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1
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Yang YC, Ho KH, Hua KT, Chien MH. Roles of K(H)SRP in modulating gene transcription throughout cancer progression: Insights from cellular studies to clinical perspectives. Biochim Biophys Acta Rev Cancer 2024; 1879:189202. [PMID: 39447687 DOI: 10.1016/j.bbcan.2024.189202] [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: 09/05/2024] [Revised: 10/15/2024] [Accepted: 10/21/2024] [Indexed: 10/26/2024]
Abstract
The KH-type splicing regulatory protein (KHSRP), also known as KSRP, is an RNA-binding protein that regulates gene expressions through various mechanisms, including messenger (m)RNA degradation, micro (mi)RNA maturation, and transcriptional activity. KSRP has been implicated in a wide range of physiological and pathological processes, with emerging evidence highlighting its role in modulating diverse aspects of cancer behaviors. In this review, we provide a comprehensive overview of KSRP's clinical relevance and its multifaceted regulatory mechanisms in cancer. Our extensive pan-cancer analysis uncovers associations of KSRP with clinical outcomes and identifies cell cycle progression as a key signaling pathway correlated with KSRP expression. Furthermore, we identify miR-17-5p as critical miRNAs positively correlated with KSRP, and it is associated with poor survival in various cancers. Collectively, this review offers new insights into the potential of KSRP as a target for therapeutic strategies in cancer treatment.
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Affiliation(s)
- Yi-Chieh Yang
- Department of Medical Research, Tungs' Taichung Metro Harbor Hospital, Taichung, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; School of Oral Hygiene, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
| | - Kuo-Hao Ho
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Kuo-Tai Hua
- Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ming-Hsien Chien
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Pulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan; Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei, Taiwan.
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2
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Gu X, Li X, Zhang X, Tong L, Feng R, Liu L, Sun H, Zhang Q, Bian T, Zhang J, Gao L, Zhang C, Liu J, Liu Y. Noncoding RNA-Mediated High Expression of PFKFB3 Correlates with Poor Prognosis and Tumor Immune Infiltration of Lung Adenocarcinoma. Onco Targets Ther 2023; 16:767-783. [PMID: 37771939 PMCID: PMC10522466 DOI: 10.2147/ott.s416155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 09/10/2023] [Indexed: 09/30/2023] Open
Abstract
Background There is growing evidence showing that 6-phosphofructo-2-kinase (PFKFB3) plays crucial roles in different types of human cancers, including LUAD; however, the specific mechanism by which PFKFB3 plays a role in LUAD remains unclear. Methods We investigated the expression of PFKFB3 and explored the underlying mechanism as well as the correlation with immune markers using several online datasets, such as Tumor Immune Estimate Resource (TIMER), UALCAN, and the Cancer Genome Atlas (TCGA) databases, miRWalk, Targetscan, MiRDB and starBase database. Western blot and immunohistochemistry analysis were performed to verify the corresponding outcomes. Results It was shown that the mRNA expression of PFKFB3 was lower in LUAD than in the normal tissues, while its protein expression was not consistent with the mRNA level. The expression of PFKFB3 was correlated with clinicopathological parameters and several signaling pathways. The potential long chain (lnc)RNA/microRNA/PFKFB3 axis and the possible mechanism by which tumor progression in LUAD is promoted was predicted. We obtained the LINC01798/LINC02086/AP000845.1/HAGLR-miR-17-5p-PFKFB3 axis after comprehensive analyses of expression, correlation, and survival. Moreover, the expression of PFKFB3 was positively correlated with immune cells and immune checkpoint expression, including PD-1, PD-L1 and CTLA-4. Conclusion The present study demonstrated that noncoding RNAs mediated the upregulation of PFKFB3 and was associated with a poor prognosis and immune tumor infiltration in LUAD.
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Affiliation(s)
- Xue Gu
- Department of Pathology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, People’s Republic of China
| | - Xiaoli Li
- Department of Pathology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, People’s Republic of China
| | - Xue Zhang
- Department of Oncology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, People’s Republic of China
| | - Li Tong
- Department of Pathology, Affiliated Hospital of Nantong University, Dalian Medical University, Nantong, 226001, People’s Republic of China
| | - Ran Feng
- Department of Pathology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, People’s Republic of China
| | - Lei Liu
- Department of Pathology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, People’s Republic of China
| | - Hui Sun
- Department of Pathology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, People’s Republic of China
| | - Qing Zhang
- Department of Pathology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, People’s Republic of China
| | - Tingting Bian
- Department of Pathology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, People’s Republic of China
| | - Jianguo Zhang
- Department of Pathology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, People’s Republic of China
| | - Lihua Gao
- Department of Oncology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, People’s Republic of China
| | - Chenxi Zhang
- Medical School of Nantong University, Nantong, 226001, People’s Republic of China
| | - Jian Liu
- Department of Oncology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, People’s Republic of China
| | - Yifei Liu
- Department of Pathology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, People’s Republic of China
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Öksüz Z, Gragnani L, Lorini S, Temel GÖ, Serin MS, Zignego AL. Evaluation of Plasma miR-17-5p, miR-24-3p and miRNA-223-3p Profile of Hepatitis C Virus-Infected Patients after Treatment with Direct-Acting Antivirals. J Pers Med 2023; 13:1188. [PMID: 37623439 PMCID: PMC10455277 DOI: 10.3390/jpm13081188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/21/2023] [Accepted: 07/24/2023] [Indexed: 08/26/2023] Open
Abstract
The expression of miR-223-3p, miR-17-5p, and miR-24-3p was evaluated in hepatitis C virus (HCV) patient serum samples, collected before DAA treatment and after a sustained virological response (SVR). Fifty HCV patients were stratified based on their liver damage stages into three different subgroups (21 with chronic hepatitis-CH, 15 with cirrhosis, and 14 with hepatocellular carcinoma-HCC). Considering the entire HCV population, the miRNA expression levels were significantly downregulated after the SVR compared to pre-treatment ones (p < 0.05). Stratifying the patients based on liver damage, the post-SVR values of the three miRNAs were significantly downregulated compared to the pre-treatment levels for both cirrhosis and HCC patients. No significant differences emerged from the analysis of the CH group. To our knowledge, this is the first study to detail the behavior of miR-223-3p, miR-17-5p, and miR-24-3p levels in patients with HCV-related CH, cirrhosis, and HCC after DAA therapy. Our findings show that HCV-infected patients have different miRNA profiles before and after treatment with DAAs, strongly suggesting that miRNAs may be involved in the pathogenesis of HCV-related damage. In this respect, the correlation observed among the three studied miRNAs could imply that they share common pathways by which they contribute the progression of HCV-induced chronic liver damage.
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Affiliation(s)
- Zehra Öksüz
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Mersin University, 33160 Mersin, Turkey;
| | - Laura Gragnani
- MASVE Interdepartmental Hepatology Center, Department of Experimental and Clinical Medicine, University of Florence, Center for Research and Innovation CRIA-MASVE, AOU Careggi, 50134 Firenze, Italy; (L.G.); (S.L.)
- Department of Translational Research & New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
| | - Serena Lorini
- MASVE Interdepartmental Hepatology Center, Department of Experimental and Clinical Medicine, University of Florence, Center for Research and Innovation CRIA-MASVE, AOU Careggi, 50134 Firenze, Italy; (L.G.); (S.L.)
| | - Gülhan Örekici Temel
- Department of Biostatistics, Faculty of Medicine, Mersin University, 33343 Mersin, Turkey;
| | - Mehmet Sami Serin
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Mersin University, 33160 Mersin, Turkey;
| | - Anna Linda Zignego
- MASVE Interdepartmental Hepatology Center, Department of Experimental and Clinical Medicine, University of Florence, Center for Research and Innovation CRIA-MASVE, AOU Careggi, 50134 Firenze, Italy; (L.G.); (S.L.)
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Heat Shock Protein B7 Inhibits the Progression of Endometrial Carcinoma by Inhibiting PI3K/AKT/mTOR Pathway. Reprod Sci 2023; 30:590-600. [PMID: 35859224 DOI: 10.1007/s43032-022-01041-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 07/12/2022] [Indexed: 10/17/2022]
Abstract
PURPOSE To investigate the role and mechanism of action of Heat shock protein B7 (HSPB7) in endometrial carcinoma (EC). METHODS GEPIA (Gene Expression Profiling Interactive Analysis) was used to analyze the expression and prognostic value of HSPB7 in TCGA data. HSPB7 mRNA and protein expression levels were detected by qRT-PCR and Western blot, respectively. EC cell proliferation, apoptosis, migration, and invasion were determined by colony formation, EdU, flow cytometry, and transwell assays. Mitochondrial membrane potential was determined using JC-1 probe. In addition, apoptosis-related and metastasis-related proteins were quantitatively evaluated. A gene set enrichment analysis of the signaling pathways by which HSPB7 influences EC was performed and the levels of enriched pathway-related proteins were evaluated. RESULTS We first proved that HSPB7 was downregulated in EC tissues and HSPB7 levels were positively related to survival rates. In functional assays, HSPB7 overexpression suppressed the proliferation, migration, and invasion of EC cells and conversely promoted apoptosis. Moreover, HSPB7 overexpression decreased the mitochondrial membrane potential of EC cells significantly. Bioinformatics analyses revealed that the PI3K/AKT/mTOR pathway was significantly enriched in EC. HSPB7 inhibited the phosphorylation of the PI3K/AKT/mTOR pathway to reduce proliferation, migration and invasion, and increased apoptosis in EC cells. CONCLUSION HSPB7 was downregulated in EC and influenced EC cell proliferation, invasion, migration, and apoptosis via the PI3K/AKT/mTOR signaling pathway. These findings provide a novel perspective for the development of EC treatment strategies.
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Al-Awsi GRL, Jasim SA, Fakri Mustafa Y, Alhachami FR, Ziyadullaev S, Kandeel M, Abulkassim R, Sivaraman R, M Hameed N, Mireya Romero Parra R, Karampoor S, Mirzaei R. The role of miRNA-128 in the development and progression of gastrointestinal and urogenital cancer. Future Oncol 2022; 18:4209-4231. [PMID: 36519554 DOI: 10.2217/fon-2022-0574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Increasing data have shown the significance of various miRNAs in malignancy. In this regard, parallel to its biological role in normal tissues, miRNA-128 (miR-128) has been found to play an essential immunomodulatory function in the process of cancer initiation and development. The occurrence of the aberrant expression of miR-128 in tumors and the unique properties of miRNAs raise the prospect of their use as biomarkers and the next generation of molecular anticancer therapies. The function of miR-128 in malignancies such as breast, prostate, colorectal, gastric, pancreatic, esophageal, cervical, ovarian and bladder cancers and hepatocellular carcinoma is discussed in this review. Finally, the effect of exosomal miR-128 on cancer resistance to therapeutics and cancer immunotherapy in certain malignancies is highlighted.
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Affiliation(s)
| | - Saade Abdalkareem Jasim
- Department of Medical Laboratory Techniques, Al-maarif University College, Al-Anbar-Ramadi, Iraq
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Firas Rahi Alhachami
- Department of Radiology, College of Health & Medical Technololgy, Al-Ayen University, Thi-Qar, Iraq
| | - Shukhrat Ziyadullaev
- No. 1 Department of Internal Diseases, Vice-rector for Scientific Affairs & Innovations, Samarkand State Medical University, Amir Temur Street 18, Samarkand, Uzbekistan
| | - Mahmoud Kandeel
- Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Hofuf, Al-Ahsa, 31982, Saudi Arabia.,Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelshikh University, Kafrelshikh, 33516, Egypt
| | | | - R Sivaraman
- Department of Mathematics, Dwaraka Doss Goverdhan Doss Vaishnav College, Arumbakkam, University of Madras, Chennai, India
| | - Noora M Hameed
- Anesthesia Techniques, Al-Nisour University College, Iraq
| | | | - Sajad Karampoor
- Gastrointestinal & Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Rasoul Mirzaei
- Department of Medical Biotechnology, Venom & Biotherapeutics Molecules Lab, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
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Wang Q, Feng J, Tang L. Non-Coding RNA Related to MAPK Signaling Pathway in Liver Cancer. Int J Mol Sci 2022; 23:11908. [PMID: 36233210 PMCID: PMC9570382 DOI: 10.3390/ijms231911908] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 10/03/2022] [Accepted: 10/04/2022] [Indexed: 11/16/2022] Open
Abstract
The advancement in high-throughput sequencing analysis and the evaluation of chromatin state maps have revealed that eukaryotic cells produce many non-coding transcripts/RNAs. Further, a strong association was observed between some non-coding RNAs and cancer development. The mitogen-activated protein kinases (MAPK) belong to the serine-threonine kinase family and are the primary signaling pathways involved in cell proliferation from the cell surface to the nucleus. They play an important role in various human diseases. A few non-coding RNAs associated with the MAPK signaling pathway play a significant role in the development of several malignancies, including liver cancer. In this review, we summarize the molecular mechanisms and interactions of microRNA, lncRNA, and other non-coding RNAs in the development of liver cancer that are associated with the MAPK signaling pathway. Further, we briefly discuss the therapeutic strategies for liver cancer related to ncRNA and the MAPK signaling pathway.
