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Liu G, Gao Y, Cheng Y, Wang W, Li X, Wu Y, Gao F, Zhou ZW, Sun Y, Jiang Y, Yang N, Shu Y, Sun L. Host genetic variation governs PCV2 susceptibility through CXCL13 and ELK1-mediated immune regulation. Int J Biol Macromol 2025; 310:143170. [PMID: 40267997 DOI: 10.1016/j.ijbiomac.2025.143170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Revised: 03/25/2025] [Accepted: 04/13/2025] [Indexed: 04/25/2025]
Abstract
Pathogenic viruses can drive evolutionary adaptations in host biology, leading to diversified immune responses and variable susceptibility among individuals. This study examined how genetic variation in host regulatory regions impacts susceptibility to viral infections. Utilizing a porcine model, we identified the single nucleotide polymorphism (SNP) g.-1014G>A as a critical determinant of CXCL13 expression levels following PCV2 viral exposure. Structural analyses showed that the transcription factor ELK1 specifically recognized and bound to the g.-1014G allele, but not to the g.-1014A allele, through essential residues such as Arg65. This allele-specific binding led to differential CXCL13 expression, with the G allele associated with increased resistance to viral infection. Functional studies demonstrated that CXCL13 played a multifaceted role in antiviral immunity, including the inhibition of viral replication, modulation of immune-related pathways, and attenuation of virus-induced apoptosis. The CXCL13-mediated response involved the activation of the PI3K/Akt pathway, enhancing cell survival during viral challenges. This SNP-dependent regulation of a host factor represented a novel mechanism underlying genetic differences in viral susceptibility, with potential implications for developing broadly applicable antiviral strategies.
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Affiliation(s)
- Gen Liu
- Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; Department of Pathogen Microbiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Yizhen Gao
- Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China
| | - Yijun Cheng
- Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China
| | - Wenlei Wang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian 271018, China
| | - Xiang Li
- Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China
| | - Yan Wu
- Department of Pathogen Microbiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Feng Gao
- Laboratory of Protein Engineering and Vaccines, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences (CAS), Tianjin 300308, China
| | - Zhong-Wei Zhou
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China
| | - Yi Sun
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian 271018, China
| | - Yunliang Jiang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian 271018, China.
| | - Na Yang
- Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
| | - Yuelong Shu
- Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100176, China.
| | - Litao Sun
- Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety, School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China.
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Zhou H, Hao X, Zhang P, He S. Noncoding RNA mutations in cancer. WILEY INTERDISCIPLINARY REVIEWS. RNA 2023; 14:e1812. [PMID: 37544928 DOI: 10.1002/wrna.1812] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 07/14/2023] [Accepted: 07/17/2023] [Indexed: 08/08/2023]
Abstract
Cancer is driven by both germline and somatic genetic changes. Efforts have been devoted to characterizing essential genetic variations in cancer initiation and development. Most attention has been given to mutations in protein-coding genes and associated regulatory elements such as promoters and enhancers. The development of sequencing technologies and in silico and experimental methods has allowed further exploration of cancer predisposition variants and important somatic mutations in noncoding RNAs, mainly for long noncoding RNAs and microRNAs. Association studies including GWAS have revealed hereditary variations including SNPs and indels in lncRNA or miRNA genes and regulatory regions. These mutations altered RNA secondary structures, expression levels, and target recognition and then conferred cancer predisposition to carriers. Whole-exome/genome sequencing comparing cancer and normal tissues has revealed important somatic mutations in noncoding RNA genes. Mutation hotspots and somatic copy number alterations have been identified in various tumor-associated noncoding RNAs. Increasing focus and effort have been devoted to studying the noncoding region of the genome. The complex genetic network of cancer initiation is being unveiled. This article is categorized under: RNA in Disease and Development > RNA in Disease.
