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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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2
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Yang K, Yi T. Tumor cell stemness in gastrointestinal cancer: regulation and targeted therapy. Front Mol Biosci 2024; 10:1297611. [PMID: 38455361 PMCID: PMC10918437 DOI: 10.3389/fmolb.2023.1297611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 11/14/2023] [Indexed: 03/09/2024] Open
Abstract
The cancer stem cells are a rare group of self-renewable cancer cells capable of the initiation, progression, metastasis and recurrence of tumors, and also a key contributor to the therapeutic resistance. Thus, understanding the molecular mechanism of tumor stemness regulation, especially in the gastrointestinal (GI) cancers, is of great importance for targeting CSC and designing novel therapeutic strategies. This review aims to elucidate current advancements in the understanding of CSC regulation, including CSC biomarkers, signaling pathways, and non-coding RNAs. We will also provide a comprehensive view on how the tumor microenvironment (TME) display an overall tumor-promoting effect, including the recruitment and impact of cancer-associated fibroblasts (CAFs), the establishment of an immunosuppressive milieu, and the induction of angiogenesis and hypoxia. Lastly, this review consolidates mainstream novel therapeutic interventions targeting CSC stemness regulation.
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Affiliation(s)
- Kangqi Yang
- School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Tuo Yi
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
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Roshani M, Molavizadeh D, Sadeghi S, Jafari A, Dashti F, Mirazimi SMA, Ahmadi Asouri S, Rajabi A, Hamblin MR, Anoushirvani AA, Mirzaei H. Emerging roles of miR-145 in gastrointestinal cancers: A new paradigm. Biomed Pharmacother 2023; 166:115264. [PMID: 37619484 DOI: 10.1016/j.biopha.2023.115264] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 07/25/2023] [Accepted: 07/31/2023] [Indexed: 08/26/2023] Open
Abstract
Gastrointestinal (GI) carcinomas are a group of cancers affecting the GI tract and digestive organs, such as the gastric, liver, bile ducts, pancreas, small intestine, esophagus, colon, and rectum. MicroRNAs (miRNAs) are small functional non-coding RNAs (ncRNAs) which are involved in regulating the expression of multiple target genes; mainly at the post-transcriptional level, via complementary binding to their 3'-untranslated region (3'-UTR). Increasing evidence has shown that miRNAs have critical roles in modulating of various physiological and pathological cellular processes and regulating the occurrence and development of human malignancies. Among them, miR-145 is recognized for its anti-oncogenic properties in various cancers, including GI cancers. MiR-145 has been implicated in diverse biological processes of cancers through the regulation of target genes or signaling, including, proliferation, differentiation, tumorigenesis, angiogenesis, apoptosis, metastasis, and therapy resistance. In this review, we have summarized the role of miR-145 in selected GI cancers and also its downstream molecules and cellular processes targets, which could lead to a better understanding of the miR-145 in these cancers. In conclusion, we reveal the potential diagnostic, prognostic, and therapeutic value of miR-145 in GI cancer, and hope to provide new ideas for its application as a biomarker as well as a therapeutic target for the treatment of these cancer.
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Affiliation(s)
- Mohammad Roshani
- Internal Medicine and Gastroenterology, Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Danial Molavizadeh
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Sara Sadeghi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Ameneh Jafari
- Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Dashti
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Seyed Mohammad Ali Mirazimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Sahar Ahmadi Asouri
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for BasicSciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Ali Rajabi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, South Africa
| | - Ali Arash Anoushirvani
- Department of Internal Medicine, Firoozgar Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Hamed Mirzaei
- Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Internal Medicine, Firoozgar Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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Tohidast M, Memari N, Amini M, Hosseini SS, Jebelli A, Doustvandi MA, Baradaran B, Mokhtarzadeh A. MiR-145 inhibits cell migration and increases paclitaxel chemosensitivity in prostate cancer cells. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2023; 26:1350-1359. [PMID: 37886001 PMCID: PMC10598815 DOI: 10.22038/ijbms.2023.70878.15397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 07/09/2023] [Indexed: 10/28/2023]
Abstract
Objectives Prostate cancer (PC) is one of the most commonly diagnosed malignancies among men worldwide. Paclitaxel is a chemotherapeutic agent widely used to treat different types of cancer. Recent studies revealed miRNAs control various genes that influence the regulation of many biological and pathological processes such as the formation and development of cancer, chemotherapy resistance, etc. Materials and Methods Between three PC cell lines (PC3, DU-145, LNCAP), PC3 showed the lowest miR-145 expression and was chosen for experiments. PC3 cells were treated with paclitaxel and miR-145 separately or in combination. To measure the cell viability, migratory capacity, autophagy, cell cycle progression, and apoptosis induction, the MTT assay, wound-healing assay, and Annexin V/PI apoptosis assay were used, respectively. Moreover, quantitative real-time PCR (qRT-PCR) was employed to measure the expression level of genes involved in apoptosis, migration, and stemness properties. Results Obtained results illustrated that miR-145 transfection could enhance the sensitivity of PC3 cells to paclitaxel and increase paclitaxel-induced apoptosis by modulating the expression of related genes, including Caspase-3, Caspase-9, Bax, and Bcl-2. Also, results showed combination therapy increased cell cycle arrest at the sub-G1 phase. miR-145 and paclitaxel cooperatively reduced migration ability and related-metastatic and stemness gene expression, including MMP-2, MMP-9, CD44, and SOX-2. In addition, combination therapy can suppress MDR1 expression. Conclusion These results confirmed that miR-145 combined with paclitaxel cooperatively could inhibit cell proliferation and migration and increase the chemosensitivity of PC3 cells compared to mono treatment. So, miR-145 combination therapy may be used as a promising approach for PC treatment.
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Affiliation(s)
- Maryam Tohidast
- Department of Biological Science, Faculty of Basic Science, Higher Education Institute of Rab-Rashid, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- These authors contributed eqully to this work
| | - Neda Memari
- Department of Biological Science, Faculty of Basic Science, Higher Education Institute of Rab-Rashid, Tabriz, Iran
- These authors contributed eqully to this work
| | - Mohammad Amini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Asiyeh Jebelli
- Department of Biological Science, Faculty of Basic Science, Higher Education Institute of Rab-Rashid, Tabriz, Iran
- Clinical Research Development Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Targeting the Hippo Pathway in Gastric Cancer and Other Malignancies in the Digestive System: From Bench to Bedside. Biomedicines 2022; 10:biomedicines10102512. [PMID: 36289774 PMCID: PMC9599207 DOI: 10.3390/biomedicines10102512] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 09/29/2022] [Accepted: 09/30/2022] [Indexed: 12/24/2022] Open
Abstract
The Hippo pathway is an evolutionally conserved signaling cascade that controls organ size and tissue regeneration under physiological conditions, and its aberrations have been well studied to promote tumor initiation and progression. Dysregulation of the Hippo tumor suppressor signaling frequently occurs in gastric cancer (GC) and other solid tumors and contributes to cancer development through modulating multiple aspects, including cell proliferation, survival, metastasis, and oncotherapy resistance. In the clinic, Hippo components also possess diagnostic and prognostic values for cancer patients. Considering its crucial role in driving tumorigenesis, targeting the Hippo pathway may greatly benefit developing novel cancer therapies. This review summarizes the current research progress regarding the core components and regulation of the Hippo pathway, as well as the mechanism and functional roles of their dysregulation in gastrointestinal malignancies, especially in GC, and discusses the therapeutic potential of targeting the Hippo pathway against cancers.
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Rao X, Zhang C, Luo H, Zhang J, Zhuang Z, Liang Z, Wu X. Targeting Gastric Cancer Stem Cells to Enhance Treatment Response. Cells 2022; 11:cells11182828. [PMID: 36139403 PMCID: PMC9496718 DOI: 10.3390/cells11182828] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 09/02/2022] [Accepted: 09/05/2022] [Indexed: 11/16/2022] Open
Abstract
Gastric cancer (GC) was the fourth deadliest cancer in the world in 2020, and about 770,000 people died from GC that year. The death of patients with GC is mainly caused by the metastasis, recurrence, and chemotherapy resistance of GC cells. The cancer stem cell theory defines cancer stem cells (CSCs) as a key factor in the metastasis, recurrence, and chemotherapy resistance of cancer. It considers targeting gastric cancer stem cells (GCSCs) to be an effective method for the treatment of GC. For GCSCs, genes or noncoding RNAs are important regulatory factors. Many experimental studies have found that some drugs can target the stemness of gastric cancer by regulating these genes or noncoding RNAs, which may bring new directions for the clinical treatment of gastric cancer. Therefore, this review mainly discusses related genes or noncoding RNAs in GCSCs and drugs that target its stemness, thereby providing some information for the treatment of GC.
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Dai X, Chen Y, Chen N, Dou J, Zhuang H, Wang J, Zhao X, Zhang X, Zhao H. KLF5-mediated aquaporin 3 activated autophagy to facilitate cisplatin resistance of gastric cancer. Immunopharmacol Immunotoxicol 2022; 45:140-152. [PMID: 36083020 DOI: 10.1080/08923973.2022.2122498] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Resistance to chemotherapeutic drugs limits the control of gastric cancer (GC) development. The study intended to probe into the mechanism of aquaporin 3 (AQP3) on the chemoresistance of GC. METHODS Cisplatin (CDDP)-resistant cells were constructed. Parental AGS and HGC-27 cells and their respective CDDP-resistant cells were transfected with AQP3 overexpression plasmid, AQP3 short hairpin RNA (sh-AQP3) and sh-Kruppel-like factor 5 (shKLF5). The expressions of AQP3 and factors related to autophagy (LC3 I, LC3 II, Atg5, Beclin-1, p62)/epithelial-mesenchymal transition (EMT; E-cadherin and snail) were assessed by Western blot and qRT-PCR. Cell counting kit-8 assay was adopted to test cell viability and half maximal inhibitory concentration (IC 50) was determined. Transwell assay was used for the examination of cell migration and invasion. The regulatory relationship of AQP3 and KLF5 was tested by chromatin immunoprecipitation (ChIP) and dual luciferase reporter assays. RESULTS AQP3 was highly-expressed in GC cells and its level was even higher in CDDP-resistant GC cells. AQP3 silencing inhibited viability, autophagy and EMT in CDDP-resistant GC cells, while AQP3 overexpression had the opposite effect. KLF5 positively modulated AQP3 in GC cells resistant to CDDP. KLF5 knockdown reversed AQP3-induced autophagy, viability, migration, invasion and EMT in CDDP-resistant GC cells. CONCLUSION KLF5-modulated AQP3 activated autophagy to facilitate the resistance of GC to CDDP.