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Affiliation(s)
- Qiuxia Wang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
| | - Jianguo Feng
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
- Laboratory of Anesthesiology, Southwest Medical University, Luzhou 646000, China
| | - Liling Tang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
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7
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Liao Y, Weng J, Chen L, Hu N, Yuan X, Wang J, He F, Cai Y, Huang Q, Wang J, Huang L. Comprehensive analysis of SLC43A2 on the tumor immune microenvironment and prognosis of liver hepatocellular carcinoma. Front Genet 2022; 13:911378. [PMID: 36186480 PMCID: PMC9523210 DOI: 10.3389/fgene.2022.911378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 08/04/2022] [Indexed: 12/05/2022] Open
Abstract
Background: Tumor cells outcompete T cells for methionine via overexpressing SLC43A2, causing T cells exhaustion. We explored the influence of SLC43A2 on tumor immune microenvironment (TIME), immune-related genes (IRGs) and the prognosis of liver hepatocellular carcinoma (LIHC) patients. Methods: The TCGA-LIHC dataset (n = 374) and the ICGC-LIRI-JP-LIHC (n = 231) datasets were used as training and validation cohort, respectively. IRGs were obtained from ImmPort. Statistical analyses were performed using R (V 4.0.5). Online databases such as GEPIA, GSCALite, the Kaplan–Meier plotter, KEGG, TIMER2, and CMap were used for differential expression, immune infiltration, functional enrichment, survival, and drug-induced gene perturbation analysis. Results: SLC43A2 expression was higher in LIHC, correlated with worse survival, but could not predict prognosis of LIHC separately (AUC = 0.467). SLC43A2 positively correlated with immune exhaustion markers (all p < 0.001) and with increased infiltration of Tregs, macrophages and myeloid-derived suppressor cells (MDSC) (all p < 0.05). SLC43A2 may regulate 120 IRGs. A prognostic risk score model was developed using the TCGA-LIHC cohort and validated by the ICGC-LIRI-JP cohort. Arachidonic acid, SB-202190 and guanethidine were identified as possible immunomodulators pharmacologically targeting SLC43A2 in LIHC. Conclusion: SLC43A2 may create suppressive tumor microenvironment and regulate related IRGs, thus affecting the prognosis of LIHC. Arachidonic acid, SB-202190, and guanethidine may be worthy of further study as immunomodulators on SLC43A2.
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Affiliation(s)
- Yan Liao
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- The Reproductive Medical Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Junmei Weng
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Lian Chen
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Nan Hu
- Department of Neurology and Laboratory of Clinical Genetics, Peking Union Medical College Hospital, Beijing, China
| | - Xun Yuan
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jianhua Wang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Feng He
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yixin Cai
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qin Huang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jianing Wang
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Liu Huang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- *Correspondence: Liu Huang,
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Guo J, Jin K, Tang T, Liu HM, Xie YA. A new biomarker to enhance the radiosensitivity of hepatocellular cancer: miRNAs. Future Oncol 2022; 18:3217-3228. [PMID: 35968820 DOI: 10.2217/fon-2022-0136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aims: This review summarizes findings regarding miRNAs that modulate radiation in hepatocellular carcinoma (HCC) and evaluates their potential clinical therapeutic uses. Materials & methods: We searched the relevant English-language medical databases for papers on miRNAs and radiation therapy for tumors to identify miRNAs that are linked with radiosensitivity and radioresistance, focusing on those associated with HCC radiation. Results: There were 88 papers assessed for miRNAs associated with tumor radiation, 56 of which dealt with radiosensitization, 21 with radioresistance and 11 with radiosensitization for HCC. Conclusion: Further work in this area would enable future evaluation of radiation responses and the potential use of miRNAs as therapeutic agents in HCC patients.
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Affiliation(s)
- Ju Guo
- Graduate School of Guangxi Traditional Chinese Medical University, Nanning, Guangxi, 530299, PR China.,Guangxi Key Laboratory of Reproductive Health & Birth Defects Prevention, Nanning, Guangxi, 530002, PR China
| | - Kai Jin
- Graduate School of Guangxi Traditional Chinese Medical University, Nanning, Guangxi, 530299, PR China
| | - Ting Tang
- Graduate School of Guangxi Traditional Chinese Medical University, Nanning, Guangxi, 530299, PR China
| | - Hong-Mei Liu
- Department of Radiation Oncology, Affiliated Cancer Hospital of Guangxi Medical University & Cancer Institute of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, 530021, PR China
| | - Yu-An Xie
- Graduate School of Guangxi Traditional Chinese Medical University, Nanning, Guangxi, 530299, PR China.,Guangxi Key Laboratory of Reproductive Health & Birth Defects Prevention, Nanning, Guangxi, 530002, PR China.,Experimental Research Department, Affiliated Cancer Hospital of Guangxi Medical University & Cancer Institute of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, 530021, PR China.,Guangxi Zhuang Autonomous Region Women & Children Care Hospital, Nanning, Guangxi, 530002, PR China
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Hu H, Zhang T, Wu Y, Deng M, Deng H, Yang X. Cross-regulation between microRNAs and key proteins of signaling pathways in hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol 2022; 16:753-765. [PMID: 35833844 DOI: 10.1080/17474124.2022.2101994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is a subtype of primary liver cancer and a major cause of death. Although miRNA plays an important role in hepatocellular carcinoma, the specific regulatory network remains unclear. Therefore, this paper comprehensively describes the miRNA-related signaling pathways in HCC and the possible interactions among different signaling pathways. The aim is to lay the foundation for the discovery of new molecular targets and multi-target therapy. AREAS COVERED Based on miRNA, HCC, and signaling pathways, the literature was searched on Web of Science and PubMed. Then, common targets between different signaling pathways were found from KEGG database, and possible cross-regulation mechanisms were further studied. In this review, we elaborated from two aspects, respectively, laying a foundation for studying the regulatory mechanism and potential targets of miRNA in HCC. EXPERT OPINION Non-coding RNAs have become notable molecules in cancer research in recent years, and many types of targeted drugs have emerged. From the outset, molecular targets and signal pathways are interlinked, which suggests that signal pathways and regulatory networks should be concerned in basic research, which also provides a strong direction for future mechanism research.
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Affiliation(s)
- Haihong Hu
- School of Pharmacy, Hengyang Medical College, University of South China, Hengyang, Hunan, China
| | - Taolan Zhang
- School of Pharmacy, Hengyang Medical College, University of South China, Hengyang, Hunan, China.,The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Yiwen Wu
- School of Pharmacy, Hengyang Medical College, University of South China, Hengyang, Hunan, China
| | - Meina Deng
- School of Pharmacy, Hengyang Medical College, University of South China, Hengyang, Hunan, China
| | - Huiling Deng
- School of Pharmacy, Hengyang Medical College, University of South China, Hengyang, Hunan, China
| | - Xiaoyan Yang
- School of Pharmacy, Hengyang Medical College, University of South China, Hengyang, Hunan, China.,The Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China, Hengyang, Hunan, China
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10
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Öksüz Z, Üçbilek E, Serin MS, Yaraş S, Temel GÖ, Sezgin O. hsa-miR-17-5p: A Possible Predictor of Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir ± Ribavirin Therapy Efficacy in Hepatitis C Infection. Curr Microbiol 2022; 79:186. [PMID: 35524830 DOI: 10.1007/s00284-022-02882-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 04/18/2022] [Indexed: 11/25/2022]
Abstract
Although persistent sustained viral response rates are increased in hepatitis C infection following administration of direct-acting antiviral (DAA) agents, the pre-use predictive parameters of these antivirals and the clinical progression in patients post-treatment remain unknown. To obtain data pertaining to the predictive parameters prior to the use of ombitavir/paritaprevir/ritonavir + dasabuvir and the clinical progression in patients following antiviral treatment. The expression profiles of miR-223-3p, miR-17-5p, miR-24-3p, and TLR2 - 196 to - 174 del/ins polymorphisms from the blood/serum of 34 hepatitis C virus (HCV)-infected patients pre- and post-ombitavir/paritaprevir/ritonavir + dasabuvir treatment were determined by RT-qPCR. The expression levels of miR-17-5p (P < 0.001) and miR-24-3p (P = 0.011) were significantly downregulated post-treatment as compared with those pre-treatment; however, there was no significant difference between these two groups in terms of miR-223-3p expression. In addition, there was no significant difference in TLR2 genotype or allele distribution between pre-and post-treatment (P > 0.05); nevertheless, the TLR2 del allele was decreased post-treatment (16.2%) as compared with that pre-treatment (19.1%), although the difference was not statistically significant. Moreover, a significant difference was found between the mRNA levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and HCV RNA pre-and post-treatment (P < 0.05). Further, miR-17-5p expression correlated with both ALT and AST mRNA levels post-treatment (P.
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Affiliation(s)
- Zehra Öksüz
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Mersin University, Mersin, Turkey.
| | - Enver Üçbilek
- Department of Gastroenterology, Faculty of Medicine, Mersin University, Mersin, Turkey
| | - Mehmet Sami Serin
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Mersin University, Mersin, Turkey
| | - Serkan Yaraş
- Department of Gastroenterology, Faculty of Medicine, Mersin University, Mersin, Turkey
| | - Gülhan Örekici Temel
- Department of Biostatistics, Faculty of Medicine, Mersin University, Mersin, Turkey
| | - Orhan Sezgin
- Department of Gastroenterology, Faculty of Medicine, Mersin University, Mersin, Turkey
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Chen M, Wang W, Hu S, Tong Y, Li Y, Wei Q, Yu L, Zhu L, Zhu Y, Liu L, Ju Z, Wang X, Jin H, Feng L. Co-targeting WIP1 and PARP induces synthetic lethality in hepatocellular carcinoma. Cell Commun Signal 2022; 20:39. [PMID: 35346236 PMCID: PMC8962187 DOI: 10.1186/s12964-022-00850-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Accepted: 02/22/2022] [Indexed: 11/24/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is one of the most fatal cancers. Due to limited strategies for effective treatments, patients with advanced HCC have a very poor prognosis. This study aims to identify new insights in HCC to develop novel strategies for HCC management. Methods The role of WIP1 (wild type p53 induced protein phosphatase1) in HCC was analyzed in HCC cells, xenograft model, DEN (Diethylnitrosamine) induced mice liver cancer model with WIP1 knockout mice, and TCGA database. DNA damage was evaluated by Gene Set Enrichment Analysis, western blotting, comet assay, and Immunofluorescence. Results High expression of WIP1 is associated with the poor prognosis of patients with HCC. Genetically and chemically suppression of WIP1 drastically reduced HCC cell proliferation. Besides, WIP1 knockout retarded DEN induced mice hepato-carcinogenesis. Mechanically, WIP1 inhibition induced DNA damage by increasing H2AX phosphorylation (γH2AX). Therefore, suppression of WIP1 and PARP induced synthetic lethality in HCC in vitro and in vivo by augmenting DNA damage. Conclusion WIP1 plays an oncogenic effect in HCC development, and targeting WIP1-dependent DNA damage repair alone or in combination with PARP inhibition might be a reasonable strategy for HCC management.
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12
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Jiang F, Hu X, Cao H, Shen X. Hsa_circ_0000081 promotes the function of gastric cancer through sponging hsa-miR-423-5p to influence 3-phosphoinositide-dependent kinase 1 expression. Bioengineered 2022; 13:8277-8290. [PMID: 35302432 PMCID: PMC9162021 DOI: 10.1080/21655979.2022.2053796] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignancies in the world, and effective therapeutic targets need to be identified for this type of cancer. In this study, circular RNA (circRNA) microarray analysis was utilized to screen differentially expressed circRNA in GC. Using quantitative reverse transcription polymerase chain reaction (qRT-PCR), hsa_circ_0000081 (circRNA-0000081) expression was found to be up-regulated in tissues and cells and was negative correlated with patients' survival time. RNase R and Actinomycin D assays indicated that circRNA-0000081 was significantly more resistant to R enzyme and had a longer half-life than linear RNA. Moreover, the knockdown or overexpression of circRNA-000081 could influence the proliferation, migration, and invasion potential of GC. Finally, dual luciferase reporter, RNA immunoprecipitation, qRT-PCR, and western blotting assays were used to verify the targeting relationship between circRNA-000081 and miRNA-423-5p or miRNA-423-5p and 3-phosphoinositide-dependent kinase 1 (PDPK1). In conclusion, circRNA-0000081 promotes the function of GC through sponging hsa-miR-423-5p to influence PDPK1 expression, which has a promising therapeutic potential for treating patients with GC.
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Affiliation(s)
- Fei Jiang
- Key Laboratory of Environmental Medical Engineering and Education Ministry, Nanjing Public Health College, Southeast University, Nanjing, China.,Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, China
| | - Xueju Hu
- Key Laboratory of Environmental Medical Engineering and Education Ministry, Nanjing Public Health College, Southeast University, Nanjing, China.,Department of Occupational and Environmental Health, School of Public Health, Southeast University, Nanjing, China
| | - Hongyong Cao
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Xiaobing Shen
- Key Laboratory of Environmental Medical Engineering and Education Ministry, Nanjing Public Health College, Southeast University, Nanjing, China.,Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, China.,Department of Occupational and Environmental Health, School of Public Health, Southeast University, Nanjing, China
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13
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Zhao S, Zheng W, Yu C, Xu G, Zhang X, Pan C, Feng Y, Yang K, Zhou J, Ma Y. The Role of Ferroptosis in the Treatment and Drug Resistance of Hepatocellular Carcinoma. Front Cell Dev Biol 2022; 10:845232. [PMID: 35309918 PMCID: PMC8927068 DOI: 10.3389/fcell.2022.845232] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 02/04/2022] [Indexed: 01/11/2023] Open
Abstract
Cell death is a fundamental feature of multicellular organisms’ development and a key driver of degenerative diseases. Ferroptosis is a new regulatory cell death mediated by iron-dependent lipid peroxidation, which is different from apoptosis and necrosis in morphology, pathophysiology and mechanism. Recent studies have found that ferroptosis is involved in the development of many diseases including hepatocellular carcinoma (HCC). As further research progresses, specific mechanisms of ferroptosis in HCC are being revealed. In this review, we summarize these recent advances about the treatment of drug-resistance in HCC and the latest ferroptosis-related treatment for HCC.