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Affiliation(s)
- Honghong Zhou
- Key Laboratory of RNA Biology, Center for Big Data Research in Health, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Xinpei Hao
- Key Laboratory of RNA Biology, Center for Big Data Research in Health, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Peng Zhang
- Key Laboratory of RNA Biology, Center for Big Data Research in Health, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Shunmin He
- Key Laboratory of RNA Biology, Center for Big Data Research in Health, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
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Zhang MH, Yuan YF, Liu LJ, Wei YX, Yin WY, Zheng LZY, Tang YY, Lv Z, Zhu F. Dysregulated microRNAs as a biomarker for diagnosis and prognosis of hepatitis B virus-associated hepatocellular carcinoma. World J Gastroenterol 2023; 29:4706-4735. [PMID: 37664153 PMCID: PMC10473924 DOI: 10.3748/wjg.v29.i31.4706] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 06/29/2023] [Accepted: 08/01/2023] [Indexed: 08/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignancy with a high incidence and fatality rate worldwide. Hepatitis B virus (HBV) infection is one of the most important risk factors for its occurrence and development. Early detection of HBV-associated HCC (HBV-HCC) can improve clinical decision-making and patient outcomes. Biomarkers are extremely helpful, not only for early diagnosis, but also for the development of therapeutics. MicroRNAs (miRNAs), a subset of non-coding RNAs approximately 22 nucleotides in length, have increasingly attracted scientists' attention due to their potential utility as biomarkers for cancer detection and therapy. HBV profoundly impacts the expression of miRNAs potentially involved in the development of hepatocarcinogenesis. In this review, we summarize the current progress on the role of miRNAs in the diagnosis and treatment of HBV-HCC. From a molecular standpoint, we discuss the mechanism by which HBV regulates miRNAs and investigate the exact effect of miRNAs on the promotion of HCC. In the near future, miRNA-based diagnostic, prognostic, and therapeutic applications will make their way into the clinical routine.
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Affiliation(s)
- Ming-He Zhang
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Yu-Feng Yuan
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Li-Juan Liu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Yu-Xin Wei
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Wan-Yue Yin
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Lan-Zhuo-Yin Zheng
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Ying-Ying Tang
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Zhao Lv
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Fan Zhu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Hubei Province Key Laboratory of Allergy & Immunology, Wuhan University, Wuhan 430071, Hubei Province, China
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Chen S, Wang Y, Li D, Wang H, Zhao X, Yang J, Chen L, Guo M, Zhao J, Chen C, Zhou Y, Liang G, Xu L. Mechanisms Controlling MicroRNA Expression in Tumor. Cells 2022; 11:cells11182852. [PMID: 36139427 PMCID: PMC9496884 DOI: 10.3390/cells11182852] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 09/06/2022] [Accepted: 09/09/2022] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs) are widely present in many organisms and regulate the expression of genes in various biological processes such as cell differentiation, metabolism, and development. Numerous studies have shown that miRNAs are abnormally expressed in tumor tissues and are closely associated with tumorigenesis. MiRNA-based cancer gene therapy has consistently shown promising anti-tumor effects and is recognized as a new field in cancer treatment. So far, some clinical trials involving the treatment of malignancies have been carried out; however, studies of miRNA-based cancer gene therapy are still proceeding slowly. Therefore, furthering our understanding of the regulatory mechanisms of miRNA can bring substantial benefits to the development of miRNA-based gene therapy or other combination therapies and the clinical outcome of patients with cancer. Recent studies have revealed that the aberrant expression of miRNA in tumors is associated with promoter sequence mutation, epigenetic alteration, aberrant RNA modification, etc., showing the complexity of aberrant expression mechanisms of miRNA in tumors. In this paper, we systematically summarized the regulation mechanisms of miRNA expression in tumors, with the aim of providing assistance in the subsequent elucidation of the role of miRNA in tumorigenesis and the development of new strategies for tumor prevention and treatment.
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Affiliation(s)
- Shipeng Chen
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Ya Wang
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Dongmei Li
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Hui Wang
- The Second Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Xu Zhao
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Jing Yang
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Longqing Chen
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Mengmeng Guo
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Juanjuan Zhao
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Chao Chen
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
| | - Ya Zhou
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China
- Department of Medical Physics, Zunyi Medical University, Zunyi 563000, China
- Correspondence: (Y.Z.); (G.L.); (L.X.)
| | - Guiyou Liang
- Department of Cardiovascular Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang 550031, China
- Department of Cardiovascular Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
- Correspondence: (Y.Z.); (G.L.); (L.X.)
| | - Lin Xu
- Special Key Laboratory of Gene Detection and Therapy & Base for Talents in Biotherapy of Guizhou Province, Zunyi 563000, China
- Department of Immunology, Zunyi Medical University, Zunyi 563000, China
- Correspondence: (Y.Z.); (G.L.); (L.X.)