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Affiliation(s)
- Xudong Dai
- Department of General Surgery, Lianshui People's Hospital Affiliated to Kangda College of Nanjing Medical University
| | - Yong Chen
- Division of Gastrointestinal Surgery, Department of General Surgery, The Affiliated Huai'an Hospital of Xuzhou Medical University
| | - Ning Chen
- Division of Gastrointestinal Surgery, Department of General Surgery, The Affiliated Huai'an Hospital of Xuzhou Medical University
| | - Jin Dou
- Division of Gastrointestinal Surgery, Department of General Surgery, The Affiliated Huai'an Hospital of Xuzhou Medical University
| | - Haiwen Zhuang
- Division of Gastrointestinal Surgery, Department of General Surgery, The Affiliated Huai'an Hospital of Xuzhou Medical University
| | - Jian Wang
- Division of Gastrointestinal Surgery, Department of General Surgery, The Affiliated Huai'an Hospital of Xuzhou Medical University
| | - Xin Zhao
- Division of Gastrointestinal Surgery, Department of General Surgery, The Affiliated Huai'an Hospital of Xuzhou Medical University
| | - Xiaoyu Zhang
- Division of Gastrointestinal Surgery, Department of General Surgery, The Affiliated Huai'an Hospital of Xuzhou Medical University
| | - Haijian Zhao
- Division of Gastrointestinal Surgery, Department of General Surgery, The Affiliated Huai'an Hospital of Xuzhou Medical University
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Tang S, Liao K, Shi Y, Tang T, Cui B, Huang Z. Bioinformatics analysis of potential Key lncRNA-miRNA-mRNA molecules as prognostic markers and important ceRNA axes in gastric cancer. Am J Cancer Res 2022; 12:2397-2418. [PMID: 35693096 PMCID: PMC9185605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Accepted: 03/11/2022] [Indexed: 06/15/2023] Open
Abstract
Gastric cancer (GC), the fifth most common malignancy worldwide, has an extremely poor prognosis at the advanced stage or the early stage if inadequately treated. Long noncoding RNAs (lncRNAs), microRNAs (miRNAs) and mRNAs all function as competing endogenous RNAs (ceRNAs) that target and regulate each other. Changes in their expression and their regulatory bioprocesses play important roles in GC. However, the roles of key RNAs and their regulatory networks remain unclear. In this study, RNA profiles were extracted from The Cancer Genome Atlas database, and R language was used to discover the differentially expressed (DE) lncRNAs, miRNAs and mRNAs in GC. Then, the DERNAs were paired by miRcode, miRDB, TargetScan and DIANA, and the ceRNA network was further constructed and visualized using Cytoscape. Moreover, a functional enrichment analysis was performed using Metascape. Afterward, the "survival" package was employed to identify candidate prognostic targets (DERNA-os) in the ceRNA network. Ultimately, the ceRNA network was analyzed to identify crucial lncRNA/miRNA/mRNA axes. Based on 374 gastric adenocarcinoma and gastric adenoma samples, 283 DEceRNAs (69 lncRNAs, 10 miRNAs, and 204 mRNAs) were identified. The 204 mRNAs were significantly enriched in some interesting functional clusters, such as the trans-synaptic signaling cluster and the protein digestion and absorption cluster. The ceRNA network consisted of 43 ceRNAs (13 lncRNAs, 2 miRNAs, and 28 mRNAs) that were related to prognosis. Among them, 2 lncRNAs (LNC00469 and AC010145.1) and 1 mRNA (PRRT4) were potential new biomarkers. In addition, according to the lncRNA/miRNA/mRNA regulatory relationships among the 43 ceRNAs, we identified four axes that might play important roles in the progression of GC and investigated the potential mechanism of the most promising axis (POU6F2-AS2/hsa-mir-137/OPCML) in promoting the proliferation and invasiveness of GC.
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Affiliation(s)
- Siqi Tang
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical UniversityDongguan 523808, Guangdong, China
- The Second School of Clinical Medicine, Guangdong Medical UniversityDongguan 523808, Guangdong, China
| | - Keyong Liao
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical UniversityDongguan 523808, Guangdong, China
- The Second School of Clinical Medicine, Guangdong Medical UniversityDongguan 523808, Guangdong, China
| | - Yongpeng Shi
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical UniversityDongguan 523808, Guangdong, China
- The Second School of Clinical Medicine, Guangdong Medical UniversityDongguan 523808, Guangdong, China
| | - Tingting Tang
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical UniversityDongguan 523808, Guangdong, China
| | - Beibei Cui
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical UniversityDongguan 523808, Guangdong, China
| | - Zunnan Huang
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical UniversityDongguan 523808, Guangdong, China
- Marine Medical Research Institute of Guangdong ZhanjiangZhanjiang 524023, Guangdong China
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Zhou F, Ding W, Mao Q, Jiang X, Chen J, Zhao X, Xu W, Huang J, Zhong L, Sun X. The regulation of hsacirc_004413 promotes proliferation and drug resistance of gastric cancer cells by acting as a competing endogenous RNA for miR-145-5p. PeerJ 2022; 10:e12629. [PMID: 35415017 PMCID: PMC8995023 DOI: 10.7717/peerj.12629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 11/22/2021] [Indexed: 01/07/2023] Open
Abstract
Background Whether circRAN, which acts as a microRNA sponge, plays a role in 5-fluorouracil (5-Fu) resistant gastric cancer has not been reported. In this study, a 5-Fu resistant cell line with an IC50 of 16.59 µM was constructed. Methods Using comparative analysis of circRNA in the transcriptomics of resistant and sensitive strains, 31 differentially expressed circRNAs were detected, and the microRNA interacting with them was predicted. Results Hsacirc_004413 was selected for verification in drug resistant and sensitive cells. By interfering with hsacirc_004413 using antisense RNA, the sensitivity of drug resistant cells to 5-Fu was significantly promoted, and the apoptosis and necrosis of the cells were significantly increased. In sensitive cells, inhibition by inhibitors enhanced the resistance of cells to 5-Fu. We hypothesize that hsacirc_004413 makes gastric cancer cells resistant to 5-Fu mainly through adsorption of miR-145-5p.
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Affiliation(s)
- Fusheng Zhou
- Department of Gastroenterology, Huashan Hospital North, Fudan University, Shanghai, China
| | - Weiqun Ding
- Department of Gastroenterology, Huashan Hospital, Fudan University, Shanghai, China
| | - Qiqi Mao
- Department of Gastroenterology, Huashan Hospital North, Fudan University, Shanghai, China
| | - Xiaoyun Jiang
- Department of Gastroenterology, Huashan Hospital North, Fudan University, Shanghai, China
| | - Jiajie Chen
- Department of Gastroenterology, Huashan Hospital North, Fudan University, Shanghai, China
| | - Xianguang Zhao
- Department of Gastroenterology, Huashan Hospital North, Fudan University, Shanghai, China
| | - Weijia Xu
- Department of Gastroenterology, Huashan Hospital North, Fudan University, Shanghai, China
| | - Jiaxin Huang
- Department of Gastroenterology, Huashan Hospital North, Fudan University, Shanghai, China
| | - Liang Zhong
- Department of Gastroenterology, Huashan Hospital North, Fudan University, Shanghai, China
| | - Xu Sun
- Department of Gastroenterology, Huashan Hospital North, Fudan University, Shanghai, China
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Zhu S, Yang N, Niu C, Wang W, Wang X, Bai J, Qiao Y, Deng S, Guan Y, Chen J. The miR-145–MMP1 axis is a critical regulator for imiquimod-induced cancer stemness and chemoresistance. Pharmacol Res 2022; 179:106196. [DOI: 10.1016/j.phrs.2022.106196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 03/10/2022] [Accepted: 03/25/2022] [Indexed: 11/28/2022]
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Vera DB, Fredes AN, Garrido MP, Romero C. Role of Mitochondria in Interplay between NGF/TRKA, miR-145 and Possible Therapeutic Strategies for Epithelial Ovarian Cancer. LIFE (BASEL, SWITZERLAND) 2021; 12:life12010008. [PMID: 35054401 PMCID: PMC8779980 DOI: 10.3390/life12010008] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/24/2021] [Accepted: 11/29/2021] [Indexed: 12/20/2022]
Abstract
Ovarian cancer is the most lethal gynecological neoplasm, and epithelial ovarian cancer (EOC) accounts for 90% of ovarian malignancies. The 5-year survival is less than 45%, and, unlike other types of cancer, the proportion of women who die from this disease has not improved in recent decades. Nerve growth factor (NGF) and tropomyosin kinase A (TRKA), its high-affinity receptor, play a crucial role in pathogenesis through cell proliferation, angiogenesis, invasion, and migration. NGF/TRKA increase their expression during the progression of EOC by upregulation of oncogenic proteins as vascular endothelial growth factor (VEGF) and c-Myc. Otherwise, the expression of most oncoproteins is regulated by microRNAs (miRs). Our laboratory group reported that the tumoral effect of NGF/TRKA depends on the regulation of miR-145 levels in EOC. Currently, mitochondria have been proposed as new therapeutic targets to activate the apoptotic pathway in the cancer cell. The mitochondria are involved in a myriad of functions as energy production, redox control, homeostasis of Ca+2, and cell death. We demonstrated that NGF stimulation produces an augment in the Bcl-2/BAX ratio, which supports the anti-apoptotic effects of NGF in EOC cells. The review aimed to discuss the role of mitochondria in the interplay between NGF/TRKA and miR-145 and possible therapeutic strategies that may decrease mortality due to EOC.
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Affiliation(s)
- Daniela B. Vera
- Laboratory of Endocrinology and Reproductive Biology, Clinical Hospital University of Chile, Santiago 8380456, Chile; (D.B.V.); (A.N.F.)
| | - Allison N. Fredes
- Laboratory of Endocrinology and Reproductive Biology, Clinical Hospital University of Chile, Santiago 8380456, Chile; (D.B.V.); (A.N.F.)
| | - Maritza P. Garrido
- Laboratory of Endocrinology and Reproductive Biology, Clinical Hospital University of Chile, Santiago 8380456, Chile; (D.B.V.); (A.N.F.)
- Obstetrics and Gynecology Departament, Faculty of Medicine, University of Chile, Santiago 8380453, Chile
- Correspondence: (M.P.G.); (C.R.)
| | - Carmen Romero
- Laboratory of Endocrinology and Reproductive Biology, Clinical Hospital University of Chile, Santiago 8380456, Chile; (D.B.V.); (A.N.F.)
- Obstetrics and Gynecology Departament, Faculty of Medicine, University of Chile, Santiago 8380453, Chile
- Correspondence: (M.P.G.); (C.R.)
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12
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Liu Y, Ao X, Ji G, Zhang Y, Yu W, Wang J. Mechanisms of Action And Clinical Implications of MicroRNAs in the Drug Resistance of Gastric Cancer. Front Oncol 2021; 11:768918. [PMID: 34912714 PMCID: PMC8667691 DOI: 10.3389/fonc.2021.768918] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/15/2021] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignant tumors of digestive systems worldwide, with high recurrence and mortality. Chemotherapy is still the standard treatment option for GC and can effectively improve the survival and life quality of GC patients. However, with the emergence of drug resistance, the clinical application of chemotherapeutic agents has been seriously restricted in GC patients. Although the mechanisms of drug resistance have been broadly investigated, they are still largely unknown. MicroRNAs (miRNAs) are a large group of small non-coding RNAs (ncRNAs) widely involved in the occurrence and progression of many cancer types, including GC. An increasing amount of evidence suggests that miRNAs may play crucial roles in the development of drug resistance by regulating some drug resistance-related proteins as well as gene expression. Some also exhibit great potential as novel biomarkers for predicting drug response to chemotherapy and therapeutic targets for GC patients. In this review, we systematically summarize recent advances in miRNAs and focus on their molecular mechanisms in the development of drug resistance in GC progression. We also highlight the potential of drug resistance-related miRNAs as biomarkers and therapeutic targets for GC patients.