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Affiliation(s)
| | | | | | | | | | | | | | - Kunxing Yang
- *Correspondence: Kunxing Yang, ; Jin Zhou, ; Yong Ma,
| | - Jin Zhou
- *Correspondence: Kunxing Yang, ; Jin Zhou, ; Yong Ma,
| | - Yong Ma
- *Correspondence: Kunxing Yang, ; Jin Zhou, ; Yong Ma,
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14
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Ali F, Shen A, Islam W, Saleem MZ, Muthu R, Xie Q, Wu M, Cheng Y, Chu J, Lin W, Peng J. Role of MicroRNAs and their corresponding ACE2/Apelin signaling pathways in hypertension. Microb Pathog 2021; 162:105361. [PMID: 34919993 DOI: 10.1016/j.micpath.2021.105361] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 12/12/2021] [Accepted: 12/12/2021] [Indexed: 11/28/2022]
Abstract
Hypertension is controlled via the alteration of microRNAs (miRNAs), their therapeutic targets angiotensin II type I receptor (AT1R) and cross talk of signaling pathways. The stimulation of the Ang II/AT1R pathway by deregulation of miRNAs, has also been linked to cardiac remodeling as well as the pathophysiology of high blood pressure. As miRNAs have been associated to ACE2/Apelin and Mitogen-activated protein kinases (MAPK) signaling, it has revealed an utmost protective impact over hypertension and cardiovascular system. The ACE2-coupled intermodulation between RAAS, Apelin system, MAPK signaling pathways, and miRNAs reveal the practicalities of high blood pressure. The research of miRNAs may ultimately lead to the expansion of an innovative treatment strategy for hypertension, which indicates the need to explore them further at the molecular level. Therefore, here we have focused on the mechanistic importance of miRNAs in hypertension, ACE2/Apelin signaling as well as their biological functions, with a focus on interplay and crosstalk between ACE2/Apelin signaling, miRNAs, and hypertension, and the progress in miRNA-based diagnostic techniques with the goal of facilitating the development of new hypertension-controlling therapeutics.
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Affiliation(s)
- Farman Ali
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China
| | - Aling Shen
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China
| | - Waqar Islam
- Xinjiang Key Laboratory of Desert Plant Roots Ecology and Vegetation Restoration, Xinjiang Institute of Ecology and Geography, Chinese Academy of Sciences, Urumqi, 830011, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | | | - Ragunath Muthu
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China
| | - Qiurong Xie
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China
| | - Meizhu Wu
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China
| | - Ying Cheng
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China
| | - Jiangfeng Chu
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China
| | - Wei Lin
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China
| | - Jun Peng
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Chen Keji Academic Thought Inheritance Studio, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China; Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, China.
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15
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Zhang R, Tang L, Li Q, Tian Y, Zhao B, Zhou B, Yang L. Cholesterol modified DP7 and pantothenic acid induce dendritic cell homing to enhance the efficacy of dendritic cell vaccines. MOLECULAR BIOMEDICINE 2021; 2:37. [PMID: 35006477 PMCID: PMC8643384 DOI: 10.1186/s43556-021-00058-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 10/26/2021] [Indexed: 02/08/2023] Open
Abstract
Dendritic cell (DC)-based cancer vaccines have so far achieved good therapeutic effects in animal experiments and early clinical trials for certain malignant tumors. However, the overall objective response rate in clinical trials rarely exceeds 15%. The poor efficiency of DC migration to lymph nodes (LNs) (< 5%) is one of the main factors limiting the effectiveness of DC vaccines. Therefore, increasing the efficiency of DC migration is expected to further enhance the efficacy of DC vaccines. Here, we used DP7-C (cholesterol modified VQWRIRVAVIRK), which can promote DC migration, as a medium. Through multiomics sequencing and biological experiments, we found that it is the metabolite pantothenic acid (PA) that improves the migration and effectiveness of DC vaccines. We clarified that both DP7-C and PA regulate DC migration by regulating the chemokine receptor CXCR2 and inhibiting miR-142a-3p to affect the NF-κB signaling pathway. This study will lay the foundation for the subsequent use of DP7-C as a universal substance to promote DC migration, further enhance the antitumor effect of DC vaccines, and solve the bottleneck problem of the low migration efficiency and unsatisfactory clinical response rate of DC vaccines.
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Affiliation(s)
- Rui Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China
| | - Lin Tang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China
| | - Qing Li
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China
| | - Yaomei Tian
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China
| | - Binyan Zhao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China
| | - Bailing Zhou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China
| | - Li Yang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, People's Republic of China.
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16
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Xie G, Dong P, Chen H, Xu L, Liu Y, Ma Y, Zheng Y, Yang J, Zhou Y, Chen L, Shen L. Decreased expression of ATF3, orchestrated by β-catenin/TCF3, miR-17-5p and HOXA11-AS, promoted gastric cancer progression via increased β-catenin and CEMIP. Exp Mol Med 2021; 53:1706-1722. [PMID: 34728784 PMCID: PMC8639750 DOI: 10.1038/s12276-021-00694-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 06/09/2021] [Accepted: 08/24/2021] [Indexed: 01/04/2023] Open
Abstract
ATF3 has been reported to be dysregulated in various cancers and involved in various steps of tumorigenesis. However, the mechanisms underlying the abnormal expression of ATF3 and its biological function in gastric cancer (GC) have not been well investigated. Here, we report ATF3 as one of the key regulators of GC development and progression. Patients with low ATF3 expression had shorter survival and a poorer prognosis. In vitro and in vivo assays investigating ATF3 alterations revealed a complex integrated phenotype that affects cell growth and migration. Strikingly, high-throughput sequencing and microarray analysis of cells with ATF3 silencing or of ATF3-low GC tissues indicated alterations in the Wnt signaling pathway, focal adhesions and adherens junctions. Mechanistically, the expression of β-catenin and cell migration inducing hyaluronidase 1 (CEMIP) was significantly upregulated in GC cells with downregulated ATF3, which was synergistically repressed by the β-catenin/TCF3 signaling axis and noncoding RNA miR-17-5p and HOXA11-AS. In addition, we found that WDR5 expression was promoted by TCF3 and is involved in miR-17-5p and HOXA11-AS activation in GC cells. Taken together, our findings revealed the mechanism of ATF3 downregulation and its biological role in regulating the expression of Wnt signaling-related genes during GC progression, suggesting new informative biomarkers of malignancy and therapeutic directions for GC patients. New treatments for gastric cancer could involve controlling the activity of a regulatory gene and associated signaling pathway. Over-activation of the Wnt signaling pathway, which regulates many cellular functions, occurs in around half of gastric cancers. Further, the activating transcription factor 3 gene (ATF3) is thought to influence tumorigenesis, although its role in gastric cancer is unclear. Guohua Xie and co-workers at Shanghai Jiao Tong University, China, explored the function of ATF3 in human gastric cancer tissues. Patients with low ATF3 expression had poorer prognosis and shorter life expectancy. The team discovered that reduced expression of ATF3 triggered the increased expression of two of its target genes, which then altered Wnt signaling. Reduced ATF3 expression also boosted the invasiveness of gastric cancer cells. Initial results suggest that overexpression of ATF3 could suppress gastric cancer progression.
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Affiliation(s)
- Guohua Xie
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Ping Dong
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Chen
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ling Xu
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yi Liu
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yanhui Ma
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yingxia Zheng
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Junyao Yang
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yunlan Zhou
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lei Chen
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Lisong Shen
- Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. .,Faculty of Medical Laboratory Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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17
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Liao H, Shi J, Wen K, Lin J, Liu Q, Shi B, Yan Y, Xiao Z. Molecular Targets of Ferroptosis in Hepatocellular Carcinoma. J Hepatocell Carcinoma 2021; 8:985-996. [PMID: 34466409 PMCID: PMC8403010 DOI: 10.2147/jhc.s325593] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 08/11/2021] [Indexed: 12/14/2022] Open
Abstract
Ferroptosis is a special form of regulatory cell death caused by the accumulation of intracellular iron and lipid peroxidation. Here, we summarize the research progress on ferroptosis in hepatocellular carcinoma (HCC), trace the development of the concept of ferroptosis and its key regulatory factors, and discuss the application value of ferroptosis in the treatment of HCC from different perspectives. We believe that exploring the relationship between ferroptosis and HCC and clarifying the metabolism and expression of ferroptosis-specific genes and molecules will accelerate the development of novel ferroptosis-related molecules as HCC markers and therapeutic targets. We hope to provide a theoretical basis for better diagnosis and treatment to effectively improve the prognosis of patients with HCC.
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Affiliation(s)
- Hao Liao
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Juanyi Shi
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Kai Wen
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Jianhong Lin
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Qinghua Liu
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Bingchao Shi
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Yongcong Yan
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
| | - Zhiyu Xiao
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China
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18
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Zhang Y, Wu J, Zeng C, Xu L, Wei W, Li Y. The role of NFAT2/miR-20a-5p signaling pathway in the regulation of CD8 + naïve T cells activation and differentiation. Immunobiology 2021; 226:152111. [PMID: 34237654 DOI: 10.1016/j.imbio.2021.152111] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 06/18/2021] [Accepted: 06/28/2021] [Indexed: 11/25/2022]
Abstract
T cell dysfunction is a common characteristic in leukemia patients that significantly impacts clinical treatment and prognosis. However, the mechanism underlying T cell dysfunction and its reversal remains unclear. In this study, in accordance with our previous findings, we found that the expression of NFAT2 and pri-miR-17 ~ 92 are lower in peripheral blood CD3+ T cells from chronic myelogenous leukemia (CML) patients by gene expression analysis. We further demonstrate that the NFAT2-induced activation, differentiation, and expression of cytokines in human umbilical cord blood CD8+ naïve T cells are miR-20a-5p dependent. We also preliminarily explored the relationship between NFAT2 and miR-20a-5p in naive T cells. These results suggest that NFAT2 and miR-20a are crucial for regulating functional CD8+ T cells. Additionally, their alteration may be related to CD8+ T cell dysfunction in CML patients; thus, NFAT2 and miR-20a-5p may be considered potential targets for revising T cell function in leukemia immunotherapy.
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Affiliation(s)
- Yikai Zhang
- Depart of Hematology, First Affiliated Hospital, Jinan University, Guangzhou 510632, China; Guangzhou Municipality Tianhe Nuoya Bio-engineering Co. Ltd, Guangzhou 510663, China; Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, 601 Huang Pu Da Dao Xi, 510632 Guangzhou, China
| | - Jialu Wu
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, 601 Huang Pu Da Dao Xi, 510632 Guangzhou, China
| | - Chengwu Zeng
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, 601 Huang Pu Da Dao Xi, 510632 Guangzhou, China
| | - Ling Xu
- Depart of Hematology, First Affiliated Hospital, Jinan University, Guangzhou 510632, China; Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, 601 Huang Pu Da Dao Xi, 510632 Guangzhou, China.
| | - Wei Wei
- Guangzhou Municipality Tianhe Nuoya Bio-engineering Co. Ltd, Guangzhou 510663, China.
| | - Yangqiu Li
- Depart of Hematology, First Affiliated Hospital, Jinan University, Guangzhou 510632, China; Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, 601 Huang Pu Da Dao Xi, 510632 Guangzhou, China.
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Huang PS, Chang CC, Wang CS, Lin KH. Functional roles of non-coding RNAs regulated by thyroid hormones in liver cancer. Biomed J 2021; 44:272-284. [PMID: 33077406 PMCID: PMC8358202 DOI: 10.1016/j.bj.2020.08.009] [Citation(s) in RCA: 11] [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: 07/08/2020] [Revised: 08/19/2020] [Accepted: 08/24/2020] [Indexed: 02/06/2023] Open
Abstract
Recent reports have shown the important role of the non-coding part of human genome RNA (ncRNA) in cancer formation and progression. Among several kinds of ncRNAs, microRNAs (miRNA) play a pivotal role in cancer biology. Accumulating researches have been focused on the importance of non-coding genes in various diseases. In addition to miRNAs, long non-coding RNAs (lncRNAs) have also been extensively documented. Recently, the study of human liver cancer has gradually shifted to these non-coding RNAs that were originally considered "junk". Notably, dysregulated ncRNAs maybe influence on cell proliferation, angiogenesis, anti-apoptosis, and metastasis. Thyroid hormones play critical roles in human development and abnormalities in thyroid hormone levels are associated with various diseases, such as liver cancer. Thyroid hormone receptors (TR) act as ligand-activated nuclear transcription factors to affect multiple functions through the gene-level regulation in the cells and several studies have revealed that thyroid hormone associated with ncRNAs expression. TR actions are complex and tissue- and time-specific, aberrant expression of the various TR isoforms have different effects and are associated with different types of tumor or stages of development. In this review, we discuss various aspects of the research on the thyroid hormones modulated ncRNAs to affect the functions of human liver cells.
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Affiliation(s)
- Po-Shuan Huang
- Department of Biochemistry, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Cheng-Chih Chang
- Department of General Surgery, Chang Gung Memorial Hospital at Chia yi, Chia yi, Taiwan
| | - Chia-Siu Wang
- Department of General Surgery, Chang Gung Memorial Hospital at Chia yi, Chia yi, Taiwan
| | - Kwang-Huei Lin
- Department of Biochemistry, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan; Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan.