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Genetic variants in miR-145 gene are associated with the risk of asthma in Taiwan. Sci Rep 2022; 12:15155. [PMID: 36071121 PMCID: PMC9452491 DOI: 10.1038/s41598-022-18587-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 08/16/2022] [Indexed: 11/29/2022] Open
Abstract
Asthma is a chronic airway inflammation disease and the diagnosis and treatment strategies remain difficult. MicroRNAs play important roles in many biological and pathological processes including asthma development. There is no study confirming the contribution of genetic variants in miR-145 to asthma etiology. We hypothesize that single nucleotide polymorphisms (SNPs) in the promoter region of miR-145 may be associated with the risk of asthma in Taiwanese. We used a case–control study to test this hypothesis. In 198 asthma patients and 453 healthy controls, the genotypes of miR-145 rs4705342 and rs4705343 were determined, and the associations of miR-145 genotypes with asthma risk and severity were evaluated. The distribution of miR-145 rs4705342 genotypes between asthma patients and non-asthmatic control groups were significantly different (p = 0.0187). In multivariable logistic regression analysis, compared with the wild-type TT genotype, individuals carrying the variant genotypes had progressively decreased risks of asthma: the odds ratio (OR) for the heterogeneous variant genotype (CT) and homozygous variant genotype (CC) was 0.77 (95% CI 0.55–1.10, p = 0.1788) and 0.41 (95% CI 0.21–0.79, p = 0.0102), respectively (p for trend = 0.0187). In allelic test, the C allele was associated with a 31% reduced risk of asthma (OR = 0.69, 95% CI 0.53–0.90, p = 0.0070). In addition, the rs4705342 variant genotypes were correlated with the symptom severity (p = 3 × 10–5). Furthermore, the variant genotypes correlated with lower miR-145-5p expression level in serum (p = 0.0001). As for rs4705343, there was no differential distribution of genotypes between cases and controls. Our data provide evidence for miR-145 rs4705342 to serve as a novel biomarker for asthma risk prediction.
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Kong D, Duan Y, Wang J, Liu Y. A functional polymorphism of microRNA-143 is associated with the risk of type 2 diabetes mellitus in the northern Chinese Han population. Front Endocrinol (Lausanne) 2022; 13:994953. [PMID: 36213264 PMCID: PMC9538736 DOI: 10.3389/fendo.2022.994953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 09/05/2022] [Indexed: 11/24/2022] Open
Abstract
OBJECTIVE To explore the association between two polymorphisms of microRNA-143 (miR-143) and the risk of type 2 diabetes mellitus (T2DM) in the northern Chinese Han population. STUDY DESIGN This case-control study involved 326 patients with T2DM and 342 healthy controls. Two genetic variants (rs4705342 and rs353292) of miR-143 were genotyped by the polymerase chain reaction/ligase detection reaction (PCR-LDR) method. The levels of miR-143 in the serum from 52 T2DM patients and 55 healthy subjects were investigated by quantitative real-time PCR (qRT-PCR). RESULTS The CC genotype frequency of rs4705342 was significantly higher in the T2DM patients than in the healthy controls (P = 0.012). After adjusting for sex, age, and body mass index, the rs4705342 CC genotype was also related to a significantly increased risk of T2DM compared with the TT genotype (adjusted OR: 1.87; 95% CI = 1.09-3.19; P = 0.022). Stratified analyses demonstrated that T2DM patients with the rs4705342 CC genotype had significantly higher levels of low-density lipoprotein cholesterol (LDL-C), fasting blood glucose (FBG), and glycated haemoglobin (HbA1C) than those carrying the rs4705342 TT genotype. The qRT-PCR results showed that the expression levels of miR-143 were significantly higher in the serum of cases than in the serum of controls (P < 0.001). Furthermore, the levels of miR-143 were significantly higher in the serum of T2DM patients carrying the rs4705342 CC genotype than in those carrying the TC and TT genotypes of rs4705342 (P = 0.005 and 0.003, respectively). CONCLUSION The CC genotype of rs4705342 might be a risk factor for developing T2DM by increasing the expression of miRNA-143 in the northern Chinese Han population.