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Affiliation(s)
- Ying Liu
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China.,School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Xiang Ao
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Guoqiang Ji
- Clinical Laboratory, Linqu People's Hospital, Linqu, China
| | - Yuan Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Wanpeng Yu
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Jianxun Wang
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
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13
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Emerging Therapeutic Agents for Colorectal Cancer. Molecules 2021; 26:molecules26247463. [PMID: 34946546 PMCID: PMC8707340 DOI: 10.3390/molecules26247463] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/03/2021] [Accepted: 12/06/2021] [Indexed: 02/07/2023] Open
Abstract
There are promising new therapeutic agents for CRC patients, including novel small-molecule inhibitors and immune checkpoint blockers. We focused on emerging CRC’s therapeutic agents that have shown the potential for progress in clinical practice. This review provides an overview of tyrosine kinase inhibitors targeting VEGF and KIT, BRAF and MEK inhibitors, TLR9 agonist, STAT3 inhibitors, and immune checkpoint blockers (PD1/PDL-1 inhibitors), for which recent advances have been reported. These new agents have the potential to provide benefits to CRC patients with unmet medical needs.
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14
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Hassn Mesrati M, Syafruddin SE, Mohtar MA, Syahir A. CD44: A Multifunctional Mediator of Cancer Progression. Biomolecules 2021; 11:1850. [PMID: 34944493 PMCID: PMC8699317 DOI: 10.3390/biom11121850] [Citation(s) in RCA: 218] [Impact Index Per Article: 54.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/23/2021] [Accepted: 11/02/2021] [Indexed: 12/15/2022] Open
Abstract
CD44, a non-kinase cell surface transmembrane glycoprotein, has been widely implicated as a cancer stem cell (CSC) marker in several cancers. Cells overexpressing CD44 possess several CSC traits, such as self-renewal and epithelial-mesenchymal transition (EMT) capability, as well as a resistance to chemo- and radiotherapy. The CD44 gene regularly undergoes alternative splicing, resulting in the standard (CD44s) and variant (CD44v) isoforms. The interaction of such isoforms with ligands, particularly hyaluronic acid (HA), osteopontin (OPN) and matrix metalloproteinases (MMPs), drive numerous cancer-associated signalling. However, there are contradictory results regarding whether high or low CD44 expression is associated with worsening clinicopathological features, such as a higher tumour histological grade, advanced tumour stage and poorer survival rates. Nonetheless, high CD44 expression significantly contributes to enhanced tumourigenic mechanisms, such as cell proliferation, metastasis, invasion, migration and stemness; hence, CD44 is an important clinical target. This review summarises current research regarding the different CD44 isoform structures and their roles and functions in supporting tumourigenesis and discusses CD44 expression regulation, CD44-signalling pathways and interactions involved in cancer development. The clinical significance and prognostic value of CD44 and the potential of CD44 as a therapeutic target in cancer are also addressed.
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Affiliation(s)
- Malak Hassn Mesrati
- Nanobiotechnology Research Group, Department of Biochemistry, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang 43400 UPM, Selangor, Malaysia;
| | - Saiful Effendi Syafruddin
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (S.E.S.); (M.A.M.)
| | - M. Aiman Mohtar
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (S.E.S.); (M.A.M.)
| | - Amir Syahir
- Nanobiotechnology Research Group, Department of Biochemistry, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang 43400 UPM, Selangor, Malaysia;
- UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang 43400 UPM, Selangor, Malaysia
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15
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Mondal P, Meeran SM. microRNAs in cancer chemoresistance: The sword and the shield. Noncoding RNA Res 2021; 6:200-210. [PMID: 34977437 PMCID: PMC8669341 DOI: 10.1016/j.ncrna.2021.12.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 12/03/2021] [Accepted: 12/03/2021] [Indexed: 02/07/2023] Open
Abstract
Cancer is a multifactorial disease and one of the leading causes of mortality worldwide. Cancer cells develop multiple strategies to reduce drug sensitivity and eventually lead to chemoresistance. Chemoresistance is initiated either by intrinsic factors or due to the prolonged use of chemotherapeutics as acquired resistance. Further, chemoresistance is also one of the major reasons behind tumor recurrence and metastasis. Therefore, overcoming chemoresistance is one of the primary challenges in cancer therapy. Several mechanisms are involved in chemoresistance. Among them, the key role of ABC transporters and tumor microenvironment have been well studied. Recently, microRNAs (miRNAs) regulation in tumor development, metastasis, and chemotherapy has got wider interest due to its role in regulating genes involved in cancer progression and therapy. Noncoding RNAs, including miRNAs, have been associated with the regulation of tumor-suppressor and tumor-promoter genes. Further, miRNA can also be used as a reliable diagnostic and prognostic marker to predict the stage and types of cancer. Recent evidences have revealed that miRNAs regulation also influences the function of drug transporters and the tumor microenvironment, which affects chemosensitivity to cancer cells. Therefore, miRNAs can be a promising target to reverse back chemosensitivity in cancer cells. This review comprehensively discusses the mechanisms involved in cancer chemoresistance and its regulation by miRNAs.
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Affiliation(s)
- Priya Mondal
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, 570020, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Syed Musthapa Meeran
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, 570020, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
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16
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Ma Y, Ren Y, Wen H, Cui C. circCOL1A1 Promotes the Progression of Gastric Cancer Cells through Sponging miR-145 to Enhance RABL3 Expression. J Immunol Res 2021; 2021:6724854. [PMID: 34631898 PMCID: PMC8494588 DOI: 10.1155/2021/6724854] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 07/19/2021] [Indexed: 12/09/2022] Open
Abstract
Circular RNA has been reported to be a new noncoding RNA which plays important roles in tumor progression. One of the most common functions of circular RNA is to regulate microRNA expression by acting as a microRNA sponge. However, the circular RNA expression profile and function remain mostly unclear in gastric cancer. In the study, we explored the expression and function of circCOL1A1 (hsa_circ_0044556) in gastric cancer. We performed RT-PCR with divergent primers, mRNA stability assay, and RNase R digestion assay to characterize circCOL1A1 in gastric cancer cell lines. qRT-PCR was applied to detect the level of circCOL1A1 in both gastric cancer cell lines and tissues. Gain- and loss-of-function studies were carried out to detect the influence of circCOL1A1 on gastric cancer cells by performing CCK8, migration, and invasion assays. The regulation of the downstream genes was identified by qRT-PCR, western blot assay, dual luciferase assay, and RNA pull-down assay. The results showed that circCOL1A1 was highly expressed in both gastric cancer cells and tissues. Silence of circCOL1A1 inhibited the proliferation, migration, and invasion of gastric cancer cells. circCOL1A1 regulated the expression of miR-145 by acting as a microRNA sponge, and the influence of circCOL1A1 could be abrogated by miR-145 mimics. Our research shows that miR-145 plays its functions through targeting and regulating RABL3. Inhibition of circCOL1A1/miR-145/RABL3 could effectively suppress gastric cancer cell proliferation, migration, and invasion. circCOL1A1 also promote the transformation of M1 into M2 macrophage. Our study identified circCOL1A1 as a novel oncogenic circRNA and will provide more information for gastric cancer therapy.
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Affiliation(s)
- Yue Ma
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu 610072, Sichuan Province, China
| | - Yanyi Ren
- Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu 610072, Sichuan Province, China
| | - Huitao Wen
- Department of Nephrology, Chengdu First People's Hospital, No. 18 Norn Vientiane Road, Chengdu, Hi-Tech Zone 610041, Sichuan Province, China
| | - Chengcheng Cui
- Department of Pediatrics, Huai'an Second People's Hospital, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, China
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17
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Yang A, Liu X, Liu P, Feng Y, Liu H, Gao S, Huo L, Han X, Wang J, Kong W. LncRNA UCA1 promotes development of gastric cancer via the miR-145/MYO6 axis. Cell Mol Biol Lett 2021; 26:33. [PMID: 34238213 PMCID: PMC8268585 DOI: 10.1186/s11658-021-00275-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Accepted: 06/28/2021] [Indexed: 12/13/2022] Open
Abstract
Background Long noncoding RNA (lncRNA), urothelial carcinoma-associated 1 (UCA1) is aberrantly expressed in multiple cancers and has been verified as an oncogene. However, the underlying mechanism of UCA1 in the development of gastric cancer is not fully understood. In the present study, we aimed to identify how UCA1 promotes gastric cancer development. Methods The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) data were used to analyze UCA1 and myosin VI (MYO6) expression in gastric cancer. Western blot and quantitative real-time PCR (QPCR) were performed to test the expression level of the UCA1/miR-145/MYO6 axis in gastric cancer cell lines and tissues. The roles of the UCA1/miR-145/MYO6 axis in gastric cancer in vitro and in vivo were investigated by CCK-8 assay, flow cytometry, siRNAs, immunohistochemistry, and a mouse xenograft model. The targeted relationship among UCA1, miR-145, and MYO6 was predicted using LncBase Predicted v.2 and TargetScan online software, and then verified by luciferase activity assay and RNA immunoprecipitation. Results UCA1 expression was higher but miR-145 expression was lower in gastric cancer cell lines or tissues, compared to the adjacent normal cell line or normal tissues. Function analysis verified that UCA1 promoted cell proliferation and inhibited cell apoptosis in the gastric cancer cells in vitro and in vivo. Mechanistically, UCA1 could bind directly to miR-145, and MYO6 was found to be a downstream target gene of miR-145. miR-145 mimics or MYO6 siRNAs could partly reverse the effect of UCA1 on gastric cancer cells. Conclusions UCA1 accelerated cell proliferation and inhibited cell apoptosis through sponging miR-145 to upregulate MYO6 expression in gastric cancer, indicating that the UCA1/miR-145/MYO6 axis may serve as a potential therapeutic target for gastric cancer.
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Affiliation(s)
- An Yang
- Handan Central Hospital, Handan, 056001, Hebei Province, China
| | - Xin Liu
- Affiliated Hospital of Hebei University of Engineering, Handan, 056002, Hebei Province, China
| | - Ping Liu
- Handan Central Hospital, Handan, 056001, Hebei Province, China
| | - Yunzhang Feng
- Handan Central Hospital, Handan, 056001, Hebei Province, China
| | - Hongbo Liu
- Handan Central Hospital, Handan, 056001, Hebei Province, China
| | - Shen Gao
- Handan First Hospital, Handan, 056002, Hebei Province, China
| | - Limin Huo
- Handan First Hospital, Handan, 056002, Hebei Province, China
| | - Xinyan Han
- Handan Central Hospital, Handan, 056001, Hebei Province, China
| | - Jurong Wang
- Handan Central Hospital, Handan, 056001, Hebei Province, China
| | - Wei Kong
- Handan Central Hospital, Handan, 056001, Hebei Province, China.