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20
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Morishita A, Oura K, Tadokoro T, Fujita K, Tani J, Masaki T. MicroRNAs in the Pathogenesis of Hepatocellular Carcinoma: A Review. Cancers (Basel) 2021; 13:cancers13030514. [PMID: 33572780 PMCID: PMC7866004 DOI: 10.3390/cancers13030514] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/22/2021] [Accepted: 01/25/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is one of the most frequently occurring cancers, and the prognosis for late-stage HCC remains poor. A better understanding of the pathogenesis of HCC is expected to improve outcomes. MicroRNAs (miRNAs) are small, noncoding, single-stranded RNAs that regulate the expression of various target genes, including those in cancer-associated genomic regions or fragile sites in various human cancers. We summarize the central roles of miRNAs in the pathogenesis of HCC and discuss their potential utility as valuable biomarkers and new therapeutic agents for HCC. Abstract Hepatocellular carcinoma (HCC) is the seventh most frequent cancer and the fourth leading cause of cancer mortality worldwide. Despite substantial advances in therapeutic strategies, the prognosis of late-stage HCC remains dismal because of the high recurrence rate. A better understanding of the etiology of HCC is therefore necessary to improve outcomes. MicroRNAs (miRNAs) are small, endogenous, noncoding, single-stranded RNAs that modulate the expression of their target genes at the posttranscriptional and translational levels. Aberrant expression of miRNAs has frequently been detected in cancer-associated genomic regions or fragile sites in various human cancers and has been observed in both HCC cells and tissues. The precise patterns of aberrant miRNA expression differ depending on disease etiology, including various causes of hepatocarcinogenesis, such as viral hepatitis, alcoholic liver disease, or nonalcoholic steatohepatitis. However, little is known about the underlying mechanisms and the association of miRNAs with the pathogenesis of HCC of various etiologies. In the present review, we summarize the key mechanisms of miRNAs in the pathogenesis of HCC and emphasize their potential utility as valuable diagnostic and prognostic biomarkers, as well as innovative therapeutic targets, in HCC diagnosis and treatment.
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He D, Zhang X, Zhu X, Maharjan N, Wang Y, Luo P, Liang C, Tu J. Identify and Validate the Transcriptomic, Functional Network, and Predictive Validity of FBXL19-AS1 in Hepatocellular Carcinoma. Front Oncol 2020; 10:609601. [PMID: 33344260 PMCID: PMC7744744 DOI: 10.3389/fonc.2020.609601] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 11/04/2020] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common neoplastic diseases worldwide. Available biomarkers are not sensitive enough for the diagnosis of HCC, hence seeking new biomarkers of HCC is urgent and challenging. The purpose of this study was to investigate the role of F-box and leucine-rich repeat protein 19-antisense RNA 1 (FBXL19-AS1) through a functional network and inquire into its diagnostic and prognostic value in HCC. A comprehensive strategy of genomic data mining, bioinformatics and experimental validation was used to evaluate the clinical value of FBXL19-AS1 in the diagnosis and prognosis of HCC and to identify the pathways in which FBXL19-AS1 might be involved. FBXL19-AS1 was up-regulated in HCC tissues, and its high expression was associated with TNM stage and poor prognosis of HCC patients. The combination of FBXL19-AS1 and alpha-fetoprotein (AFP) in plasma could prominently improve the diagnostic validity for HCC. FBXL19-AS1 might stabilize FBXL19 to reduce the amount of macrophage M1, and then promote the occurrence and development of HCC. Meanwhile, FBXL19-AS1 might participate in regulating HCC related pathways through FBXL19-AS1-miRNA-mRNA network. Our findings indicated that FBXL19-AS1 not only serves as a potential biomarker for HCC diagnosis and prognosis, but also might be functionally carcinogenic.
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Affiliation(s)
- Dingdong He
- Department & Program of Clinical Laboratory Medicine, Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Xiaokang Zhang
- Department & Program of Clinical Laboratory Medicine, Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Xinyu Zhu
- Department & Program of Clinical Laboratory Medicine, Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Narayani Maharjan
- Department & Program of Clinical Laboratory Medicine, Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yingchao Wang
- Department & Program of Clinical Laboratory Medicine, Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Ping Luo
- Department & Program of Clinical Laboratory Medicine, Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Chunzi Liang
- Department & Program of Clinical Laboratory Medicine, Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Jiancheng Tu
- Department & Program of Clinical Laboratory Medicine, Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China
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Raafat N, Zaher TI, Etewa RL, El-gerby KM, Rezk NA. Heat shock protein-27 and MiR-17-5p are novel diagnostic and prognostic biomarkers for hepatocellular carcinoma in Egyptian patients. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2020.100822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Li Z, Wang J, Yang J. TUG1 knockdown promoted viability and inhibited apoptosis and cartilage ECM degradation in chondrocytes via the miR-17-5p/FUT1 pathway in osteoarthritis. Exp Ther Med 2020; 20:154. [PMID: 33093892 PMCID: PMC7571376 DOI: 10.3892/etm.2020.9283] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 07/14/2020] [Indexed: 12/19/2022] Open
Abstract
Osteoarthritis (OA) is a degenerative disease characterized by cartilage destruction. Previous research has demonstrated that long non-coding RNAs serve a role in OA progression. The current study aimed to determine the function and mechanism of taurine upregulated gene (TUG) 1 in OA. The results of reverse transcription quantitative PCR revealed that TUG1 was elevated in OA cartilage tissues and interleukin (IL)-1β-induced chondrocytes. Cell Counting kit-8 and flow cytometry analysis revealed that TUG1 knockdown promoted cell viability and inhibited cell apoptosis. Furthermore, matrix metalloprotein (MMP) 13, collagen II and aggrecan expression was determined by western blotting, of which the results demonstrated that TUG1 knockdown significantly decreased MMP13 expression and increased collagen II and aggrecan expression in IL-1β-stimulated chondrocytes, indicating that extracellular matrix (ECM) damage was inhibited. Additionally, using bioinformatics analysis, dual-luciferase reporter and RNA immunoprecipitation assays, TUG1 was revealed to upregulate fucosyltransferase (FUT) 1 by targeting miR-17-5p. Furthermore, miR-17-5p was downregulated and FUT1 upregulated in OA cartilage tissues and IL-1β-induced chondrocytes. TUG1 overexpression reversed the aforementioned effects on cell viability, cell apoptosis and ECM degradation mediated by miR-17-5p in IL-1β-activated chondrocytes. Additionally, the effects of FUT1 knockdown on cell viability, apoptosis and ECM degradation mediated by FUT1 knockdown were reversed by miR-17-5p inhibition. In conclusion, TUG1 knockdown inhibited OA progression by downregulating FUT1 via miR-17-5p.
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Affiliation(s)
- Zhichao Li
- Department of Hand, Foot and Vascular Surgery, Hanyang Hospital, Wuhan University of Science and Technology, Wuhan, Hubei 430050, P.R. China
| | - Jin Wang
- Department of Hand, Foot and Vascular Surgery, Hanyang Hospital, Wuhan University of Science and Technology, Wuhan, Hubei 430050, P.R. China
| | - Jing Yang
- Department of Cardiology, Renmin Hospital, Wuhan University, Wuhan, Hubei 430060, P.R. China
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miR-876 Inhibits EMT and Liver Fibrosis via POSTN to Suppress Metastasis in Hepatocellular Carcinoma. BIOMED RESEARCH INTERNATIONAL 2020; 2020:1964219. [PMID: 33083453 PMCID: PMC7559219 DOI: 10.1155/2020/1964219] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 07/19/2020] [Accepted: 08/14/2020] [Indexed: 02/06/2023]
Abstract
Background The asymptomatic onset, frequent recurrence, and poor prognosis of hepatocellular carcinoma (HCC) prompted us to identify new therapeutic targets or predictive markers of HCC diagnosis or prognosis. Methods In this study, bioinformatics analysis was used to screen for target miRNAs from the open-access TCGA database. Transwell assays, Western blotting, and qRT-PCR analyses were used to detect cellular functions and gene expression in HCC cells and samples. A nude mouse tumorigenesis model was established to facilitate the observation of HCC progression. Other assays included luciferase reporter assays, IHC, and survival analysis. Results We found that the identified miR-876 from TCGA was expressed at low levels in HCC cell lines and that low miR-876 expression was corrected with liver cirrhosis, tumor thrombus, and TNM stage. Further research revealed that miR-876 regulated cell invasion, EMT, and collagen expression by targeting POSTN expression. miR-876 and POSTN were inversely correlated in HCC samples and associated with EMT status and liver fibrosis in clinical HCC tissues. miR-876 inhibited the liver cancer progression in in vivo animal assays. Finally, both miR-876 and POSTN were risk factors for HCC survival, and HCC patients with combined low miR-876 and high POSTN expression had worse prognosis. Conclusions miR-876 inhibited HCC EMT and fibrosis by targeting POSTN, thus affecting HCC progression and prognosis. miR-876 and POSTN may be useful therapeutic targets or prognostic markers of HCC.
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Zhao Y, Wu H, Xing X, Ma Y, Ji S, Xu X, Zhao X, Wang S, Jiang W, Fang C, Zhang L, Yan F, Wang X. CD13 Induces Autophagy to Promote Hepatocellular Carcinoma Cell Chemoresistance Through the P38/Hsp27/CREB/ATG7 Pathway. J Pharmacol Exp Ther 2020; 374:512-520. [PMID: 32571958 DOI: 10.1124/jpet.120.265637] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 06/17/2020] [Indexed: 12/13/2022] Open
Abstract
The chemoresistance of hepatocellular carcinoma (HCC) is a serious problem that directly hinders the effect of chemotherapeutic agents. We previously reported that Aminopeptidase N (CD13) inhibition can enhance the cytotoxic efficacy of chemotherapy agents. In the present study, we use liver cancer cells to explore the molecular mechanism accounting for the relationship between CD13 and chemoresistance. We demonstrate that CD13 overexpression activates the P38/heat shock protein 27/cAMP response element-binding protein (CREB) signaling pathway to limit the efficacy of cytotoxic agents. Moreover, blockade of P38 or CREB sensitizes HCC cells to 5-fluorouracil. Then we reveal that CREB binds to the autophagy related 7 (ATG7) promoter to induce autophagy and promote HCC cell chemoresistance. CD13 inhibition also downregulates the expression of ATG7, autophagy, and tumor cell growth in vivo. Overall, the combination a CD13 inhibitor and chemotherapeutic agents may be a potential strategy for overcoming drug resistance in HCC. SIGNIFICANCE STATEMENT: Our study demonstrates that Aminopeptidase N (CD13) promotes hepatocellular carcinoma (HCC) cell chemoresistance via the P38/heat shock protein 27/cAMP response element-binding protein (CREB) pathway. CREB regulates autophagy related 7 transcription and expression to induce autophagy. Our results collectively suggest that CD13 may serve as a potential target for overcoming HCC resistance.
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Affiliation(s)
- Yan Zhao
- School of Pharmacy, Weifang Medical University, Weifang, Shandong, China (Y.Z., H.W., X.Xi., Y.M., S.J., X.Xu., X.Z., S.W., W.J., C.F., L.Z., F.Y., X.W.) and Department of pharmacy, Southwestern Lu Hospital, Liaocheng, Shandong, China (H.W.)
| | - Huina Wu
- School of Pharmacy, Weifang Medical University, Weifang, Shandong, China (Y.Z., H.W., X.Xi., Y.M., S.J., X.Xu., X.Z., S.W., W.J., C.F., L.Z., F.Y., X.W.) and Department of pharmacy, Southwestern Lu Hospital, Liaocheng, Shandong, China (H.W.)
| | - Xiaoyan Xing
- School of Pharmacy, Weifang Medical University, Weifang, Shandong, China (Y.Z., H.W., X.Xi., Y.M., S.J., X.Xu., X.Z., S.W., W.J., C.F., L.Z., F.Y., X.W.) and Department of pharmacy, Southwestern Lu Hospital, Liaocheng, Shandong, China (H.W.)
| | - Yuqian Ma
- School of Pharmacy, Weifang Medical University, Weifang, Shandong, China (Y.Z., H.W., X.Xi., Y.M., S.J., X.Xu., X.Z., S.W., W.J., C.F., L.Z., F.Y., X.W.) and Department of pharmacy, Southwestern Lu Hospital, Liaocheng, Shandong, China (H.W.)
| | - Shengping Ji
- School of Pharmacy, Weifang Medical University, Weifang, Shandong, China (Y.Z., H.W., X.Xi., Y.M., S.J., X.Xu., X.Z., S.W., W.J., C.F., L.Z., F.Y., X.W.) and Department of pharmacy, Southwestern Lu Hospital, Liaocheng, Shandong, China (H.W.)
| | - Xinyue Xu
- School of Pharmacy, Weifang Medical University, Weifang, Shandong, China (Y.Z., H.W., X.Xi., Y.M., S.J., X.Xu., X.Z., S.W., W.J., C.F., L.Z., F.Y., X.W.) and Department of pharmacy, Southwestern Lu Hospital, Liaocheng, Shandong, China (H.W.)
| | - Xin Zhao
- School of Pharmacy, Weifang Medical University, Weifang, Shandong, China (Y.Z., H.W., X.Xi., Y.M., S.J., X.Xu., X.Z., S.W., W.J., C.F., L.Z., F.Y., X.W.) and Department of pharmacy, Southwestern Lu Hospital, Liaocheng, Shandong, China (H.W.)
| | - Sensen Wang
- School of Pharmacy, Weifang Medical University, Weifang, Shandong, China (Y.Z., H.W., X.Xi., Y.M., S.J., X.Xu., X.Z., S.W., W.J., C.F., L.Z., F.Y., X.W.) and Department of pharmacy, Southwestern Lu Hospital, Liaocheng, Shandong, China (H.W.)
| | - Wenyan Jiang
- School of Pharmacy, Weifang Medical University, Weifang, Shandong, China (Y.Z., H.W., X.Xi., Y.M., S.J., X.Xu., X.Z., S.W., W.J., C.F., L.Z., F.Y., X.W.) and Department of pharmacy, Southwestern Lu Hospital, Liaocheng, Shandong, China (H.W.)
| | - Chunyan Fang
- School of Pharmacy, Weifang Medical University, Weifang, Shandong, China (Y.Z., H.W., X.Xi., Y.M., S.J., X.Xu., X.Z., S.W., W.J., C.F., L.Z., F.Y., X.W.) and Department of pharmacy, Southwestern Lu Hospital, Liaocheng, Shandong, China (H.W.)
| | - Lei Zhang
- School of Pharmacy, Weifang Medical University, Weifang, Shandong, China (Y.Z., H.W., X.Xi., Y.M., S.J., X.Xu., X.Z., S.W., W.J., C.F., L.Z., F.Y., X.W.) and Department of pharmacy, Southwestern Lu Hospital, Liaocheng, Shandong, China (H.W.)
| | - Fang Yan
- School of Pharmacy, Weifang Medical University, Weifang, Shandong, China (Y.Z., H.W., X.Xi., Y.M., S.J., X.Xu., X.Z., S.W., W.J., C.F., L.Z., F.Y., X.W.) and Department of pharmacy, Southwestern Lu Hospital, Liaocheng, Shandong, China (H.W.)
| | - Xuejian Wang
- School of Pharmacy, Weifang Medical University, Weifang, Shandong, China (Y.Z., H.W., X.Xi., Y.M., S.J., X.Xu., X.Z., S.W., W.J., C.F., L.Z., F.Y., X.W.) and Department of pharmacy, Southwestern Lu Hospital, Liaocheng, Shandong, China (H.W.)