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Affiliation(s)
- Dexian Kong
- Department of Endocrinology, Fourth Affiliated Hospital, Hebei Medical University, Shijiazhuang, China
| | - Ya Duan
- Department of Obstetrics, Hebei General Hospital, Shijiazhuang, China
| | - Jinli Wang
- Department of Infirmary, Hebei Public Security Police Vocational College, Shijiazhuang, China
| | - Yabin Liu
- Department of General Surgery, Fourth Affiliated Hospital, Hebei Medical University, Shijiazhuang, China
- *Correspondence: Yabin Liu,
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Gong J, Jiang J, Qu J, Li J, Chen X, Ruan Z, Lu G, He Y, He X, Sun R. Association between the rs3733846 in the flanking region of miR-143/145 and risk of cervical squamous cell carcinoma. Biomark Med 2021; 15:891-897. [PMID: 34229450 DOI: 10.2217/bmm-2020-0865] [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: 12/10/2020] [Accepted: 04/15/2021] [Indexed: 11/21/2022] Open
Abstract
Aim: To investigate the effect of rs3733846 in the flanking region of miR-143/145 on susceptibility to cervical squamous cell carcinoma (CSCC). Materials & methods: We collected venous blood samples from 242 CSCC patients and 250 healthy controls. The rs3733846 polymorphism was genotyped by SnaPshot and Sanger sequencing. The expression of miR-143/145 in CSCC tissues was detected by quantitative real-time PCR. Results: The rs3733846 AG genotype was associated with a decreased risk of CSCC in genetic model (AGvs.AA: adjusted odds ratio [OR]: 0.44; 95% CI: 0.30-0.66; p < 0.001). Patients with the rs3733846 AG/GG genotypes had a reduced risk of developing poorly differential status (OR: 0.57; 95% CI: 0.33-0.98; p < 0.04) and lymph node metastasis (OR: 0.49; 95% CI: 0.26-0.92; p < 0.03). Conclusion: The rs3733846 in the flanking region of miR-143/145 was related to the susceptibility of CSCC.
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Affiliation(s)
- Jianyu Gong
- School of Basic Medicine, Yunnan University of Chinese Medicine, Yunnan, Kunming, China
| | - Jike Jiang
- School of Basic Medicine, Yunnan University of Chinese Medicine, Yunnan, Kunming, China
| | - Jianwen Qu
- School of Basic Medicine, Yunnan University of Chinese Medicine, Yunnan, Kunming, China
| | - Ju Li
- School of Basic Medicine, Yunnan University of Chinese Medicine, Yunnan, Kunming, China
| | - Xin Chen
- School of Basic Medicine, Yunnan University of Chinese Medicine, Yunnan, Kunming, China
| | - Zhiguo Ruan
- School of Basic Medicine, Yunnan University of Chinese Medicine, Yunnan, Kunming, China
| | - Gangxu Lu
- School of Basic Medicine, Yunnan University of Chinese Medicine, Yunnan, Kunming, China
| | - Yuxiao He
- School of Basic Medicine, Yunnan University of Chinese Medicine, Yunnan, Kunming, China
| | - Xiaoshan He
- School of Basic Medicine, Yunnan University of Chinese Medicine, Yunnan, Kunming, China
| | - Ruifen Sun
- School of Basic Medicine, Yunnan University of Chinese Medicine, Yunnan, Kunming, China
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Yang X, Guo Z, Cao F, Teng Z, Huang Z, Sun X. Rs41291957 polymorphism in the promoter region of microRNA‑143 serves as a prognostic biomarker for patients with intracranial hemorrhage. Mol Med Rep 2021; 23:295. [PMID: 33649782 PMCID: PMC7930929 DOI: 10.3892/mmr.2021.11928] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Accepted: 11/06/2020] [Indexed: 12/30/2022] Open
Abstract