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18
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Dai ZT, Xiang Y, Duan YY, Wang J, Li JP, Zhang HM, Cheng C, Wang Q, Zhang TC, Liao XH. MiR-17-5p and MKL-1 modulate stem cell characteristics of gastric cancer cells. Int J Biol Sci 2021; 17:2278-2293. [PMID: 34239355 PMCID: PMC8241736 DOI: 10.7150/ijbs.57338] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Accepted: 05/22/2021] [Indexed: 12/13/2022] Open
Abstract
Effectively targeting cancer stem cells to treat cancer has great therapeutic prospects. However, the effect of microRNA miR-17/MKL-1 on gastric cancer stem cells has not been studied yet. This study preliminarily explored the mechanism of miR-17/MKL-1 in gastric cancer stem cells. Many previous reports have indicated that microRNA and EMT regulated cancer stem cell characteristics, and miR-17 and MKL-1 were involved as a critical gene in migration and invasion in the EMT pathway. Through RT-PCR, Western Blot, flow cytometry, immunofluorescence, sphere formation xenograft tumor assays and drug resistance, the role of miR-17-5p and MKL-1 on promoting stem cell-like properties of gastric cancer were verified in vivo and vitro. Next, MKL-1 targets CD44, EpCAM, and miR -17-5p promoter verified by luciferase assay and ChIP. Besides, the TCGA database analysis found that both miR-17-5p and MKL-1 increased in gastric cancer, and the prognostic survival of the MKL-1 high expression group was reduced. It is found that MKL-1 promotes expression by targeting miR-17, CD44 and EpCAM promoters. Besides, the TCGA database analysis found that both miR-17-5p and MKL-1 increased in gastric cancer, and the prognostic survival of the MKL-1 high expression group was reduced. These findings reveal new regulatory signaling pathways for gastric cancer stem cells, thus it give new insights on potential early diagnosis and/or molecular therapy for gastric cancer.
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Affiliation(s)
- Zhou-Tong Dai
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China
| | - Yuan Xiang
- Department of Medical Laboratory, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Hubei, 430014, P.R. China
| | - Yuan-Yuan Duan
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China
| | - Jun Wang
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China
| | - Jia Peng Li
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China
| | - Hui-Min Zhang
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China
| | - Chao Cheng
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qiong Wang
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China
| | - Tong-Cun Zhang
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China.,Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, Tinajin, 300457, P.R. China
| | - Xing-Hua Liao
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China
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19
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Gallardo Martin E, Cousillas Castiñeiras A. Vitamin D modulation and microRNAs in gastric cancer: prognostic and therapeutic role. Transl Cancer Res 2021; 10:3111-3127. [PMID: 35116620 PMCID: PMC8797897 DOI: 10.21037/tcr-20-2813] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Accepted: 10/10/2020] [Indexed: 12/11/2022]
Abstract
Gastric adenocarcinoma arises after a complex interaction between the host and environmental factors. Tumor location and TNM are the tools that currently guide treatment decisions. Surgery is the only curative treatment, but relapse is common. After relapse or advanced staged disease survival is poor and systemic treatment has modestly improved survival. An association between sun exposure, vitamin D status and gastric cancer (GC) incidence and mortality has been reported. The molecular differences of the histological subtypes and the new molecular classifications account for the great heterogeneity of this disease and are the basis for the discovery of new therapeutic targets. New prognostic and predictive factors are essential and microRNAs (miRNAs) are endogenous small non-coding RNA molecules with a great potential for diagnosis, prognosis and treatment of cancer. There are hundreds of miRNAs with altered expression in tumor gastric tissue when compared to normal gastric tissue. Many of these miRNAs are associated with clinicopathological variables and survival in patients with GC. Furthermore, the expression of some of these miRNAs with prognostic importance in CG is influenced by vitamin D and others are mediators of some of the actions of this vitamin. This review aims to update the evidence on several miRNAs with prognostic value and therapeutic potential in GC, whose expression may be influenced by vitamin D or may regulate vitamin D signaling.
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Affiliation(s)
- Elena Gallardo Martin
- Medical Oncology Department in Complejo Hospitalario Universitario de Pontevedra, University Hospital of Pontevedra, CP 36001 Pontevedra, Spain
| | - Antia Cousillas Castiñeiras
- Medical Oncology Department in Complejo Hospitalario Universitario de Pontevedra, University Hospital of Pontevedra, CP 36001 Pontevedra, Spain
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20
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Gomari MM, Farsimadan M, Rostami N, Mahmoudi Z, Fadaie M, Farhani I, Tarighi P. CD44 polymorphisms and its variants, as an inconsistent marker in cancer investigations. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2021; 787:108374. [PMID: 34083044 DOI: 10.1016/j.mrrev.2021.108374] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 12/23/2020] [Accepted: 03/18/2021] [Indexed: 12/24/2022]
Abstract
Among cell surface markers, CD44 is considered the main marker for identifying and isolating the cancer stem cells (CSCs) among other cells and has attracted significant attention in a variety of research areas. Many studies have shown the essential roles of CD44 in initiation, metastasis, and tumorigenesis in different types of cancer; however, the validity of CD44 as a therapeutic or diagnostic target has not been fully confirmed in some other studies. Whereas the association of specific single nucleotide polymorphisms (SNPs) in the CD44 gene and related variants with cancer risk have been observed in clinical investigations, the significance of these findings remains controversial. Here, we aimed to provide an up-to-date overview of recent studies on the association of CD44 polymorphisms and its variants with different kinds of cancer to determine whether or not it can be used as an appropriate candidate for cancer tracking.
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Affiliation(s)
- Mohammad Mahmoudi Gomari
- Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Marziye Farsimadan
- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran
| | - Neda Rostami
- Department of Chemical Engineering, Faculty of Engineering, Arak University, Iran
| | - Zahra Mahmoudi
- Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mahmood Fadaie
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ibrahim Farhani
- Department of Medical Biotechnology, Faculty of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Golestan, Iran
| | - Parastoo Tarighi
- Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran.
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21
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Yang WQ, Zhao WJ, Zhu LL, Xu SJ, Zhang XL, Liang Y, Ding XF, Kiselyov A, Chen G. XMD-17-51 Inhibits DCLK1 Kinase and Prevents Lung Cancer Progression. Front Pharmacol 2021; 12:603453. [PMID: 33762936 PMCID: PMC7982674 DOI: 10.3389/fphar.2021.603453] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 01/15/2021] [Indexed: 11/13/2022] Open
Abstract
Doublecortin-like kinase 1 (DCLK1) is a cancer stem cell marker that is highly expressed in various types of human cancer, and a protein kinase target for cancer therapy that is attracting increasing interest. However, no drug candidates targeting DCLK1 kinase have been developed in clinical trials to date. XMD-17-51 was found herein to possess DCLK1 kinase inhibitory activities by cell-free enzymatic assay. In non-small cell lung carcinoma (NSCLC) cells, XMD-17-51 inhibited DCLK1 and cell proliferation, while DCLK1 overexpression impaired the anti-proliferative activity of XMD-17-51 in A549 cell lines. Consequently, XMD-17-51 decreased Snail-1 and zinc-finger-enhancer binding protein 1 protein levels, but increased those of E-cadherin, indicating that XMD-17-51 reduces epithelial-mesenchymal transition (EMT). Furthermore, sphere formation efficiency was significantly decreased upon XMD-17-51 treatment, and XMD-17-51 reduced the expression of stemness markers such as β-catenin, and pluripotency factors such as SOX2, NANOG and OCT4. However, the percentage of ALDH+ cells was increased significantly following treatment with XMD-17-51 in A549 cells, possibly due to EMT inhibition. In combination, the present data indicated that XMD-17-51 inhibited DCLK1 kinase activity in a cell-free assay with an IC50 of 14.64 nM, and decreased DCLK1 protein levels, cell proliferation, EMT and stemness in NSCLC cell lines. XMD-17-51 has the potential to be a candidate drug for lung cancer therapy.
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Affiliation(s)
- Wei-Qiang Yang
- Department of Clinical Medicine, School of Medicine, Taizhou University, Taizhou, China.,Graduate School of Medicine, Hebei North University, Zhangjiakou, China
| | - Wei-Jun Zhao
- Department of Clinical Medicine, School of Medicine, Taizhou University, Taizhou, China.,Graduate School of Medicine, Hebei North University, Zhangjiakou, China
| | - Liu-Lian Zhu
- Department of Clinical Medicine, School of Medicine, Taizhou University, Taizhou, China.,Graduate School of Medicine, Hebei North University, Zhangjiakou, China
| | - Shuai-Jun Xu
- Department of Clinical Medicine, School of Medicine, Taizhou University, Taizhou, China.,Graduate School of Medicine, Hebei North University, Zhangjiakou, China
| | | | - Yong Liang
- Department of Clinical Medicine, School of Medicine, Taizhou University, Taizhou, China
| | - Xiao-Fei Ding
- Department of Experimental and Clinical Medicine, School of Medicine, Taizhou University, Taizhou, China
| | - Alexander Kiselyov
- Department of Pharmaceutical Engineering, School of Pharmaceutical Chemical and Materials Engineering, Taizhou University, Taizhou, China
| | - Guang Chen
- Department of Pharmacology, School of Medicine, Taizhou University, Taizhou, China
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22
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Zeng X, Wang HY, Bai SY, Pu K, Wang YP, Zhou YN. The Roles of microRNAs in Multidrug-Resistance Mechanisms in Gastric Cancer. Curr Mol Med 2021; 20:667-674. [PMID: 32209033 DOI: 10.2174/1566524020666200226124336] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 02/10/2020] [Accepted: 02/14/2020] [Indexed: 12/24/2022]
Abstract
Multidrug resistance (MDR) is one of the most significant reasons for the
chemotherapeutics failure in gastric cancer. Although accumulating investigations and
researches have been made to elucidate the mechanisms of multidrug resistance, the
detail is far from completely understood. The importance of microRNAs in cancer
chemotherapeutic resistance has been demonstrated recently, which provides a new
strategy to overcome multidrug resistance. The different mechanisms are related to the
phenomena of MDR itself and the roles of miRNAs in these multi-mechanisms by which
MDR is acquired. In turn, the aim of this review was to summarize recent publications of
microRNAs in regulating MDR in gastric cancer, thereby potentially developing as
targeted therapies. Further unraveling the roles of microRNAs in MDR mechanisms
including the ATP-binding cassette (ABC) transporter family, autophagy induction,
cancer stem cell regulation, hypoxia induction, DNA damage and repair, epigenetic
regulation, and exosomes in gastric cancer will be helpful for us to win the battle against
it.
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Affiliation(s)
- Xi Zeng
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
| | - Hao-Ying Wang
- Department of Gastroenterology, The first Hospital of Lanzhou University, Lanzhou, China
| | - Su-Yang Bai
- Department of Gastroenterology, The first Hospital of Lanzhou University, Lanzhou, China
| | - Ke Pu
- Department of Gastroenterology, The first Hospital of Lanzhou University, Lanzhou, China
| | - Yu-Ping Wang
- Department of Gastroenterology, The first Hospital of Lanzhou University, Lanzhou, China
| | - Yong-Ning Zhou
- Department of Gastroenterology, The first Hospital of Lanzhou University, Lanzhou, China
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23
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Xu H, Niu M, Yuan X, Wu K, Liu A. CD44 as a tumor biomarker and therapeutic target. Exp Hematol Oncol 2020; 9:36. [PMID: 33303029 PMCID: PMC7727191 DOI: 10.1186/s40164-020-00192-0] [Citation(s) in RCA: 215] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Accepted: 11/21/2020] [Indexed: 12/15/2022] Open
Abstract
CD44, a complex transmembrane glycoprotein, exists in multiple molecular forms, including the standard isoform CD44s and CD44 variant isoforms. CD44 participates in multiple physiological processes, and aberrant expression and dysregulation of CD44 contribute to tumor initiation and progression. CD44 represents a common biomarker of cancer stem cells, and promotes epithelial-mesenchymal transition. CD44 is involved in the regulation of diverse vital signaling pathways that modulate cancer proliferation, invasion, metastasis and therapy-resistance, and it is also modulated by a variety of molecules in cancer cells. In addition, CD44 can serve as an adverse prognostic marker among cancer population. The pleiotropic roles of CD44 in carcinoma potentially offering new molecular target for therapeutic intervention. Preclinical and clinical trials for evaluating the pharmacokinetics, efficacy and drug-related toxicity of CD44 monoclonal antibody have been carried out among tumors with CD44 expression. In this review, we focus on current data relevant to CD44, and outline CD44 structure, the regulation of CD44, functional properties of CD44 in carcinogenesis and cancer progression as well as the potential CD44-targeting therapy for cancer management.