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Qu J, Zhang X, Lv X. Zinc finger protein 750(ZNF750), negatively regulated by miR-17-5p, inhibits proliferation, motility and invasion of colonic cancer cells. J Gene Med 2020; 22:e3195. [PMID: 32246873 DOI: 10.1002/jgm.3195] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 03/08/2020] [Accepted: 03/21/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND The present study aimed to investigate the expression, function and clinical implication of zinc finger protein 750 (ZNF750) in colonic cancer and explore the mechanism of its dysregulation. METHODS The expression of ZNF750 in 76 pairs of colonic cancer tissues was determined using immunohistochemistry. The expression of ZNF750 in colonic cancer cells was detected using western blotting. The correlation between the expression level of ZNF750 and clinicopathological parameters in patients with colonic cancer was analyzed using a chi-squared test. CCK-8 and colony formation assays were used to monitor cell proliferation. Additionally, flow cytometry was used to detect apoptosis of cells; scratch healing and Transwell assays were conducted to evaluate the migration and invasion of cells. Ultimately, the binding relationship between miR-17-5p and ZNF750 was validated using western blotting, a real-time polymerase chaub reaction and a dual-luciferase reporter gene assay. RESULTS The expression level of ZNF750 in colonic cancer tissues, as well as colonic cancer cell lines, was significantly down-regulated. Low expression of ZNF750 was associated with larger tumor size and poor tumor differentiation. The over-expression of ZNF750 inhibited the proliferation, motility and invasion but promoted the apoptosis of colonic cancer cells. After the cells were transfected with miR-17-5p mimics, the expression of ZNF750 at both mRNA and protein levels was markedly decreased, whereas the expression of ZNF750 was markedly increased after transfection of miR-17-5p inhibitors. MiR-17-5p could suppresses the malignant biological behaviors via negatively regulating ZNF750. CONCLUSIONS ZNF750 is negatively regulated by miR-17-5p and inhibits the progression of colonic cancer.
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Affiliation(s)
- Jie Qu
- Department of Oncology, Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Xiuqin Zhang
- Department of Oncology, Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Xiying Lv
- Department of Oncology, Affiliated Hospital of Chengde Medical University, Chengde, China
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Wu CH, Chen CY, Yeh CT, Lin KH. Radiosensitization of Hepatocellular Carcinoma through Targeting Radio-Associated MicroRNA. Int J Mol Sci 2020; 21:ijms21051859. [PMID: 32182776 PMCID: PMC7084923 DOI: 10.3390/ijms21051859] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 03/03/2020] [Accepted: 03/06/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide. For patients who are resistant to monotherapy, multimodal therapy is a basic oncologic principle that incorporates surgery, radiotherapy (RT), and chemotherapy providing survival benefits for patients with most types of cancer. Although liver has low tolerance for radiation, high-precision RT for local HCC minimizes the likelihood of radiation-induced liver disease (RILD) in noncancerous liver tissue. RT have several therapeutic benefits, including the down-staging of tumors to make them resectable and repression of metastasis. The DNA damage response (DDR) is a cellular response to irradiation (IR), including DNA repair of injured cells and induction of programmed cell death, thereby resulting in maintenance of cell homeostasis. Molecules that block the activity of proteins in DDR pathways have been found to enhance radiotherapeutic effects. These molecules include antibodies, kinase inhibitors, siRNAs and miRNAs. MicroRNAs (miRNAs) are short non-coding regulatory RNAs binding to the 3'-untranslated regions (3'-UTR) of the messenger RNAs (mRNAs) of target genes, regulating their translation and expression of proteins. Thus, miRNAs and their target genes constitute complicated interactive networks, which interact with other molecules during carcinogenesis. Due to their promising roles in carcinogenesis, miRNAs were shown to be the potential factors that mediated radiosensitivity and optimized outcomes of the combination of systemic therapy and radiotherapy.
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Affiliation(s)
- Cheng-Heng Wu
- Department of Biochemistry, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan;
| | - Cheng-Yi Chen
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan;
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan;
| | - Kwang-Huei Lin
- Department of Biochemistry, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan;
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan;
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
- Correspondence: ; Tel./Fax: +886-3-2118263
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Lai H, Zhang J, Zuo H, Liu H, Xu J, Feng Y, Lin Y, Mo X. Overexpression of miR-17 is correlated with liver metastasis in colorectal cancer. Medicine (Baltimore) 2020; 99:e19265. [PMID: 32118734 PMCID: PMC7478658 DOI: 10.1097/md.0000000000019265] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in men and women. The presence of systemic disease, with metastatic spread to distant sites such as the liver, considerably reduces the survival rate in CRC. Cancer stem cells contribute to the metastatic potential of CRC. However, the mechanism underlying metastasis in CRC remains unclear. Thus, this study aimed to examine the expression of microRNAs (miRNAs) in CRC stem cells in cases of liver metastases and assess their correlation with clinicopathological features. METHODS miRNAs showing high expression in liver metastases and primary lesions were selected through data mining of gene expression omnibus datasets, and miRNAs characteristic of stem cells were selected through COREMINE medical text mining. Subsequently, paired formalin-fixed paraffin-embedded tissue samples of primary CRC and liver metastasis from 30 patients were examined for the expression of miRNAs common to these lists (hsa-miR-20a, hsa-miR-26b, hsa-miR-146a, hsa-miR-17, hsa-miR-451, hsa-miR-23a, and hsa-miR-29a) using quantitative real-time polymerase chain reaction. Further, miRNA expression was compared between liver metastases and the primary tumor in each patient and the factors associated with differential expression were analyzed. RESULTS hsa-miR-17 was significantly upregulated in liver metastases (P < .05), but no significant difference in the expression of hsa-miR-26b, hsa-miR-146a, hsa-miR-451, hsa-miR-23a, and hsa-miR-29a was observed between primary tumors and liver metastases. The higher expression of hsa-miR-17 in liver metastases was associated with the administration of neoadjuvant chemotherapy and tumor differentiation (P < .05) but was not associated with age, sex, tumor location, or lymphatic metastasis. CONCLUSIONS High expression of miR-17 may contribute to liver metastasis in CRC. Therefore, an in-depth understanding of its downstream pathways could help in elucidating the mechanisms underlying liver metastases in CRC. However, additional studies are warranted to validate these findings.
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Affiliation(s)
- Hao Lai
- Gastrointestinal Surgery Department, Guangxi Medical University Cancer Hospital
- Guangxi Clinical Research Center for Colorectal Cancer
| | - Jie Zhang
- Gastrointestinal Surgery Department, Guangxi Medical University Cancer Hospital
- Guangxi Clinical Research Center for Colorectal Cancer
| | - Hongqun Zuo
- Gastrointestinal Surgery Department, Guangxi Medical University Cancer Hospital
- Guangxi Clinical Research Center for Colorectal Cancer
| | - Haizhou Liu
- Research Department, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Zhuang Autonomous Region, P.R. China
| | - Jing Xu
- Gastrointestinal Surgery Department, Guangxi Medical University Cancer Hospital
- Guangxi Clinical Research Center for Colorectal Cancer
| | - Yan Feng
- Research Department, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Zhuang Autonomous Region, P.R. China
| | - Yuan Lin
- Gastrointestinal Surgery Department, Guangxi Medical University Cancer Hospital
- Guangxi Clinical Research Center for Colorectal Cancer
| | - Xianwei Mo
- Gastrointestinal Surgery Department, Guangxi Medical University Cancer Hospital
- Guangxi Clinical Research Center for Colorectal Cancer
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Ziogas IA, Sioutas G, Mylonas KS, Tsoulfas G. Role of MicroRNA in the Diagnosis and Management of Hepatocellular Carcinoma. Microrna 2020; 9:25-40. [PMID: 31218966 DOI: 10.2174/2211536608666190619155406] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 03/11/2019] [Accepted: 05/06/2019] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Hepatocellular Carcinoma (HCC) is one of the most common malignant tumors in the world and comes third in cancer-induced mortality. The need for improved and more specific diagnostic methods that can detect early-stage disease is immense, as it is amenable to curative modalities, while advanced HCC is associated with low survival rates. microRNA (miRNA) expression is deregulated in HCC and this can be implemented both diagnostically and therapeutically. OBJECTIVE To provide a concise review on the role of miRNA in diagnosis, prognosis, and treatment of HCC. METHODS We conducted a comprehensive review of the PubMed bibliographic database. RESULTS Multiple miRNAs are involved in the pathogenesis of HCC. Measurement of the levels of these miRNAs either in tumor tissue or in the blood constitutes a promising diagnostic, as well as prognostic tool. OncomiRs are miRNAs that promote tumorigenesis, thus inhibiting them by administering antagomiRs is a promising treatment option. Moreover, replacement of the depleted miRNAs is another potential therapeutic approach for HCC. Modification of miRNA levels may also regulate sensitivity to chemotherapeutic agents. CONCLUSION miRNA play a pivotal role in HCC pathogenesis and once the underlying mechanisms are elucidated, they will become part of everyday clinical practice against HCC.
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Affiliation(s)
- Ioannis A Ziogas
- Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Surgery Working Group, Society of Junior Doctors, Athens, Greece
| | - Georgios Sioutas
- Surgery Working Group, Society of Junior Doctors, Athens, Greece
- Medical School, Democritus University of Thrace, Alexandroupolis, Greece
| | - Konstantinos S Mylonas
- Surgery Working Group, Society of Junior Doctors, Athens, Greece
- Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Georgios Tsoulfas
- 1st Department of Surgery, Aristotle University of Thessaloniki, Thessaloniki, Greece
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Zhong Z, Zhong W, Zhang Q, Zhang Q, Yu Z, Wu H. Circulating microRNA expression profiling and bioinformatics analysis of patients with coronary artery disease by RNA sequencing. J Clin Lab Anal 2020; 34:e23020. [PMID: 31489700 PMCID: PMC6977390 DOI: 10.1002/jcla.23020] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 08/03/2019] [Accepted: 08/05/2019] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND MicroRNAs play a vital role in coronary artery disease. Abnormal expression of microRNAs has been found to be associated with the occurrence of CAD. METHODS We identified significantly differentially expressed microRNAs in plasma between 40 patients with CAD and 10 controls with NCA using RNA sequencing. The differentially expressed microRNAs were analyzed for Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. RESULTS Fifty cDNA libraries were constructed and sequenced, and a total of 1871.82 M raw reads were obtained, and 2135 microRNAs were found. Compared to the expressed microRNAs of NCA controls, 159 microRNAs were differentially expressed in CAD patients, including 119 upregulated microRNAs and 40 downregulated microRNAs. The top 10 upregulated miRNAs were miR-144-3p, miR-34a-5p, miR-15b-3p, miR-22-3p, miR-29b-3p, miR-1270, miR-6891-5p, miR-106a-5p, miR-15b-5p, and hsa-miR-499b-3p. The top ten downregulated miRNAs were miR-4437, miR-6842-3p, miR-4664-3p, miR-671-3p, miR-219a-1-3p, miR-7848-3p, miR-664a-3p, miR-1284, miR-361-3p, and miR-6780a-5p. The target genes of differentially expressed microRNAs were related to many basic biological terms, such as biological process, cellular component, and molecular function. According to the KEGG pathway analysis, the most enriched pathways of the differentially expressed microRNAs were endocytosis, focal adhesion, axon guidance, and so on. Furthermore, six upregulated and two downregulated microRNAs were detected by qRT-PCR (Quantitative Real-time PCR) and ROC analysis for diagnosing CAD. CONCLUSION The results suggest that the expression levels of some microRNAs may play a vital role in the physiological and pathological course of CAD. Our study may provide useful information for the diagnosis and treatment of CAD.
