppressed paclitaxel and doxorubicin resistance in GC cells. Ectopic expression of HOTAIR promoted drug resistance and increased GC cell proliferation, cell cycle, and migration by targeting miR-217. These data suggested that overexpression of HOTAIR enhanced paclitaxel and doxorubicin resistance in GC cells through inhibiting miR-217 expression.
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Affiliation(s)
- Hui Wang
- Department of Gastroenterology, The Affiliated YanAn Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Rong Qin
- Department of Gastroenterology, The Affiliated YanAn Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Aoran Guan
- Department of General Surgery, The Affiliated YanAn Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Ying Yao
- Department of Gastroenterology, The Affiliated YanAn Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Yun Huang
- Department of Gastroenterology, The Affiliated YanAn Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Hongping Jia
- Department of Gastroenterology, The Affiliated YanAn Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Weikang Huang
- Department of Gastroenterology, The Affiliated YanAn Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Jianpeng Gao
- Department of Gastroenterology, The Affiliated YanAn Hospital of Kunming Medical University, Kunming, Yunnan, China
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Upregulation of microRNA-524-5p enhances the cisplatin sensitivity of gastric cancer cells by modulating proliferation and metastasis via targeting SOX9. Oncotarget 2018; 8:574-582. [PMID: 27880941 PMCID: PMC5352179 DOI: 10.18632/oncotarget.13479] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Accepted: 11/14/2016] [Indexed: 12/21/2022] Open
Abstract
Cisplatin-based chemotherapy is the most commonly used treatment regimen for gastric cancer (GC), however, the resistance to cisplatin represents the key limitation for the therapeutic efficacy. Aberrant expression of MiR-524-5p appears to be involves in tumorigenesis and chemoresistance. However, the mechanism by which miR-524-5p mediates effects of cisplatin treatment in GC remains poorly understood. Expressions of MiR-524-5p was detected in GC tissues and cell lines by qRT-PCR. Cell proliferation was observed by MTT assay; Cell migration was detected by transwell migration and invasion assay. The targeting protein of miR-524-5p was identified by luciferase reporter assay and western blot. We found that downregulation of miR-524-5p in GC tissues and cell lines. SC-M1 and AZ521 cells resistant to cisplatin expressed low levels of miR-524-5p in comparison to the sensitive parental cells. Overexpression of miR-524-5p expression in SC-M1 and AZ521 cells inhibited cell proliferation, migration, and invasion, and conferred sensitivity to cisplatin-resistant GC cells. Subsequently, we identified SOX9 as a functional target protein of miR-524-5p and found that SOX9 overexpression could counteracts the chemosensitizing effects of miR-524-5p. These results provide novel insight into the regulation of GC tumorigenesis and progression by miRNAs. Restoration of miR-524-5p may have therapeutic potential against GC.
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Yao Q, Gu A, Wang Z, Xue Y. MicroRNA-144 functions as a tumor suppressor in gastric cancer by targeting cyclooxygenase-2. Exp Ther Med 2018; 15:3088-3095. [PMID: 29456712 DOI: 10.3892/etm.2018.5763] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Accepted: 11/29/2017] [Indexed: 12/23/2022] Open
Abstract
Gastric cancer (GC) poses a serious public health threat and the 5-year survival rate of patients with GC is low. MicroRNAs (miRNAs/miRs) may serve oncogenic or tumor suppressor functions during tumorigenesis by regulating cell proliferation, apoptosis, migration and invasion and it has been demonstrated that they may be dysregulated in various types of cancer. The present study demonstrated that miR-144 and GATA4 were downregulated in GC tissues and cell lines and suggested that this may be due to hypermethylation. Additionally, miR-144 and GATA4 had synergistic effects on GC cells by repressing cell proliferation and inducing cell cycle arrest and apoptosis. The results of bioinformatics and a luciferase reporter assay indicated that cyclooxygenase-2 (COX-2) is a direct target of miR-144 and that miR-144 negatively regulated the expression of COX-2, which inhibits the viability of GC cells. GATA4 also induced a similar effect on COX-2. Taken together, the results of the present study may improve understanding of the underlying mechanism of miR-144 and GATA4 in GC.