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Affiliation(s)
- Hanxiao Xu
- Department of Pediatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Mengke Niu
- Department of Medical Oncology, The Affiliated Tumor Hospital of Zhengzhou University: Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Xun Yuan
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China
| | - Kongming Wu
- Department of Medical Oncology, The Affiliated Tumor Hospital of Zhengzhou University: Henan Cancer Hospital, Zhengzhou, 450008, China. .,Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China.
| | - Aiguo Liu
- Department of Pediatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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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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Zheng RP, Ma DK, Li Z, Zhang HF. MiR-145 Regulates the Chemoresistance of Hepatic Carcinoma Cells Against 5-Fluorouracil by Targeting Toll-Like Receptor 4. Cancer Manag Res 2020; 12:6165-6175. [PMID: 32801865 PMCID: PMC7398893 DOI: 10.2147/cmar.s257598] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 06/19/2020] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND 5-fluorouracil (5-FU) is a common drug for hepatic carcinoma (HCC), but the drug resistance of clinical chemotherapy restricts its use. Studies have demonstrated that miRNA molecules can act as a chemoresistance regulator in drug resistance of tumors, whereas the role of miR-145 in the 5-FU-resistant HCC remains unclear. OBJECTIVE To explore the prognostic value of miR-145 in HCC and its molecular mechanism in 5-FU-resistant HCC cells. METHODS A qRT-PCR assay was conducted to quantify miR-145 in HCC tissues and 5-FU-resistant HCC cells. The Cell Counting Kit-8 (CCK-8) and flow cytometry were adopted to analyze the proliferation and apoptosis of 5-FU-resistant HCC cells. The Western blot was adopted to quantify toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and apoptosis-related proteins. Moreover, an in vivo tumor xenotransplantation of nude mice was conducted to determine the effect of miR-145 on 5-FU-resistant HCC cells. RESULTS MiR-145 was expressed lowly in HCC tissues and cells, and linked to high TNM staging and lymph node metastasis of HCC patients. Down-regulation of miR-145 indicated a poorer prognosis and it promoted drug resistance of HCC cells and inhibited cell apoptosis. In contrast, miR-145 overexpression improved the sensitivity of HCC cells to 5-FU and enhanced the inhibition of 5-FU on tumor growth. The luciferase reporter gene assay showed that TLR4 was the direct target of miR-145, and the Western blot assay revealed that overexpression of TLR4 reversed the inhibitory effect of miR-145 overexpression on TLR4 and MyD88 protein and the effects of it on apoptosis-related proteins. CONCLUSION MiR-145 is an inhibiting factor in HCC and can target TLR4 to mediate the chemoresistance of HCC, which may provide novel ideas for treating HCC.
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Affiliation(s)
- Rui-Peng Zheng
- Department of Interventional Therapy, The First Hospital of Jilin University, Changchun, Jilin Province130021, People’s Republic of China
| | - Dong-Kai Ma
- Department of Gastroenterology and Hepatology, Qian Wei Hospital of Jilin Province, Changchun, Jilin Province130012, People’s Republic of China
| | - Zhuo Li
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin Province130021, People’s Republic of China
| | - Hai-Feng Zhang
- Department of Interventional Therapy, The First Hospital of Jilin University, Changchun, Jilin Province130021, People’s Republic of China
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Xu W, Hua Y, Deng F, Wang D, Wu Y, Zhang W, Tang J. MiR-145 in cancer therapy resistance and sensitivity: A comprehensive review. Cancer Sci 2020; 111:3122-3131. [PMID: 32506767 PMCID: PMC7469794 DOI: 10.1111/cas.14517] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 05/22/2020] [Accepted: 05/27/2020] [Indexed: 12/13/2022] Open
Abstract
MircoRNA (miRNA) are a group of small, non–coding, regulatory RNA with an average length of approximately 22 nucleotides, which mostly modulate gene expression post–transcriptionally through complementary binding to the 3ʹ‐untranslated region (3ʹ‐UTR) of multiple target genes. Emerging evidence has shown that miRNA are frequently dysregulated in a variety of human malignancies. Among them, microRNA‐145 (miR‐145) has been increasingly identified as a critical suppressor of carcinogenesis and therapeutic resistance. Resistance to tumor therapy is a challenge in cancer treatment due to the daunting range of resistance mechanisms. We reviewed the status quo of recent advancements in the knowledge of the functional role of miR‐145 in therapeutic resistance and the tumor microenvironment. It may serve as an innovative biomarker for therapeutic response and cancer prognosis.
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Affiliation(s)
- Wenxiu Xu
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yuting Hua
- Department of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China
| | - Fei Deng
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Dandan Wang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yang Wu
- The Jiangsu Province Research Institute for Clinical Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wei Zhang
- The Jiangsu Province Research Institute for Clinical Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jinhai Tang
- Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Men Y, Zhang L, Ai H. [MicroRNA-145-5p over-expression suppresses proliferation, migration and invasion and promotes apoptosis of human endometrial cancer cells by targeting dual specific phosphatase 6]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2020; 40:61-66. [PMID: 32376567 DOI: 10.12122/j.issn.1673-4254.2020.01.10] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To investigate the role of microRNA-145-5p (miR-145-5p) in regulating the proliferation, migration, invasion and apoptosis of human endometrial carcinoma cells. METHODS Human endometrial carcinoma Ishikawa cells were transfected with miR-145-5p mimic, miR-145-5p inhibitor, or their negative controls via liposome (Lipo2000), and the changes in the expression of miR-145-5p was verified by real-time PCR. The effects of overexpression or inhibition of miR-145-5p on the proliferation, migration, invasion and apoptosis of the cells were evaluated using MTT assay, wound healing assay, Transwell assay or flow cytometry. Bioinformatic analysis was performed to predict the target genes of miR-145-5p. The mRNA and protein expression levels of the downstream target of miR-145-5p, namely dual specific phosphatase 6 (DUSP6), were detected using real-time PCR and Western blotting. RESULTS Transfection of the cells with miR-145-5p mimic significantly suppressed the proliferation of Ishikawa cells, while transfection with miR-145-5p inhibitor obvious enhanced the proliferation of the cells (P < 0.05). Over-expression of miR-145-5p significantly suppressed the migration and invasion and promoted apoptosis of the cells, and inhibition of miR-145-5p caused the reverse changes (P < 0.05). Bioinformatic analysis showed that DUSP6 was the potential target gene of miR-145-5p. Over-expression of miR-145-5p significantly lowered while inhibition of miR-145-5p significantly enhanced the expression of DUSP6 protein (P < 0.05). CONCLUSIONS Overexpression of miR-145-5p inhibits the proliferation, migration and invasion and promotes apoptosis of endometrial cancer cells possibly by negative regulation of DUSP6 expression.
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Affiliation(s)
- Yingchao Men
- Department of Biochemistry and Molecular Biology, Jinzhou Medical University, Jinzhou 121000, China
| | - Lei Zhang
- Department of Biochemistry and Molecular Biology, Jinzhou Medical University, Jinzhou 121000, China
| | - Hao Ai
- Department of Gynecology, Third Affiliated Hospital, Jinzhou Medical University, Jinzhou 121000, China
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Zhou J, Zhang X, Li W, Chen Y. MicroRNA-145-5p regulates the proliferation of epithelial ovarian cancer cells via targeting SMAD4. J Ovarian Res 2020; 13:54. [PMID: 32366274 PMCID: PMC7199349 DOI: 10.1186/s13048-020-00656-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 04/24/2020] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Epithelial ovarian cancer (EOC) is one of the most prevalent malignancies affecting females worldwide; however, its etiology mechanism remains unclear. In various malignancies, miR-145-5p is a widely accepted and versatile miRNA. Therefore, our research focused on exploring the activity and etiology of miR-145-5p in the modulation of metastasis, migration, and proliferation of EOC cells. The direct reactions between the 3'UTRs of SMAD4 mRNA and miR-145-5p were verified using dual luciferase reporter test. SKOV-3 cells were subsequently transfected using miR-145-5p mimics. Cell migration, death, and proliferation were evaluated using MTT, flow cytometry, and Transwell test. In addition, SMAD4 transcription and translation were evaluated using qRT-PCR and Western blot. RESULTS We found that miR-145-5p expression was repressed prevalently in EOC tissues, apart from SMAD4 upregulation. Excessive miR-145-5p expression remarkably reinforced EOC cell death and repressed EOC cell proliferation. Furthermore, upregulated miR-145-5p expression noticeably repressed migration via MMP-2 and MMP-9 downregulation. Moreover, SMAD4 was downregulated via miR-145-5p transfection. The dual luciferase test revealed that miR-145-5p directly targeted SMAD4. CONCLUSIONS Our research suggests that miR-145-5p serves as a malignancy repressor and exerts an essential impact on inhibiting malignancy generation and reinforcing EOC death via targeting SMAD4. MiR-145-5p application could serve as a promising strategy to treat EOC.
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Affiliation(s)
- Jie Zhou
- Department of Obstetrics and Gynecology, Xi’an Gaoxin Hospital, No. 16 Tuanjie South Road, Xi’an, 710075 Shaanxi China
| | - Xiyi Zhang
- Department of Obstetrics and Gynecology, Xi’an Gaoxin Hospital, No. 16 Tuanjie South Road, Xi’an, 710075 Shaanxi China
| | - Weiling Li
- Department of Obstetrics and Gynecology, Xi’an Gaoxin Hospital, No. 16 Tuanjie South Road, Xi’an, 710075 Shaanxi China
| | - Yuanyuan Chen
- Department of Obstetrics and Gynecology, Xi’an Gaoxin Hospital, No. 16 Tuanjie South Road, Xi’an, 710075 Shaanxi China
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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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Yang J. Identification of novel biomarkers, MUC5AC, MUC1, KRT7, GAPDH, CD44 for gastric cancer. Med Oncol 2020; 37:34. [PMID: 32219571 DOI: 10.1007/s12032-020-01362-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 03/10/2020] [Indexed: 01/19/2023]
Abstract
Gastric cancer (GC) is one of the most common malignant tumors in the world, and it is also the third largest cause of cancer-related death in the world. As far as we know, no biomarker has been widely accepted for early diagnosis and prognosis prediction of gastric cancer. The purpose of this study is to find potential biomarkers to predict the prognosis of GC. The gene expression profiles of GSE2685 were downloaded from GEO database. Morpheus was used to calculate the differentially expressed genes (DEGs) between primary advanced gastric cancer tissues and noncancerous gastric tissues. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were performed, and protein-protein interaction (PPI) network of DEGs was constructed. Kaplan-Meier Plotter was used to determine the overall survival (OS) outcomes of UC5AC, MUC1, KRT7, GAPDH, CD44, and GEPIA was used to determine the Pearson correlation analysis. In total, 710 DEGs were identified in GC, including 396 upregulated genes and 314 downregulated genes. GO enrichment revealed that they were mainly enriched in binding, catalytic activity, cellular process and cell. KEGG pathway revealed that they were mainly enriched in metabolic pathways, pathways in cancer and PI3K-Akt signaling pathway. MUC5AC, MUC1, KRT7, GAPDH, CD44 were identified from the PPI network. MUC5AC, MUC1, KRT7, GAPDH, CD44 were demonstrated to have prognostic value for patients with GC. MUC5AC, MUC1 exhibited low expression levels in GC tissues, KRT7, GAPDH, CD44 presented high expression levels in GC tissues. In particular, KRT7 is hardly expressed in normal gastric tissues. MUC5AC and MUC1 were negatively correlated with GAPDH, CD44, respectively; and GAPDH was positively correlated with CD44 and KRT7, respectively. Moreover. MUC5AC, MUC1, KRT7, GAPDH, and CD44 are not only related to GC but also to apoptosis pathway. Results from the present study suggested that MUC5AC, MUC1, KRT7, GAPDH, CD44 may represent novel prognostic biomarkers for GC.