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Affiliation(s)
- Zhixiong Zhong
- Center for Cardiovascular DiseasesMeizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou Hospital Affiliated to Sun Yat‐sen UniversityMeizhouChina
- Guangdong Provincial Key Laboratory of Precision Medicine, Clinical and Translational Research in Hakka PopulationMeizhouChina
- Guangdong Provincial Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular DiseasesMeizhouChina
- Meizhou Municipal Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular DiseasesMeizhouChina
| | - Wei Zhong
- Center for Cardiovascular DiseasesMeizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou Hospital Affiliated to Sun Yat‐sen UniversityMeizhouChina
- Guangdong Provincial Key Laboratory of Precision Medicine, Clinical and Translational Research in Hakka PopulationMeizhouChina
- Guangdong Provincial Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular DiseasesMeizhouChina
- Meizhou Municipal Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular DiseasesMeizhouChina
| | - Qifeng Zhang
- Center for Cardiovascular DiseasesMeizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou Hospital Affiliated to Sun Yat‐sen UniversityMeizhouChina
- Guangdong Provincial Key Laboratory of Precision Medicine, Clinical and Translational Research in Hakka PopulationMeizhouChina
- Guangdong Provincial Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular DiseasesMeizhouChina
- Meizhou Municipal Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular DiseasesMeizhouChina
| | - Qunji Zhang
- Guangdong Provincial Key Laboratory of Precision Medicine, Clinical and Translational Research in Hakka PopulationMeizhouChina
- Guangdong Provincial Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular DiseasesMeizhouChina
- Meizhou Municipal Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular DiseasesMeizhouChina
- Meizhou Municipal Engineering and Technology Research Center for Molecular Diagnostics of Major Genetic DisordersMeizhouChina
- Center for Precision MedicineMeizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou Hospital Affiliated to Sun Yat‐sen UniversityMeizhouChina
| | - Zhikang Yu
- Guangdong Provincial Key Laboratory of Precision Medicine, Clinical and Translational Research in Hakka PopulationMeizhouChina
- Guangdong Provincial Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular DiseasesMeizhouChina
- Meizhou Municipal Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular DiseasesMeizhouChina
- Meizhou Municipal Engineering and Technology Research Center for Molecular Diagnostics of Major Genetic DisordersMeizhouChina
- Center for Precision MedicineMeizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou Hospital Affiliated to Sun Yat‐sen UniversityMeizhouChina
| | - Heming Wu
- Guangdong Provincial Key Laboratory of Precision Medicine, Clinical and Translational Research in Hakka PopulationMeizhouChina
- Guangdong Provincial Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular DiseasesMeizhouChina
- Meizhou Municipal Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular DiseasesMeizhouChina
- Meizhou Municipal Engineering and Technology Research Center for Molecular Diagnostics of Major Genetic DisordersMeizhouChina
- Center for Precision MedicineMeizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou Hospital Affiliated to Sun Yat‐sen UniversityMeizhouChina
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Wang Y, Shi L, Li J, Li L, Wang H, Yang H. Involvement of p38 MAPK pathway in benzo(a)pyrene-induced human hepatoma cell migration and invasion. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2019; 26:35838-35845. [PMID: 31707611 DOI: 10.1007/s11356-019-06733-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/23/2019] [Accepted: 10/10/2019] [Indexed: 06/10/2023]
Abstract
The objective of this study was to investigate the potential role of p38 mitogen-activated protein kinases (MAPK) in benzo(a)pyrene (BaP)-induced hepatoma cell migration and invasion. Western blot assay was applied to detect the expression of proteins. qRT-PCR assay was used to measure the expression of mRNA. Wound healing assay and Transwell invasion assay were performed to evaluate cell migratory ability and cell invasive ability, respectively. Our data showed that BaP exposure increased the expression of p-p38 protein in human hepatoma HepG2 cells. Exposure to BaP facilitated HepG2 cell migration and invasion, which could be blocked by p38 MAPK inhibitors. In addition, BaP exposure induced upregulation of MMP9 mRNA expression, which was modulated by p-p38. In conclusion, p38 MAPK pathway was involved in BaP-induced hepatoma cell migration and invasion.
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Affiliation(s)
- Yadong Wang
- Department of Toxicology, Henan Center for Disease Control and Prevention, No. 105 of South Nongye Road, Zhengzhou, 450016, China.
| | - Li Shi
- Department of Epidemiology, School of Public Health, Zhengzhou University, No. 100 of Science Avenue, Zhengzhou, 450001, China
| | - Jiangmin Li
- Department of Toxicology, Henan Center for Disease Control and Prevention, No. 105 of South Nongye Road, Zhengzhou, 450016, China
| | - Li Li
- Department of Toxicology, Henan Center for Disease Control and Prevention, No. 105 of South Nongye Road, Zhengzhou, 450016, China
| | - Haiyu Wang
- Department of Toxicology, Henan Center for Disease Control and Prevention, No. 105 of South Nongye Road, Zhengzhou, 450016, China
| | - Haiyan Yang
- Department of Epidemiology, School of Public Health, Zhengzhou University, No. 100 of Science Avenue, Zhengzhou, 450001, China.
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Epigenetic Alterations of Heat Shock Proteins (HSPs) in Cancer. Int J Mol Sci 2019; 20:ijms20194758. [PMID: 31557887 PMCID: PMC6801855 DOI: 10.3390/ijms20194758] [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: 08/22/2019] [Revised: 09/20/2019] [Accepted: 09/23/2019] [Indexed: 12/15/2022] Open
Abstract
Heat shock proteins (HSPs) are associated with various physiological processes (protein refolding and degradation) involved in the responses to cellular stress, such as cytotoxic agents, high temperature, and hypoxia. HSPs are overexpressed in cancer cells and play roles in their apoptosis, invasion, proliferation, angiogenesis, and metastasis. The regulation or translational modification of HSPs is recognized as a therapeutic target for the development of anticancer drugs. Among the regulatory processes associated with HSP expression, the epigenetic machinery (miRNAs, histone modification, and DNA methylation) has key functions in cancer. Moreover, various epigenetic modifiers of HSP expression have also been reported as therapeutic targets and diagnostic markers of cancer. Thus, in this review, we describe the epigenetic alterations of HSP expression in cancer cells and suggest that HSPs be clinically applied as diagnostic and therapeutic markers in cancer therapy via controlled epigenetic modifiers.
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MAT2B mediates invasion and metastasis by regulating EGFR signaling pathway in hepatocellular carcinoma. Clin Exp Med 2019; 19:535-546. [PMID: 31493275 DOI: 10.1007/s10238-019-00579-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 08/30/2019] [Indexed: 01/15/2023]
Abstract
The poor prognosis of hepatocellular carcinoma (HCC) patients is mainly due to cancer metastasis. Methionine adenosyltransferase 2β (MAT2B) encodes a regulatory subunit (β) for methionine adenosyltransferase. Previous studies reveal that MAT2B provides a growth advantage for HCC, but its role in metastasis is unknown. This study showed that both in the xenograft zebra fish model and in the lung metastasis model in nude mice, the stable inhibition of MAT2B could suppress the metastasis of HCC cancer cells. Silencing of MAT2B in HCC cell lines could remarkably inhibit migration and invasion. By analysis of human phospho-kinase array membranes, we found several differentially expressed proteins, including phosphor-AKT, phospho-EGFR, phospho-Src family, phospho-FAK, phospho-STAT3 and phospho-ERK. We further confirmed the change of these EGFR pathway-related proteins was in accordance with MAT2B expression pattern through immunoblotting test. Finally, we found that MAT2B was overexpressed in HCC caner tissues and correlated with poor prognosis for HCC patients in clinical manifestation. Our study demonstrated that silencing of MAT2B could suppress liver cancer cell migration and invasion through the inhibition of EGFR signaling, which suggested that MAT2B might serve as a new prognostic marker and therapeutic target for HCC.
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Lee H, Li C, Zhang Y, Zhang D, Otterbein LE, Jin Y. Caveolin-1 selectively regulates microRNA sorting into microvesicles after noxious stimuli. J Exp Med 2019; 216:2202-2220. [PMID: 31235510 PMCID: PMC6719430 DOI: 10.1084/jem.20182313] [Citation(s) in RCA: 155] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 04/23/2019] [Accepted: 05/31/2019] [Indexed: 12/23/2022] Open
Abstract
Emerging evidence suggests that extracellular vesicle (EV)-containing miRNAs mediate intercellular communications in response to noxious stimuli. It remains unclear how a cell selectively sorts the cellular miRNAs into EVs. We report that caveolin-1 (cav-1) is essential for sorting of selected miRNAs into microvesicles (MVs), a main type of EVs generated by outward budding of the plasma membrane. We found that cav-1 tyrosine 14 (Y14)-phosphorylation leads to interactions between cav-1 and hnRNPA2B1, an RNA-binding protein. The cav-1/hnRNPA2B1 complex subsequently traffics together into MVs. Oxidative stress induces O-GlcNAcylation of hnRNPA2B1, resulting in a robustly altered hnRNPA2B1-bound miRNA repertoire. Notably, cav-1 pY14 also promotes hnRNPA2B1 O-GlcNAcylation. Functionally, macrophages serve as the principal recipient of epithelial MVs in the lung. MV-containing cav-1/hnRNPA2B1 complex-bound miR-17/93 activate tissue macrophages. Collectively, cav-1 is the first identified membranous protein that directly guides RNA-binding protein into EVs. Our work delineates a novel mechanism by which oxidative stress compels epithelial cells to package and secrete specific miRNAs and elicits an innate immune response.
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Affiliation(s)
- Heedoo Lee
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Boston University Medical Campus, Boston, MA
| | - Chunhua Li
- Department of Computational Medicine and Bioinformatics Department of Biological Chemistry, The University of Michigan, Ann Arbor, MI
| | - Yang Zhang
- Department of Computational Medicine and Bioinformatics Department of Biological Chemistry, The University of Michigan, Ann Arbor, MI
| | - Duo Zhang
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Boston University Medical Campus, Boston, MA
| | - Leo E Otterbein
- Department of Surgery, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA
| | - Yang Jin
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Boston University Medical Campus, Boston, MA
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Lin X, Xiaoqin H, Jiayu C, Li F, Yue L, Ximing X. Long non-coding RNA miR143HG predicts good prognosis and inhibits tumor multiplication and metastasis by suppressing mitogen-activated protein kinase and Wnt signaling pathways in hepatocellular carcinoma. Hepatol Res 2019; 49:902-918. [PMID: 30945380 DOI: 10.1111/hepr.13344] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 02/26/2019] [Accepted: 03/25/2019] [Indexed: 02/06/2023]
Abstract
AIM The expression of microRNA143HG (miR143HG) was significantly downregulated in hepatocellular carcinoma (HCC) tissues by bioinformatics analysis. This study aimed to determine the role of miR143HG in HCC cell proliferation and metastasis. METHODS Fifty patients with HCC were divided into two groups based on median miR143HG expression levels. The correlation between miR143HG expression and prognosis, and the correlations between miR143HG expression and the patients' clinicopathological characteristics were evaluated based on the two groups. Gain-of-function and loss-of-function measurements of miR143HG were carried out to verify the biological function of miR143HG by Cell Counting Kit-8, EdU, Transwell, and western blotting assays and flow cytometric analysis. The underlying mechanism was explored by quantitative real-time polymerase chain reaction of miRNA (miR-155-5p and miR-26b-5p), luciferase reporter assay, western blotting of Wnt signaling pathway-related proteins (β-catenin, adenomatous polyposis coli (APC), glycogen synthase kinase 3β (GSK3β), ZEB1, and E-cadherin), mitogen-activated protein kinase (MAPK) signaling pathway-related proteins (extracellular signal-regulated kinase [ERK]1/2, p-ERK1/2, c-Jun N-terminal kinase (JNK), p-JNK, P38, and p-P38), and immunofluorescence staining of β-catenin. RESULTS miR143HG expression was markedly downregulated in HCC tissues and cells. Its expression was associated with the presence or absence of portal vein tumor thrombus, hepatitis B virus infection, relapse and metastasis, and Barcelona Clinic Liver Cancer stage. Additionally, miR143HG expression predicted a good prognosis and acted as an independent prognostic factor in HCC for overall survival. Overexpression of miR143HG suppressed HCC cell proliferation and metastasis, and induced cell cycle arrest and apoptosis. Consistently, the depletion of miR143HG resulted in the opposite phenomenon of the aforementioned results. miR143HG inhibits miR-155 expression; miR-155 directly targets APC, which is a negative regulator of the Wnt/β-catenin pathway, so miR143HG can act on the Wnt pathway. miR143HG was further found to reduce the expression of β-catenin and block the nuclear accumulation of β-catenin, ultimately inhibiting the activation of the Wnt pathway. It inhibits the expression of Wnt downstream target gene ZEB1, and then E-cadherin expression is increased and cell motility is inhibited. Furthermore, miR143HG exerts its antiproliferative function by influencing the MAPK signaling pathway and then inducing G2 /M arrest in cells. CONCLUSION This study showed that miR143HG plays critical roles in the development and progression of HCC by suppressing the MAPK and Wnt signaling pathways.