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Affiliation(s)
- Qiang Yao
- Department of Gastrointestinal Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150000, P.R. China
| | - Anxin Gu
- Department of Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150000, P.R. China
| | - Zhuozhong Wang
- Department of Statistics, Harbin Medical University, Harbin, Heilongjiang 150000, P.R. China
| | - Yingwei Xue
- Department of Gastrointestinal Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150000, P.R. China
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MicroRNA-139 inhibits the proliferation and migration of osteosarcoma cells via targeting forkhead-box P2. Life Sci 2017; 191:68-73. [DOI: 10.1016/j.lfs.2017.10.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2017] [Revised: 10/05/2017] [Accepted: 10/06/2017] [Indexed: 12/22/2022]
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Current updates on microRNAs as regulators of chemoresistance. Biomed Pharmacother 2017; 95:1000-1012. [DOI: 10.1016/j.biopha.2017.08.084] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2017] [Revised: 08/11/2017] [Accepted: 08/23/2017] [Indexed: 12/28/2022] Open
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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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Zhang L, Guo X, Zhang D, Fan Y, Qin L, Dong S, Zhang L. Upregulated miR-132 in Lgr5 + gastric cancer stem cell-like cells contributes to cisplatin-resistance via SIRT1/CREB/ABCG2 signaling pathway. Mol Carcinog 2017; 56:2022-2034. [PMID: 28383763 DOI: 10.1002/mc.22656] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2017] [Accepted: 04/04/2017] [Indexed: 02/06/2023]
Abstract
Cisplatin resistance has long been a major problem that restricts its use. A novel paradigm in tumor biology suggests that gastric tumor chemo-resistance is driven by gastric cancer stem cell-like (GCSCs). Growing evidence has indicated that microRNAs (miRNAs) contributes to chemo-resistance in gastric cancer (GC). Here, Lgr5+ cells derived from gastric cancer cell lines displayed stem cell-like features. Flow cytometry demonstrated the presence of a variable fraction of Lgr5 in 19 out of 20 GC specimens. By comparing the miRNA expression profiles of Lgr5+ GCSCs and Lrg5- cells, we established the upregulation of miR-132 in Lgr5+ GCSCs. The enhanced miR-132 expression correlated chemo-resistance in GC patients. Kaplan-Meier survival curve showed that patients with low miR-132 expression survived obviously longer. Functional assays results indicated that miR-132 promoted cisplatin resistance in Lgr5+ GCSCs in vitro and in vivo. Further dual-luciferase reporter gene assays revealed that SIRT1 was the direct target of miR-132. The expression of miR-132 was inversely correlated with SIRT1 in gastric cancer specimens. Furthermore, through PCR array we discovered ABCG2 was one of the downstream targets of SIRT1. Overexpression of SIRT1 down-regulated ABCG2 expression by promoting the de-acetylation of the transcription factor CREB. CREB was further activated ABCG2 via binding to the promoter of ABCG2 to induce transcription. Thus, we concluded that miR-132 regulated SIRT1/CREB/ABCG2 signaling pathway contributing to the cisplatin resistance and might serve as a novel therapeutic target against gastric cancer.
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Affiliation(s)
- Lanfang Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan Province, People's Republic of China
| | - Xiaohe Guo
- Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan Province, People's Republic of China
| | - Dezhong Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan Province, People's Republic of China
| | - Yingying Fan
- Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan Province, People's Republic of China
| | - Lei Qin
- Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan Province, People's Republic of China
| | - Shuping Dong
- Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan Province, People's Republic of China
| | - Lanfang Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan Province, People's Republic of China
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