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Affiliation(s)
- Jie Yang
- Central Laboratory, Danyang People's Hospital of Jiangsu Province, Danyang, Jiangsu, China.
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31
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Sun B, Sun H, Wang Q, Wang X, Quan J, Dong D, Lun Y. Circular RNA circMAN2B2 promotes growth and migration of gastric cancer cells by down-regulation of miR-145. J Clin Lab Anal 2020; 34:e23215. [PMID: 32020674 PMCID: PMC7307361 DOI: 10.1002/jcla.23215] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 12/27/2019] [Accepted: 01/01/2020] [Indexed: 02/06/2023] Open
Abstract
Background CircMAN2B2 is a newly discovered circRNA that has been found to be an oncogene in lung cancer and glioma. The present study was designed to reveal the role of circMAN2B2 in gastric carcinoma (GC). Methods qRT‐PCR method was utilized to examine circMAN2B2 expression in GC tissues and paracancerous tissues. Next, circMAN2B2 expression in SNU‐16 and AGS cells was silenced by transfection. CCK‐8 assay, colony formation assay, flow cytometer, Transwell assay, and Western blot were conducted for testing cell phenotype changes. Further, the downstream genes and signaling were uncovered by qRT‐PCR and Western blot. Results As relative to paracancerous tissues, circMAN2B2 was high‐expressed in GC tissues. Silence of circMAN2B2 clearly declined SNU‐16 and AGS cells viability, survival, migration but enhanced apoptosis. Meanwhile, silence of circMAN2B2 induced the cleavage of caspases (−3 and −9), down‐regulation of MMPs (−2 and −9), and up‐regulation of miR‐145. The impacts of circMAN2B2 silence toward SNU‐16 and AGS cells were attenuated by miR‐145 silence. Moreover, circMAN2B2 silence deactivated PI3K, AKT while activated JNK through regulating miR‐145. Conclusion This work presented the oncogenic function of circMAN2B2 in GC cells growth and migration. CircMAN2B2 exerted its function possibly through regulating miR‐145 as well as PI3K/AKT and JNK pathways.
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Affiliation(s)
- Bo Sun
- Department of Gastroenterology, The Chinese People's Liberation Army Navy 971 Hospital, Qingdao, China
| | - Haiyuan Sun
- Department of Gastroenterology, The Chinese People's Liberation Army Navy 971 Hospital, Qingdao, China
| | - Qunying Wang
- Department of Gastroenterology, The Chinese People's Liberation Army Navy 971 Hospital, Qingdao, China
| | - Xinhong Wang
- Department of Gastroenterology, The Chinese People's Liberation Army Navy 971 Hospital, Qingdao, China
| | - Jingzi Quan
- Department of Gastroenterology, The Chinese People's Liberation Army Navy 971 Hospital, Qingdao, China
| | - Dongfang Dong
- Department of Gastroenterology, The Chinese People's Liberation Army Navy 971 Hospital, Qingdao, China
| | - Yue Lun
- Department of Gastroenterology, The Chinese People's Liberation Army Navy 971 Hospital, Qingdao, China
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Verma HK, Ratre YK, Mazzone P, Laurino S, Bhaskar LVKS. Micro RNA facilitated chemoresistance in gastric cancer: a novel biomarkers and potential therapeutics. ALEXANDRIA JOURNAL OF MEDICINE 2020; 56:81-92. [DOI: 10.1080/20905068.2020.1779992] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 05/28/2020] [Indexed: 12/13/2022] Open
Affiliation(s)
- Henu Kumar Verma
- Developmental and Stem Cell Biology Laboratory, Institute of Experimental Endocrinology and Oncology CNR, Naples, Italy
- Section of Stem Cell and Development, Istituto di Ricerche Genetiche “Gaetano Salvatore” Biogem, Ariano Irpino, Italy
| | | | - Pellegrino Mazzone
- Section of Stem Cell and Development, Istituto di Ricerche Genetiche “Gaetano Salvatore” Biogem, Ariano Irpino, Italy
| | - Simona Laurino
- Laboratory of Preclinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata (CROB), Rionero in Vulture, Italy
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Liu J, Li H, Liu Y, Sun Y, Wu J, Xiong Z, Li B, Jin T. MiR-143HG Gene Polymorphisms as Risk Factors for Gastric Cancer in Chinese Han Population. Curr Mol Med 2019; 20:536-547. [PMID: 31880258 DOI: 10.2174/1566524020666191227103144] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 12/05/2019] [Accepted: 12/09/2019] [Indexed: 01/10/2023]
Abstract
BACKGROUND MicroRNA (miRNA) is a pivotal regulator of the occurrence and development of various cancers. And gastric cancer (GC) is one of the most common and deadly cancers in the world. The aim of this study is to explore whether the microRNA-143 host gene (miR-143HG) polymorphisms are correlated with the risk of GC. METHODS 5 single-nucleotide polymorphisms (SNPs) were genotyped among 506 patients and 500 healthy controls in Han Chinese population. Multiple genetic models, stratification analysis and haplotype analysis were used to evaluate the association between miR-143HG polymorphisms and GC risk by calculating odds ratios (ORs), 95% confidence intervals (CIs). RESULTS Our results indicated that rs11168100 was associated with decreased risk of GC under the Codominant model (OR = 0.67, 95%CI = 0.52-0.88, p = 0.003), and under the Dominant model (OR = 0.72, 95%CI = 0.56-0.92, p = 0.009). Rs353300 was associated with increased risk of GC under the Recessive model (OR = 1.41, 95%CI = 1.06-1.87, p = 0.017). Further, rs11168100 and rs353300 were correlated with the susceptibility of GC (age > 60 years), and three SNPs (rs12654195, rs353303, and rs353300) were related with the risk of GC (age ≤ 60 years). In addition, two SNPs (rs12654195 and rs11168100) were found to be associated with decrease in the susceptibility of GC in the female subgroup. Rs353300 represented two-sided roles in the occurrence and development of GC in female. Finally, rs3533003 was associated with decreased risk of GC in stratified analysis of lymph node metastasis. CONCLUSION For the first time, our results provide some evidence on the polymorphisms of miR-143HG associated with GC risk in the Chinese Han population.
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Affiliation(s)
- Jianfeng Liu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, #229 Taibai North Road, Xi'an, 710069, China
| | - Haiyue Li
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, #229 Taibai North Road, Xi'an, 710069, China
| | - Yuanwei Liu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, #229 Taibai North Road, Xi'an, 710069, China
| | - Yao Sun
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, #229 Taibai North Road, Xi'an, 710069, China
| | - Jiamin Wu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, #229 Taibai North Road, Xi'an, 710069, China
| | - Zichao Xiong
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, #229 Taibai North Road, Xi'an, 710069, China
| | - Bin Li
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, #229 Taibai North Road, Xi'an, 710069, China
| | - Tianbo Jin
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, #229 Taibai North Road, Xi'an, 710069, China
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Seo HA, Moeng S, Sim S, Kuh HJ, Choi SY, Park JK. MicroRNA-Based Combinatorial Cancer Therapy: Effects of MicroRNAs on the Efficacy of Anti-Cancer Therapies. Cells 2019; 9:cells9010029. [PMID: 31861937 PMCID: PMC7016872 DOI: 10.3390/cells9010029] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 12/16/2019] [Accepted: 12/19/2019] [Indexed: 12/12/2022] Open
Abstract
The susceptibility of cancer cells to different types of treatments can be restricted by intrinsic and acquired therapeutic resistance, leading to the failure of cancer regression and remission. To overcome this problem, a combination therapy has been proposed as a fundamental strategy to improve therapeutic responses; however, resistance is still unavoidable. MicroRNA (miRNAs) are associated with cancer therapeutic resistance. The modulation of dysregulated miRNA levels through miRNA-based therapy comprising a replacement or inhibition approach has been proposed to sensitize cancer cells to other anti-cancer therapies. The combination of miRNA-based therapy with other anti-cancer therapies (miRNA-based combinatorial cancer therapy) is attractive, due to the ability of miRNAs to target multiple genes associated with the signaling pathways controlling therapeutic resistance. In this article, we present an overview of recent findings on the role of therapeutic resistance-related miRNAs in different types of cancer. We review the feasibility of utilizing dysregulated miRNAs in cancer cells and extracellular vesicles as potential candidates for miRNA-based combinatorial cancer therapy. We also discuss innate properties of miRNAs that need to be considered for more effective combinatorial cancer therapy.
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Affiliation(s)
- Hyun Ah Seo
- Department of Biomedical Science and Research Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (H.A.S.); (S.M.); (S.Y.C.)
| | - Sokviseth Moeng
- Department of Biomedical Science and Research Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (H.A.S.); (S.M.); (S.Y.C.)
| | - Seokmin Sim
- Generoath, Seachang-ro, Mapo-gu, Seoul 04168, Korea;
| | - Hyo Jeong Kuh
- Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
| | - Soo Young Choi
- Department of Biomedical Science and Research Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (H.A.S.); (S.M.); (S.Y.C.)
| | - Jong Kook Park
- Department of Biomedical Science and Research Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (H.A.S.); (S.M.); (S.Y.C.)
- Correspondence: or ; Tel.: +82-33-248-2114
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Shen SN, Li K, Liu Y, Yang CL, He CY, Wang HR. Silencing lncRNAs PVT1 Upregulates miR-145 and Confers Inhibitory Effects on Viability, Invasion, and Migration in EC. MOLECULAR THERAPY-NUCLEIC ACIDS 2019; 19:668-682. [PMID: 31951853 PMCID: PMC6965729 DOI: 10.1016/j.omtn.2019.11.030] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 11/23/2019] [Indexed: 02/07/2023]
Abstract
Long non-coding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) is correlated to various malignant tumors. Consequently, we explored effects of lncRNA PVT1 on esophageal carcinoma (EC) targeting microRNA-145 (miR-145). EC tissues, adjacent normal tissues, and EC-related cell lines were collected and cultured. Expression of lncRNA PVT1, miR-145, fascin-1 (FSCN1), and related genes with intervening expression of PVT1 and miR-145 was determined. Bioinformatic website, dual-luciferase reporter assay, and RNA immunoprecipitation (RIP) were carried to verify target relationship among lncRNA PVT1, FSCN1, and miR-145. Scratch test, Transwell assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and flow cytometry were performed for detection of migration, invasion, viability, and apoptosis of transfected cells, respectively. Finally, tumor formation in nude mice was measured. After database analysis, lncRNA PVT1, miR-145, and FSCN1 were selected for study. lncRNA PVT1 and FSCN1 can bind to miR-145. After overexpressing miR-145 or inhibiting lncRNA PVT1, EC cell viability, migration, and invasion were inhibited, while volume and weight of tumor formation in nude mice decreased. Expression of lncRNA PVT1, FSCN1, Bcl-2, CD147, VEGFR2, and MTA1 decreased and expression of miR-145 and Bax increased. Silencing lncRNA PVT1 can upregulate miR-145, which is a tumor suppressor in EC via knockdown of FSCN1. Thus, we might provide a potential theoretical basis for EC treatment.