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Affiliation(s)
- Xiong Lin
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - He Xiaoqin
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Chen Jiayu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Fan Li
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Li Yue
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xu Ximing
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
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Yu X, Hu Y, Wu Y, Fang C, Lai J, Chen S, Li Y, Zeng C, Zeng Y. The c‐Myc‐regulated miR‐17‐92 cluster mediates ATRA‐induced APL cell differentiation. Asia Pac J Clin Oncol 2019; 15:364-370. [DOI: 10.1111/ajco.13225] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 06/11/2019] [Indexed: 01/04/2023]
Affiliation(s)
- Xibao Yu
- Department of Experimental ResearchSun Yat‐sen University Cancer CenterState Key Laboratory Oncology in South China Guangzhou China
- Key Laboratory for Regenerative Medicine of Ministry of EducationInstitute of HematologyJinan University Guangzhou China
| | - Yanyun Hu
- Key Laboratory for Regenerative Medicine of Ministry of EducationInstitute of HematologyJinan University Guangzhou China
| | - Yifan Wu
- Key Laboratory for Regenerative Medicine of Ministry of EducationInstitute of HematologyJinan University Guangzhou China
| | - Chunsheng Fang
- Key Laboratory for Regenerative Medicine of Ministry of EducationInstitute of HematologyJinan University Guangzhou China
| | - Jing Lai
- Department of HematologyFirst Affiliated HospitalJinan University Guangzhou China
| | - Shaohua Chen
- Key Laboratory for Regenerative Medicine of Ministry of EducationInstitute of HematologyJinan University Guangzhou China
| | - Yangqiu Li
- Key Laboratory for Regenerative Medicine of Ministry of EducationInstitute of HematologyJinan University Guangzhou China
- Department of HematologyFirst Affiliated HospitalJinan University Guangzhou China
| | - Chengwu Zeng
- Key Laboratory for Regenerative Medicine of Ministry of EducationInstitute of HematologyJinan University Guangzhou China
| | - Yixin Zeng
- Department of Experimental ResearchSun Yat‐sen University Cancer CenterState Key Laboratory Oncology in South China Guangzhou China
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Papasavvas E, Azzoni L, Kossenkov AV, Dawany N, Morales KH, Fair M, Ross BN, Lynn K, Mackiewicz A, Mounzer K, Tebas P, Jacobson JM, Kostman JR, Showe L, Montaner LJ. NK Response Correlates with HIV Decrease in Pegylated IFN-α2a-Treated Antiretroviral Therapy-Suppressed Subjects. THE JOURNAL OF IMMUNOLOGY 2019; 203:705-717. [PMID: 31253727 DOI: 10.4049/jimmunol.1801511] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 06/03/2019] [Indexed: 01/27/2023]
Abstract
We previously reported that pegylated IFN-α2a (Peg-IFN-α2a) added to antiretroviral therapy (ART)-suppressed, HIV-infected subjects resulted in plasma HIV control and integrated HIV DNA decrease. We now evaluated whether innate NK cell activity or PBMC transcriptional profiles were associated with decreases in HIV measures. Human peripheral blood was analyzed prior to Peg-IFN-α2a administration (ART, baseline), after 5 wk of ART+Peg-IFN-α2a, and after 12 wk of Peg-IFN-α2a monotherapy (primary endpoint). After 5 wk of ART+Peg-IFN-α2a, immune subset frequencies were preserved, and induction of IFN-stimulated genes was noted in all subjects except for a subset in which the lack of IFN-stimulated gene induction was associated with increased expression of microRNAs. Viral control during Peg-IFN-α2a monotherapy was associated with 1) higher levels of NK cell activity and IFN-γ-induced protein 10 (IP-10) on ART (preimmunotherapy) and 2) downmodulation of NK cell KIR2DL1 and KIR2DL2/DL3 expression, transcriptional enrichment of expression of genes associated with NK cells in HIV controller subjects, and higher ex vivo IFN-α-induced NK cytotoxicity after 5 wk of ART+Peg-IFN-α2a. Integrated HIV DNA decline after immunotherapy was also associated with gene expression patterns indicative of cell-mediated activation and NK cytotoxicity. Overall, an increase in innate activity and NK cell cytotoxicity were identified as correlates of Peg-IFN-α2a-mediated HIV control.
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Affiliation(s)
| | | | | | - Noor Dawany
- The Children's Hospital of Philadelphia, Philadelphia, PA 19104
| | - Knashawn H Morales
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
| | | | | | - Kenneth Lynn
- Presbyterian Hospital-University of Pennsylvania Hospital, Philadelphia, PA 19104
| | | | - Karam Mounzer
- Jonathan Lax Immune Disorders Treatment Center, Philadelphia Field Initiating Group for HIV-1 Trials, Philadelphia, PA 19107
| | - Pablo Tebas
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
| | - Jeffrey M Jacobson
- Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140; and
| | - Jay R Kostman
- John Bell Health Center, Philadelphia Field Initiating Group for HIV-1 Trials, Philadelphia, PA 19107
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Ge MX, Shao RG, He HW. Advances in understanding the regulatory mechanism of cholesterol 7α-hydroxylase. Biochem Pharmacol 2019; 164:152-164. [DOI: 10.1016/j.bcp.2019.04.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 04/08/2019] [Indexed: 02/07/2023]
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Peng H, Li H. The encouraging role of long noncoding RNA small nuclear RNA host gene 16 in epithelial‐mesenchymal transition of bladder cancer via directly acting on miR‐17‐5p/metalloproteinases 3 axis. Mol Carcinog 2019; 58:1465-1480. [DOI: 10.1002/mc.23028] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 03/08/2019] [Accepted: 04/10/2019] [Indexed: 01/01/2023]
Affiliation(s)
- Hao Peng
- Department of Urologic SurgeryZhoukou Central HospitalZhoukou Henan China
| | - Hao Li
- Department of Urologic SurgeryZhoukou Central HospitalZhoukou Henan China
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40
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Dietrich P, Hellerbrand C, Bosserhoff A. The Delta Subunit of Rod-Specific Photoreceptor cGMP Phosphodiesterase (PDE6D) Contributes to Hepatocellular Carcinoma Progression. Cancers (Basel) 2019; 11:cancers11030398. [PMID: 30901922 PMCID: PMC6468542 DOI: 10.3390/cancers11030398] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 02/28/2019] [Accepted: 03/11/2019] [Indexed: 12/25/2022] Open
Abstract
Emerging evidence reveals crucial roles of wild type RAS in liver cancer. The delta subunit of rod-specific photoreceptor cGMP phosphodiesterase (PDE6D) regulates the trafficking of RAS proteins to the plasma membrane and thereby contributes to RAS activation. However, the expression and specific function of PDE6D in hepatocellular carcinoma (HCC) were completely unknown. In this study, PDE6D was newly found to be markedly upregulated in HCC tissues and cell lines. Overexpression of PDE6D in HCC correlated with enhanced tumor stages, tumor grading, and ERK activation. PDE6D depletion significantly reduced proliferation, clonogenicity, and migration of HCC cells. Moreover, PDE6D was induced by TGF-β1, the mediator of stemness, epithelial-mesenchymal transition (EMT), and chemoresistance. In non-resistant cells, overexpression of PDE6D conferred resistance to sorafenib-induced toxicity. Further, PDE6D was overexpressed in sorafenib resistance, and inhibition of PDE6D reduced proliferation and migration in sorafenib-resistant HCC cells. Together, PDE6D was found to be overexpressed in liver cancer and correlated with tumor stages, grading, and ERK activation. Moreover, PDE6D contributed to migration, proliferation, and sorafenib resistance in HCC cells, therefore representing a potential novel therapeutic target.
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Affiliation(s)
- Peter Dietrich
- Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander-University, Erlangen-Nürnberg, 91054 Erlangen, Germany.
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-University, Erlangen-Nürnberg, 91054 Erlangen, Germany.
| | - Claus Hellerbrand
- Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander-University, Erlangen-Nürnberg, 91054 Erlangen, Germany.
- Comprehensive Cancer Center (CCC) Erlangen-EMN, 91054 Erlangen, Germany.
| | - Anja Bosserhoff
- Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander-University, Erlangen-Nürnberg, 91054 Erlangen, Germany.
- Comprehensive Cancer Center (CCC) Erlangen-EMN, 91054 Erlangen, Germany.
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Zhang H, Zhang Y, Zhu X, Chen C, Zhang C, Xia Y, Zhao Y, Andrisani O, Kong L. DEAD Box Protein 5 Inhibits Liver Tumorigenesis by Stimulating Autophagy via Interaction with p62/SQSTM1. Hepatology 2019; 69:1046-1063. [PMID: 30281815 PMCID: PMC6411283 DOI: 10.1002/hep.30300] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 09/13/2018] [Indexed: 12/11/2022]
Abstract
In hepatocellular carcinoma (HCC), dysregulated expression of DDX5 (DEAD box protein 5) and impaired autophagy have been reported separately. However, the relationship between them has not been explored. Here we present evidence to show that, by interacting with autophagic receptor p62, DDX5 promotes autophagy and suppresses tumorigenesis. DDX5 inversely correlated with p62/sequestosome 1 (SQSTM1) expression in hepatitis B virus (HBV)-associated and non-HBV-associated HCCs. Patients with low DDX5 expression showed poor prognosis after tumor resection. We found that DDX5 overexpression induced, while DDX5 knockdown attenuated, autophagic flux in HepG2 and Huh7 cells. DDX5 promoted p62 degradation and markedly reduced the half-life of p62. Moreover, DDX5 overexpression dramatically reduced, while DDX5 knockdown promoted, cancer cell growth and tumorigenesis in vitro and in vivo. We found that DDX5 bound to p62 and interfered with p62/TRAF6 (tumor necrosis factor receptor-associated factor 6) interaction. Further findings revealed that the N-terminal domain of DDX5, involved in the interaction with p62, was sufficient to induce autophagy independent of its RNA binding and helicase activity. DDX5 overexpression decreased p62/TRAF6-mediated lysine 63-linked ubiquitination of mammalian target of rapamycin (mTOR) and subsequently inhibited the mTOR signaling pathway. Knockdown of TRAF6 blocked DDX5-induced autophagy. Furthermore, we showed that miR-17-5p downregulated DDX5 and impaired autophagy. Inhibition of miR-17-5p promoted autophagic flux and suppressed tumor growth in HCC xenograft models. Conclusion: Our findings define a noncanonical pathway that links miR-17-5p, DDX5, p62/TRAF6, autophagy, and HCC. These findings open an avenue for the treatment of HCC.
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Affiliation(s)
- Hao Zhang
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yanqiu Zhang
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xiaoyun Zhu
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Chen Chen
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Chao Zhang
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yuanzheng Xia
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yucheng Zhao
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Ourania Andrisani
- Department of Basic Medical Sciences and Purdue Center for Cancer Research, Purdue University, West Lafayette, IN
| | - Lingyi Kong
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
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Sadri Nahand J, Bokharaei-Salim F, Salmaninejad A, Nesaei A, Mohajeri F, Moshtzan A, Tabibzadeh A, Karimzadeh M, Moghoofei M, Marjani A, Yaghoubi S, Keyvani H. microRNAs: Key players in virus-associated hepatocellular carcinoma. J Cell Physiol 2018; 234:12188-12225. [PMID: 30536673 DOI: 10.1002/jcp.27956] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Accepted: 11/19/2018] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is known as one of the major health problems worldwide. Pathological analysis indicated that a variety of risk factors including genetical (i.e., alteration of tumor suppressors and oncogenes) and environmental factors (i.e., viruses) are involved in beginning and development of HCC. The understanding of these risk factors could guide scientists and clinicians to design effective therapeutic options in HCC treatment. Various viruses such as hepatitis B virus (HBV) and hepatitis C virus (HCV) via targeting several cellular and molecular pathways involved in HCC pathogenesis. Among various cellular and molecular targets, microRNAs (miRNAs) have appeared as key players in HCC progression. miRNAs are short noncoding RNAs which could play important roles as oncogenes or tumor suppressors in several malignancies such as HCC. Deregulation of many miRNAs (i.e., miR-222, miR-25, miR-92a, miR-1, let-7f, and miR-21) could be associated with different stages of HCC. Besides miRNAs, exosomes are other particles which are involved in HCC pathogenesis via targeting different cargos, such as DNAs, RNAs, miRNAs, and proteins. In this review, we summarize the current knowledge of the role of miRNAs and exosomes as important players in HCC pathogenesis. Moreover, we highlighted HCV- and HBV-related miRNAs which led to HCC progression.
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Affiliation(s)
- Javid Sadri Nahand
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | | | - Arash Salmaninejad
- Drug Applied Research Center, Student Research Committee, Tabriz University of Medical Science, Tabriz, Iran.,Department of Medical Genetics, Medical Genetics Research Center, Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abolfazl Nesaei
- Department of Basic Sciences, Faculty of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Fatemeh Mohajeri
- Department of Infectious Disease, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Azadeh Moshtzan
- Department of Infectious Disease, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Alireza Tabibzadeh
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | | | - Mohsen Moghoofei
- Department of Microbiology, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Arezo Marjani
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | - Shoeleh Yaghoubi
- Department of Infectious Disease, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Hossein Keyvani
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
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The Impact of miRNA in Colorectal Cancer Progression and Its Liver Metastases. Int J Mol Sci 2018; 19:ijms19123711. [PMID: 30469518 PMCID: PMC6321452 DOI: 10.3390/ijms19123711] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Revised: 11/19/2018] [Accepted: 11/20/2018] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies with a high incidence and mortality rate. An essential challenge in colorectal cancer management is to identify new prognostic factors that could better estimate the evolution and treatment responses of this disease. Considering their role in cancer development, progression and metastasis, miRNAs have become an important class of molecules suitable for cancer biomarkers discovery. We performed a systematic search of studies investigating the role of miRNAs in colorectal progression and liver metastasis published until October 2018. In this review, we present up-to-date information regarding the specific microRNAs involved in CRC development, considering their roles in alteration of Wnt/βcatenin, EGFR, TGFβ and TP53 signaling pathways. We also emphasize the role of miRNAs in controlling the epithelial⁻mesenchymal transition of CRC cells, a process responsible for liver metastasis in a circulating tumor cell-dependent manner. Furthermore, we discuss the role of miRNAs transported by CRC-derived exosomes in mediating liver metastases, by preparing the secondary pre-metastatic niche and in inducing liver carcinogenesis in a Dicer-dependent manner.
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Zhao X, Xu Y, Sun X, Ma Y, Zhang Y, Wang Y, Guan H, Jia Z, Li Y, Wang Y. miR-17-5p promotes proliferation and epithelial-mesenchymal transition in human osteosarcoma cells by targeting SRC kinase signaling inhibitor 1. J Cell Biochem 2018; 120:5495-5504. [PMID: 30302813 DOI: 10.1002/jcb.27832] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Accepted: 09/14/2018] [Indexed: 12/19/2022]
Abstract
MicroRNA-17-5p (miR-17-5p) and epithelial-mesenchymal transition (EMT) have been reported to participate in the development and progression of multiple cancers. However, the relationship between the miR-17-5p and EMT in osteosarcoma (OS) is still poorly understood. This study was to investigate the effects of the miR-17-5p and its potential mechanism in regulating proliferation, apoptosis, and EMT of human OS. Quantitative real-time PCR was used to detect the miR-17-5p and SRC kinase signaling inhibitor 1 (SRCIN1) messenger RNA expression in OS specimens and cell lines. After transfection with miR-17-5p inhibitors, proliferation, apoptosis, migration, and invasion of OS cells were assessed by using the Cell Counting Kit-8, the annexin V-FITC apoptosis, wound-healing, and transwell assays. The SRCIN1 was validated as a target of the miR-17-5p through bioinformatics algorithms and luciferase reporter assay. Moreover, the expression of EMT markers, E-cadherin, N-cadherin, and Snail was identified by the Western blot analysis. MiR-17-5p was significantly upregulated in OS tumor samples and cell lines. It inhibited proliferation and EMT, and promoted apoptosis in OS. The SRCIN1 was identified as a direct target of the miR-17-5p. Silenced miR-17-5p could change the expression of EMT markers, such as upregulating the expression of E-cadherin, and downregulating the expression of N-cadherin and Snail through targeting the antioncogenic SRCIN1. These findings suggest that the miR-17-5p promotes cell proliferation, and EMT in human OS by directly targeting the SRCIN1, and reveal a branch of the miR-17-5p/SRCIN1/EMT signaling pathway involved in the progression of OS.
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Affiliation(s)
- Xuefeng Zhao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Yan Xu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Xiaoya Sun
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Yuan Ma
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yan Zhang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yadong Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Hongya Guan
- Translational Medical Center, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Zhen Jia
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Yuebai Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Yisheng Wang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Wang Z, Zhang J, Zhang Z, Jiang Y, Li M, Li Q, Bai L, Yao D, Wang M, Wang X. Prognostic value of miR-17-5 p in gastrointestinal cancers: a systematic review and meta-analysis. Onco Targets Ther 2018; 11:5991-5999. [PMID: 30275704 PMCID: PMC6157989 DOI: 10.2147/ott.s157670] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND There are accumulating studies investigating the aberrant expression of microRNAs in tumor patients. As an important member of miR-17/92 cluster, miR-17-5 p has been identified as a potential prognostic factor for survival in tumor patients. We conducted this meta-analysis aimed to assess the effect of miR-17-5 p as a prognostic biomarker for gastrointestinal tumor patients. MATERIALS AND METHODS Eligible studies were enrolled by searching the online databases of PubMed, Embase, Web of Science, China National Knowledge Infrastructure, and WanFang Data until September 2017. We calculated pooled hazard ratios (HRs) and 95% CI of miR-17-5 p for overall survival and disease-free survival. RESULTS In the categorical variable analysis, we identified 11 studies with 1,279 patients. The pooled analyses suggested that overexpression of miR-17-5 p may predict poor overall survival (HR = 1.86, 95% CI: 1.55-2.25, P<0.001) and disease-free survival (HR = 1.43, 95% CI: 1.01-2.03, P=0.046) in patients with gastrointestinal tumors. Subgroup analysis showed the pooled HR of overall survival was more significant in tissue specimen, Asian patients, and digestive tract tumors. But there was no correlation between the outcomes and European patients. CONCLUSIONS This meta-analysis suggested that miR-17-5 p has predictive effects on overall survival and disease-free survival of patients with gastrointestinal tumors.
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Affiliation(s)
- Zeyu Wang
- Department of Gastroenterology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, 201318, China,
| | - Jing Zhang
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin, 300211, China
| | - Zhiguang Zhang
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin, 300211, China
| | - Yong Jiang
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin, 300211, China
| | - Man Li
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin, 300211, China
| | - Qian Li
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin, 300211, China
| | - Lu Bai
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin, 300211, China
| | - Dongying Yao
- Department of Gastroenterology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, 201318, China,
| | - Miao Wang
- Department of Gastroenterology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, 201318, China,
| | - Xiaoping Wang
- Department of Gastroenterology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, 201318, China,
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Kong W, Cheng Y, Liang H, Chen Q, Xiao C, Li K, Huang Z, Zhang J. Prognostic value of miR-17-5p in cancers: a meta-analysis. Onco Targets Ther 2018; 11:3541-3549. [PMID: 29950859 PMCID: PMC6016279 DOI: 10.2147/ott.s150340] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background Studies have shown that miR-17-5p plays an important role in the development of cancer. The aim of this meta-analysis was to quantitatively analyze the association of miR-17-5p with prognosis in various cancers. Materials and methods We searched the PubMed, EMBASE, Web of Science, and Cochrane library databases for relevant studies through August 2017. The prognostic data and clinico-pathological features of overall survival (OS) and disease-free survival (DFS) were extracted to investigate the association between miR-17-5p expression and tumor prognosis. In addition, odds ratios (ORs) were used to assess the correlations between miR-17-5p expression and clinicopathological characteristics. Results A total of ten studies were incorporated into this systematic review, and we found that high miR-17-5p expression can predict poor OS for malignancies (combined hazard ratio [HR]=1.87; 95% confidence interval [CI], 1.37–2.55; P=0.000) as well as poor DFS (combined HR=1.60; 95% CI, 1.05–2.44; P=0.027). Further subgroup analyses suggested that high miR-17-5p expression was related to poor OS in Asian patients (combined HR=1.92; 95% CI, 1.37–2.71; P=0.000) and the serum/plasma sample source subgroup (combined HR=2.13; 95% CI, 1.36–3.31; P=0.001). The combined OR indicated that the expression of miR-17-5p was associated with lymph node invasion (OR=1.28; 95% CI, 1.05–1.56; P=0.016) and venous invasion (OR=1.92; 95% CI, 1.40–2.63; P=0.000). Conclusion Elevated expression of miR-17-5p suggested a poor prognosis in cancer patients and may serve as a new tumor marker to monitor cancer development and progression.
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Affiliation(s)
- Weihao Kong
- Department of Liver Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yusheng Cheng
- Department of Liver Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hao Liang
- Department of Liver Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Qiangxing Chen
- Department of Liver Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Cuicui Xiao
- Department of Liver Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Kun Li
- Department of Liver Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zenan Huang
- Department of Liver Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jian Zhang
- Department of Liver Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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Huang C, Yu M, Yao X. MicroRNA-17 and the prognosis of human carcinomas: a systematic review and meta-analysis. BMJ Open 2018; 8:e018070. [PMID: 29858404 PMCID: PMC5988052 DOI: 10.1136/bmjopen-2017-018070] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Revised: 05/01/2018] [Accepted: 05/14/2018] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE Although the role of microRNA-17 (miR-17) has been identified as a tumour biomarker in various studies, its prognostic value in cancers remains unclear. Therefore, we performed a systematic review and meta-analysis to analyse and summarise the relationship between the miR-17 status and clinical outcome in a variety of human cancers. DESIGN Systematic review and meta-analysis. DATA SOURCES PubMed, Web of Science and Embase from the first year of records to 15 May 2017. OUTCOMES The patients' survival results were pooled, and pooled HRs with 95% CIs were calculated and used for measuring the strength of association between miR-17 and the prognosis of cancers, including hepatocellular carcinoma, lung cancer, osteosarcoma, glioma, T-cell lymphoblastic lymphoma and colon cancer. Heterogeneity, publication bias and subgroup analysis were also conducted. RESULTS A total of 1096 patients were included in this meta-analysis from 12 articles. The results indicated that the increased expression of miR-17 played an unfavourable role in overall survival in various human carcinomas with the HR of 1.342 taking into account the publication bias. In subgroup analysis, HR of ethnicity (non-Asian HR=1.48 and Asian HR=1.40), disease (digestive system HR=1.36 and blood system cancer (HR=2.38) were significant with P<0.05. For the analysis of disease-free survival and recurrence-free survival, the increased expression of miR-17 was associated with unfavourable prognosis (HR=1.40). CONCLUSIONS miR-17 may be a useful biomarker in predicting the clinical outcome of human cancers, but due to the limitations of the current studies, further verification of the role of miR-17 in human malignancies is urgently needed. PROSPERO REGISTRATION NUMBER CRD42017065749.
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Affiliation(s)
- Chengzhi Huang
- Department of General Surgery, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
- Medical College, Shantou University, Shantou, Guangdong, China
| | - Mengya Yu
- Department of General Surgery, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Xueqing Yao
- Department of General Surgery, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
- Medical College, Shantou University, Shantou, Guangdong, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
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Cheng H, Xue J, Yang S, Chen Y, Wang Y, Zhu Y, Wang X, Kuang D, Ruan Q, Duan Y, Wang G. Co-targeting of IGF1R/mTOR pathway by miR-497 and miR-99a impairs hepatocellular carcinoma development. Oncotarget 2018. [PMID: 28624790 PMCID: PMC5564620 DOI: 10.18632/oncotarget.18207] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Persistent activation of IGF1R/mTOR signaling pathway plays crucial role in the development of hepatocellular carcinoma (HCC). Therefore, our goal was to elucidate microRNAs (miRNAs) targeting IGF1R/mTOR and the therapeutic potential of single or dual miRNA on HCC development. In this study, we found that miR-497 and miR-99a that target the 3′-UTR of both IGF1R and mTOR were down-regulated in HCC human tissues and cell lines. Functional assay revealed that ectopic expression of miR-497 or miR-99a in HCC cells resulted in a significant inhibition on tumor growth and invasiveness in vitro and tumor development in vivo via repressing the expression of IGF1R and mTOR. Such inhibitory effect on tumor growth is reversed by application of IGF1 ((IGF1R ligand) or MHY1485 (mTOR agonist) in vitro. Furthermore, we found that simultaneous over-expression of both miR-497 and miR-99a exhibited much stronger inhibitory effects on tumor growth than their individual effect, which is still correlated with significantly stronger repression of IGF1R and mTOR. Overall, our results suggest that miR-497 and miR-99a both function as tumor-suppressive miRNAs by suppressing IGF1R/mTOR signaling pathway. The synergistic actions of these two miRNAs partly correlated with IGF1R and mTOR levels, which may represent new strategies for the molecular treatment of HCC.
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Affiliation(s)
- Henghui Cheng
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China.,Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China
| | - Jin Xue
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China.,Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China
| | - Shouhua Yang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China
| | - Yaobin Chen
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China.,Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China
| | - Yu Wang
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China.,Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China
| | - Yuanli Zhu
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China.,Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China
| | - Xiaoyan Wang
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China.,Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China
| | - Dong Kuang
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China.,Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China
| | - Qiurong Ruan
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China.,Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China
| | - Yaqi Duan
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China.,Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China
| | - Guoping Wang
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China.,Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China
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Gong R, Lv X, Liu F. MiRNA-17 encoded by the miR-17-92 cluster increases the potential for steatosis in hepatoma cells by targeting CYP7A1. Cell Mol Biol Lett 2018; 23:16. [PMID: 29721023 PMCID: PMC5907481 DOI: 10.1186/s11658-018-0083-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Accepted: 04/13/2018] [Indexed: 12/12/2022] Open
Abstract
Background The miRNA cluster miR-17-92 is known to act as an oncogene in various cancers. Members of this cluster were also found to be involved in some other pathological process, such as steatosis, which is a pivotal event in the initiation and progression of nonalcoholic fatty liver disease (NAFLD). This study aimed to explore whether miR-17, one of the most functional miRNAs in the miR-17-92 family, participates in the process of steatosis in hepatoma cells. Methods We developed both a miR-17-expressing transgenic mouse model and a miR-17-expressing HepG2 cell model, the latter was established via stable transfection. Real-time PCR and western blot were applied to measure the expression levels of miR-17 and the potential target gene CYP7A1. The luciferase assay was used to confirm direct binding of miR-17 and CYP7A1. The oleic acid induction assay and Oil-Red-O staining were performed to support the determination of steatotic changes in HepG2 cell. Results Extensive steatotic changes were observed in the livers of transgenic mice. Fewer were seen in the wild-type animals. CYP7A1 was confirmed as a target gene of miR-17, and the expression of CYP7A1 was found to be negatively regulated in both the transgenic mice liver cells and the miR-17-expressing HepG2 cells. CYP7A1 was found to participate in miR-17-induced steatosis, as its repressed expression in miR-17 HepG2 cells exacerbated steatotic change. Re-introduction of CYP7A1 into miR-17 HepG2 cell partially alleviated steatosis. Conclusions miR-17 is a novel regulator of CYP7A1 signaling in hepatic lipid metabolism, suggesting a potential therapeutic approach for fatty liver. Electronic supplementary material The online version of this article (10.1186/s11658-018-0083-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ruijie Gong
- 1Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou, Fujian 350008 People's Republic of China
| | - Xiaofei Lv
- 3Department of Internal Medicine, Guangdong Women and Children's Hospital, Guangzhou Medical University, 521 Xingnan Road, Guangzhou, China
| | - Fengqiong Liu
- 1Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou, Fujian 350008 People's Republic of China.,2Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fujian, China
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50
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Yin R, Guo L, Gu J, Li C, Zhang W. Over expressing miR-19b-1 suppress breast cancer growth by inhibiting tumor microenvironment induced angiogenesis. Int J Biochem Cell Biol 2018; 97:43-51. [DOI: 10.1016/j.biocel.2018.02.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Revised: 02/01/2018] [Accepted: 02/05/2018] [Indexed: 12/26/2022]
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