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Affiliation(s)
- Si-Ning Shen
- Department of Thoracic Surgery, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 450008, Henan Province, P.R. China.
| | - Ke Li
- Department of Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 450008, P.R. China
| | - Ying Liu
- Department of Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 450008, P.R. China
| | - Cheng-Liang Yang
- Department of Radiation Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 450008, P.R. China.
| | - Chun-Yu He
- Department of Radiation Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 450008, P.R. China
| | - Hao-Rang Wang
- Department of Thoracic Surgery, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 450008, Henan Province, P.R. China
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Shen S, Li K, Liu Y, Yang C, He C, Wang H. Down-regulation of long noncoding RNA PVT1 inhibits esophageal carcinoma cell migration and invasion and promotes cell apoptosis via microRNA-145-mediated inhibition of FSCN1. Mol Oncol 2019; 13:2554-2573. [PMID: 31369196 PMCID: PMC6887590 DOI: 10.1002/1878-0261.12555] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 06/30/2019] [Accepted: 07/30/2019] [Indexed: 01/08/2023] Open
Abstract
Accumulating evidence has established that long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) is a tumor regulator in many cancers. Here, we aimed to investigate the possible function of lncRNA PVT1 in esophageal carcinoma (EC) via targeting of microRNA-145 (miR-145). Initially, microarray-based gene expression profiling of EC was employed to identify differentially expressed genes. Moreover, the expression of lncRNA PVT1 was examined and the cell line presenting with the highest level of lncRNA PVT1 expression was selected for subsequent experiments. We then proceeded to examine interaction among lncRNA PVT1, FSCN1, and miR-145. The effect of lncRNA PVT1 on viability, migration, invasion, apoptosis, and tumorigenesis of transfected cells was examined with gain-of-function and loss-of-function experiments. We observed that lncRNA PVT1 was robustly induced in EC. lncRNA PVT1 could bind to miR-145 and regulate its expression, and FSCN1 is a target gene of miR-145. Overexpression of miR-145 or silencing of lncRNA PVT1 was revealed to suppress cell viability, migration, and invasion abilities, while also stimulating cell apoptosis. Furthermore, our in vivo results showed that overexpression of miR-145 or silencing of lncRNA PVT1 resulted in decreased tumor growth in nude mice. In conclusion, our research reveals that down-regulation of lncRNA PVT1 could potentially promote expression of miR-145 to repress cell migration and invasion, and promote cell apoptosis through the inhibition of FSCN1. This highlights the potential of lncRNA PVT1 as a therapeutic target for EC treatment.
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Affiliation(s)
- Si‐Ning Shen
- Department of Thoracic SurgeryAffiliated Cancer Hospital of Zhengzhou University (Henan Cancer Hospital)China
| | - Ke Li
- Department of OncologyAffiliated Cancer Hospital of Zhengzhou University (Henan Cancer Hospital)China
| | - Ying Liu
- Department of OncologyAffiliated Cancer Hospital of Zhengzhou University (Henan Cancer Hospital)China
| | - Cheng‐Liang Yang
- Department of Radiation OncologyAffiliated Cancer Hospital of Zhengzhou University (Henan Cancer Hospital)China
| | - Chun‐Yu He
- Department of Radiation OncologyAffiliated Cancer Hospital of Zhengzhou University (Henan Cancer Hospital)China
| | - Hao‐Rang Wang
- Department of Thoracic SurgeryAffiliated Cancer Hospital of Zhengzhou University (Henan Cancer Hospital)China
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Luo YJ, Huang QM, Ren Y, Liu ZL, Xu CF, Wang H, Xiao JW. Non-coding RNA in drug resistance of gastric cancer. World J Gastrointest Oncol 2019; 11:957-970. [PMID: 31798777 PMCID: PMC6883183 DOI: 10.4251/wjgo.v11.i11.957] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 09/21/2019] [Accepted: 10/03/2019] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer (GC) is the third leading cause of cancer-related mortality worldwide. The poorly prognosis and survival of GC are due to diagnose in an advanced, non-curable stage and with a limited response to chemotherapy. The acquisition of drug resistance accounts for the majority of therapy failure of chemotherapy in GC patients. Although the mechanisms of anticancer drug resistance have been broadly studied, the regulation of these mechanisms has not been completely understood. Accumulating evidence has recently highlighted the role of non-coding RNAs (ncRNAs), including long non-coding RNAs and microRNAs, in the development and maintenance of drug resistance due to their regulatory features in specific genes involved in the chemoresistant phenotype of GC. We review the literature on ncRNAs in drug resistance of GC. This review summarizes the current knowledge about the ncRNAs’ characteristics, their regulation of the genes involved in chemoresistance and their potential as targeted therapies for personalized treatment in resistant GC.
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Affiliation(s)
- Ya-Jun Luo
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China
| | - Qing-Mei Huang
- Department of Oncology, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Yan Ren
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Zi-Lin Liu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Cheng-Fei Xu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Hao Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
| | - Jiang-Wei Xiao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, Sichuan Province, China
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Fänder J, Kielstein H, Büttner M, Koelblinger P, Dummer R, Bauer M, Handke D, Wickenhauser C, Seliger B, Jasinski-Bergner S. Characterizing CD44 regulatory microRNAs as putative therapeutic agents in human melanoma. Oncotarget 2019; 10:6509-6525. [PMID: 31741714 PMCID: PMC6849650 DOI: 10.18632/oncotarget.27305] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 10/21/2019] [Indexed: 01/22/2023] Open
Abstract
The multistructural and multifunctional transmembrane glycoprotein CD44 is overexpressed in many tumors of distinct origin including malignant melanoma and contributes to a poor prognosis by affecting cell proliferation, cell migration, and also the sensitivity for apoptosis induction. Previous studies reported so far 15 CD44 regulatory microRNAs (miRs) in different cell systems. Using a novel method for miR affinity purification miR-143-3p was identified as most potent binder to the 3' untranslated region (UTR) of CD44. Overexpression of miR-143-3p in melanoma cells inhibits CD44 translation, which is accompanied by a reduced proliferation, migration and enhanced daunorubicin induced apoptosis of melanoma cells in vitro. Analyses of discordant CD44 and miR-143-3p expression levels in human melanocytic nevi and dermal melanoma samples demonstrated medium to high CD44 levels with no association to tumor grading or staging. The CD44 expression correlated to PD-L1, but not to MART-1 expression in malignant melanoma. Interestingly, the CD44 expression was inversely correlated to the infiltration of pro-inflammatory immune effector cells. In conclusion, the tumor suppressive miR-143-3p was identified as the most potent CD44 inhibitory miR, which affects growth characteristics of melanoma cells suggesting the implementation of miR-143-3p as as a potential anti-CD44 therapy of malignant melanoma.
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Affiliation(s)
- Johannes Fänder
- Institute of Anatomy and Cell Biology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Heike Kielstein
- Institute of Anatomy and Cell Biology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Maximilian Büttner
- Institute of Anatomy and Cell Biology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Peter Koelblinger
- Department of Dermatology, Paracelsus Medical University, Salzburg, Austria
| | - Reinhard Dummer
- Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland
| | - Marcus Bauer
- Institute for Pathology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Diana Handke
- Institute for Medical Immunology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Claudia Wickenhauser
- Institute for Pathology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Barbara Seliger
- Institute for Medical Immunology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Simon Jasinski-Bergner
- Institute of Anatomy and Cell Biology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Halle, Germany.,Institute for Medical Immunology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Halle, Germany
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The DNMT1/miR-34a Axis Is Involved in the Stemness of Human Osteosarcoma Cells and Derived Stem-Like Cells. Stem Cells Int 2019; 2019:7028901. [PMID: 31781245 PMCID: PMC6875320 DOI: 10.1155/2019/7028901] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Accepted: 09/25/2019] [Indexed: 12/23/2022] Open
Abstract
The DNA methyltransferase 1 (DNMT1)/miR-34a axis promoted carcinogenesis of various types of cancers. However, no literature reported its contribution to the stemness of osteosarcoma cancer stem-like cells (OSLCs). We sought to determine whether the DNMT1/miR-34a axis facilitates the stemness of OSLCs. We here revealed the higher DNMT1 activity and expression, lower miR-34a expression with high methylation of its promoter, and stronger stemness of OSLCs, as manifested by elevated sphere and colony formation capacities; CD133, CD44, ABCG2, Bmi1, Sox2, and Oct4 protein amounts in vitro; and carcinogenicity in a nude mouse xenograft model, when compared to the parental U2OS cells. 5-Azacytidine (Aza-dC) repressed DNMT1 activation and upregulated miR-34a expression by promoter demethylation and suppressed the stemness of OSLCs in a dose-dependent manner. DNMT1 knockdown increased miR-34a and reduced the stemness of OSLCs. Transfection with a miR-34a mimic repressed the stemness of OSLCs but did not alter DNMT1 activity and expression. Conversely, DNMT1 overexpression declined miR-34a levels, promoting the stemness of U2OS cells. Transfection with a miR-34a inhibitor enhanced the stemness of U2OS cells, without affecting the DNMT1 activity and expression. Importantly, reexpression of miR-34a could rescue the effects of DNMT1 overexpression on miR-34a inhibition as well as the stemness promotion without affecting the activity and expression of DNMT1. Our results revealed that aberrant activation of DNMT1 caused promoter methylation of miR-34a, leading to miR-34a underexpression, and the role of the DNMT1/miR-34a axis in promoting and sustaining the stemness of OSLCs.
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The Role of MicroRNAs in the Regulation of Gastric Cancer Stem Cells: A Meta-Analysis of the Current Status. J Clin Med 2019; 8:jcm8050639. [PMID: 31075910 PMCID: PMC6572052 DOI: 10.3390/jcm8050639] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 05/04/2019] [Accepted: 05/06/2019] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) remains one of the major causes of cancer-related mortality worldwide. As for other types of cancers, several limitations to the success of current therapeutic GC treatments may be due to cancer drug resistance that leads to tumor recurrence and metastasis. Increasing evidence suggests that cancer stem cells (CSCs) are among the major causative factors of cancer treatment failure. The research of molecular CSC mechanisms and the regulation of their properties have been intensively studied. To date, molecular gastric cancer stem cell (GCSC) characterization remains largely incomplete. Among the GCSC-targeting approaches to overcome tumor progression, recent studies have focused their attention on microRNA (miRNA). The miRNAs are short non-coding RNAs which play an important role in the regulation of numerous cellular processes through the modulation of their target gene expression. In this review, we summarize and discuss recent findings on the role of miRNAs in GCSC regulation. In addition, we perform a meta-analysis aimed to identify novel miRNAs involved in GCSC homeostasis.
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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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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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Shimonosono M, Idichi T, Seki N, Yamada Y, Arai T, Arigami T, Sasaki K, Omoto I, Uchikado Y, Kita Y, Kurahara H, Maemura K, Natsugoe S. Molecular pathogenesis of esophageal squamous cell carcinoma: Identification of the antitumor effects of miR‑145‑3p on gene regulation. Int J Oncol 2019; 54:673-688. [PMID: 30535463 DOI: 10.3892/ijo.2018.4657] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 10/19/2018] [Indexed: 11/06/2022] Open
Abstract
Although miR‑145‑5p (the guide strand of the miR‑145 duplex) is established as a tumor suppressive microRNA (miRNA or miR), the functional significance of miR‑145‑3p (the passenger strand of the miR‑145 duplex) in cancer cells and its targets remains obscure. In our continuing analysis of esophageal squamous cell carcinoma (ESCC) pathogenesis, the aim of the present study was to identify important oncogenes and proteins that are controlled by miR‑145‑3p. Overexpression of miR‑145‑3p significantly reduced cancer cell proliferation, migration and invasive abilities, and further increased apoptotic abilities. In ESCC cells, 30 possible oncogenic targets were identified that might be regulated by miR‑145‑3p. Among these targets, dehydrogenase/reductase member 2 (DHRS2) and myosin IB (MYO1B) were focused on to investigate their functional roles in ESCC cells. DHRS2 and MYO1B were directly regulated by miR‑145‑3p in ESCC cells by dual luciferase reporter assays. Aberrantly expressed DHRS2 and MYOIB were detected in ESCC clinical specimens, and their overexpression enhanced cancer cell aggressiveness. Genes regulated by antitumor miR‑145‑3p were closely associated with the molecular pathogenesis of ESCC. The approach based on antitumor miRNAs may contribute to the understanding of ESCC molecular pathogenesis.
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Affiliation(s)
- Masataka Shimonosono
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima 890‑8520, Japan
| | - Tetsuya Idichi
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima 890‑8520, Japan
| | - Naohiko Seki
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba 260‑8670, Japan
| | - Yasutaka Yamada
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba 260‑8670, Japan
| | - Takayuki Arai
- Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba 260‑8670, Japan
| | - Takaaki Arigami
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima 890‑8520, Japan
| | - Ken Sasaki
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima 890‑8520, Japan
| | - Itaru Omoto
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima 890‑8520, Japan
| | - Yasuto Uchikado
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima 890‑8520, Japan
| | - Yoshiaki Kita
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima 890‑8520, Japan
| | - Hiroshi Kurahara
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima 890‑8520, Japan
| | - Kosei Maemura
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima 890‑8520, Japan
| | - Shoji Natsugoe
- Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Kagoshima 890‑8520, Japan
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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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Zhang XF, Zhang XQ, Chang ZX, Wu CC, Guo H. microRNA‑145 modulates migration and invasion of bladder cancer cells by targeting N‑cadherin. Mol Med Rep 2018; 17:8450-8456. [PMID: 29693148 DOI: 10.3892/mmr.2018.8910] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 02/28/2018] [Indexed: 11/06/2022] Open
Abstract
MicroRNA (miRNA)‑145 has been demonstrated to serve a role in several types of tumors, however, the potential molecular mechanism of action of miRNA‑145 in bladder cancer metastasis remains to be elucidated. This study aimed to investigate the potential modulation of miRNA‑145 in bladder carcinoma and elucidate the underlying molecular mechanism. The expression of miRNA‑145 in bladder adenocarcinoma tissues and bladder cancer cells was measured by reverse transcription‑quantitative polymerase chain reaction. miRNA‑145 mimics and inhibitor were transfected into bladder cancer (BC) cells to determine the role of miRNA‑145 on cell motility and invasion measured by wound healing and transwell assays. Luciferase assay was performed to confirm whether N‑cadherin was the direct target of miRNA‑145. Subsequently, expression of N‑cadherin and matrix metalloproteinase‑9 (MMP9) in BC cells were detected by western blot analysis. miRNA‑145 was significantly downregulated cells and tissues from patients with BC, compared with healthy controls. miRNA‑145 markedly inhibited the ability of BC cells to migrate and invade. Furthermore, N‑cadherin was identified as a target of miRNA‑145 in BC cells. MMP9, acting downstream of N‑cadherin, was downregulated in BC cells by miRNA‑145. In the present study, miRNA‑145 suppressed the migration and invasion of BC cells by regulating N‑cadherin. The results of the present study indicated that miRNA‑145 may function as a tumor suppressor and may have a potential to be a diagnostic and predictive biomarker, and a therapeutic target for treatment of BC.
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Affiliation(s)
- Xue-Feng Zhang
- Department of Nuclear Medicine, Affiliated Hospital of BeiHua University, Jilin, Jilin 132011, P.R. China
| | - Xue-Qi Zhang
- Department of Nuclear Medicine, Affiliated Hospital of BeiHua University, Jilin, Jilin 132011, P.R. China
| | - Zhe-Xing Chang
- Department of Oncology, Affiliated Hospital of BeiHua University, Jilin, Jilin 132011, P.R. China
| | - Cui-Cui Wu
- Department of Laboratory Medicine, Affiliated Hospital of BeiHua University, Jilin, Jilin 132011, P.R. China
| | - Hang Guo
- Department of Nuclear Medicine, Affiliated Hospital of BeiHua University, Jilin, Jilin 132011, P.R. China
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Wang R, Dong H, Zeng J, Pan J, Jin X. LncRNA DGCR5 contributes to CSC‐like properties via modulating miR‐330‐5p/CD44 in NSCLC. J Cell Physiol 2018; 233:7447-7456. [DOI: 10.1002/jcp.26590] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2017] [Accepted: 03/09/2018] [Indexed: 12/19/2022]
Affiliation(s)
- Ren Wang
- Department of Respiratory MedicineTongren HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Hui‐Xing Dong
- Department of Respiratory MedicineTongren HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Jian Zeng
- Department of Respiratory MedicineTongren HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Jing Pan
- Department of Respiratory MedicineTongren HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Xiao‐Yan Jin
- Department of Respiratory MedicineTongren HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
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Ye P, Shi Y, An N, Zhou Q, Guo J, Long X. miR-145 overexpression triggers alteration of the whole transcriptome and inhibits breast cancer development. Biomed Pharmacother 2018; 100:72-82. [DOI: 10.1016/j.biopha.2018.01.167] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 01/29/2018] [Accepted: 01/31/2018] [Indexed: 02/07/2023] Open
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Zhou S, Xiong M, Dai G, Yu L, Zhang Z, Chen J, Guo W. MicroRNA-192-5p suppresses the initiation and progression of osteosarcoma by targeting USP1. Oncol Lett 2018; 15:6947-6956. [PMID: 29731868 PMCID: PMC5920969 DOI: 10.3892/ol.2018.8180] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Accepted: 02/13/2018] [Indexed: 12/14/2022] Open
Abstract
Osteosarcoma is the most frequent primary malignant bone tumor. An increasing body of evidence has suggested that microRNAs (miRNA/miRs) have emerged as critical regulators in the initiation and progression of osteosarcoma. The present study explored the biological function of miR-192-5p and ubiquitin-specific protease 1 (USP1), and investigated whether miR-192-5p could directly interact with USP1 in osteosarcoma. The results revealed that miR-192-5p was significantly downregulated in osteosarcoma tissues and cell lines, while a reverse expression profile of USP1 was observed. Ectopic expression of miR-192-5p restrained cell proliferation, apoptosis, migration and invasion. In addition, it increased the sensitivity of osteosarcoma cells to cisplatin. USP1 was also observed to be a direct target gene of miR-192-5p in osteosarcoma. Overexpression of USP1 promoted cell proliferation, apoptosis, migration and invasion, and decreased cell chemo-sensitivity; however, it could be partially reversed via the overexpression of miR-192-5p in osteosarcoma cell lines. Taken together, the present study demonstrated that miR-192-5p suppressed the initiation and progression of osteosarcoma by targeting USP1. Therefore, miR-192-5p may serve as a valuable biomarker and the miR-192-5p/USP1 axis may function as a novel therapeutic target for osteosarcoma.
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Affiliation(s)
- Sheng Zhou
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Min Xiong
- Department of Orthopedics, Dongfeng General Hospital, Shiyan, Hubei 442001, P.R. China
| | - Guo Dai
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Ling Yu
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Zhengpei Zhang
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Jie Chen
- Department of Orthopedics, Dongfeng General Hospital, Shiyan, Hubei 442001, P.R. China
| | - Weichun Guo
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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Mei LL, Wang WJ, Qiu YT, Xie XF, Bai J, Shi ZZ. miR-145-5p Suppresses Tumor Cell Migration, Invasion and Epithelial to Mesenchymal Transition by Regulating the Sp1/NF-κB Signaling Pathway in Esophageal Squamous Cell Carcinoma. Int J Mol Sci 2017; 18:ijms18091833. [PMID: 28832500 PMCID: PMC5618482 DOI: 10.3390/ijms18091833] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Revised: 06/30/2017] [Accepted: 08/14/2017] [Indexed: 01/19/2023] Open
Abstract
MicroRNAs (miRNAs) play important roles in the progression of human cancer. Although previous reports have shown that miR-145-5p is down-regulated in esophageal squamous cell carcinoma (ESCC), the roles and mechanisms of down-regulation of miR-145-5p in ESCC are still largely unknown. Using microRNA microarray and Gene Expression Omnibus (GEO) datasets, we confirmed that miR-145-5p was down-regulated in ESCC tissues. In vitro assays revealed that ectopic miR-145-5p expression repressed cell proliferation, migration, invasion and epithelial to mesenchymal transition (EMT). miR-145-5p also reduced the expressions of cell cycle genes including cyclin A2 (CCNA2), cyclin D1 (CCND1) and cyclin E1 (CCNE1), the EMT-associated transcription factor Slug, and matrix metalloproteinases (MMPs) including MMP2, MMP7 and MMP13. Furthermore, miR-145-5p mimics reduced candidate target gene specificity protein 1 (Sp1) and nuclear factor κ B (NF-κB) (p65) both in mRNA and protein levels. Knockdown of Sp1 phenocopied the effects of miR-145-5p overexpression on cell cycle regulators, EMT and the expression of NF-κB (p65). Importantly, inhibition of the NF-κB signaling pathway or knockdown of NF-κB (p65) phenocopied the effects of miR-145-5p on the migration, invasion and EMT of ESCC cells. In conclusion, our results suggested that miR-145-5p plays tumor-suppressive roles by inhibiting esophageal cancer cell migration, invasion and EMT through regulating the Sp1/NF-κB signaling pathway.
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Affiliation(s)
- Li-Li Mei
- Medical School, Kunming University of Science and Technology, Kunming 650500, China.
| | - Wen-Jun Wang
- Medical School, Kunming University of Science and Technology, Kunming 650500, China.
| | - Yun-Tan Qiu
- Medical School, Kunming University of Science and Technology, Kunming 650500, China.
| | - Xiu-Feng Xie
- Medical School, Kunming University of Science and Technology, Kunming 650500, China.
| | - Jie Bai
- Medical School, Kunming University of Science and Technology, Kunming 650500, China.
| | - Zhi-Zhou Shi
- Medical School, Kunming University of Science and Technology, Kunming 650500, China.
- State Key Laboratory of Molecular Oncology, Cancer Hospital, CAMS, Beijing 100021, China.
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