The present study aimed to investigate the function of the single nucleotide polymorphism (SNP) rs41291957 in the prognosis of intracerebral hemorrhage (ICH). In addition, the molecular mechanisms underlying the role of microRNA (miR)‑143, Toll‑like receptor 2 (TLR2) and interleukin‑16 (IL‑16) were studied in patients with ICH that carried different alleles in the locus of the rs41291957 SNP. Kaplan‑Meier survival curves were calculated for 182 patients with ICH, genotyped as CC, presenting a cytosine in both chromosome, CT, presenting both variants, and TT, presents a thymine in both chromosomes. In addition, the possible regulatory relationships between miR‑143 and TLR2/IL‑16 were studied using computational analysis, luciferase assays and western blot assay. In addition, the inflammatory profiles of cerebrospinal fluid (CSF) and serum samples collected from the subjects were compared. The patients genotyped as TT presented the lowest survival rate, while patients genotyped as CC presented the highest survival rate. TLR2 mRNA was identified as a potential target of miR‑143, while IL‑16 showed no direct interaction with miR‑143. The above regulatory relationships were further investigated using cells transfected with miR‑143 precursor or TLR2 small interfering RNA. In addition, the expression levels of inflammatory factors, such as tumor necrosis factor α, interferon, IL‑6, IL‑10 and NF‑L‑6, were highest in the CSF/serum samples collected from patients genotyped as TT and lowest in patients genotyped as CC. By contrast, the expression levels of miR‑143 showed an opposite trend in the expression of the above inflammatory factors. The rs41291957 SNP, located in the promoter region of miR‑143, reduced the expression of miR‑143 and upregulated the expression of the pro‑inflammatory factor TLR2, eventually leading to a poorer prognosis in patients with ICH.
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Affiliation(s)
- Xiaobo Yang
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Zongduo Guo
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Fang Cao
- Department of Cerebrovascular Disease, The First Affiliated Hospital of Zunyi Medical College, Zunyi, Guizhou 563000, P.R. China
| | - Zhipeng Teng
- Chongqing Traditional Chinese Medicine Hospital, Chongqing 400000, P.R. China
| | - Zhijian Huang
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Xiaochuan Sun
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
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Wang Y, Zhou S, Zhao W, Li Z, Zhu J, Wei T, Song H. Association between functional polymorphisms in the flanking region of miR-143/145 and risk of papillary thyroid carcinoma: A case-control study. Medicine (Baltimore) 2020; 99:e23560. [PMID: 33285775 PMCID: PMC7717760 DOI: 10.1097/md.0000000000023560] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
MiR-143 and miR-145 were down-regulated in papillary thyroid carcinoma (PTC) involving in cell proliferation, apoptosis, migration, invasion, and epithelial to mesenchymal transition. In this study, we aimed to investigate the association between 2 functional polymorphisms (ie, rs4705342 and rs353292) in the flanking region of miR-143/145 and risk of PTC.A case-control study including 316 PTC patients and 347 controls was performed. The rs4705342 and rs353292 were genotyped by using the TaqMan allelic discrimination. The results were confirmed by DNA sequencing.For the rs4705342, a reduced risk of PTC was observed in heterozygous comparison, dominant genetic model and allele comparison (CC vs TT: adjusted OR = 0.37, 95% CI = 0.19-0.74, P = .003; CT/CC vs TT: adjusted OR = 0.64, 95% CI = 0.47-0.87, P = .005; C vs T: adjusted OR = 0.66, 95% CI = 0.52-0.85, P = .001, respectively). No significant difference was found in the genotypic distributions of the rs353292 between cases and controls.These findings indicate that the rs4705342 in the flanking region of miR-143/145 may be a protective factor against the occurrence of PTC. Further study is therefore required to investigate the correlation between the genotype and V-raf murine sarcoma viral oncogene homolog B1 V600E, rat sarcoma viral oncogene homolog mutations, rearranged in transformation/PTC1 and rearranged in transformation/PTC3.
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Affiliation(s)
- Yichao Wang
- Department of Thyroid and Parathyroid Surgery Center
| | - Shengliang Zhou
- West China School of Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Wanjun Zhao
- Department of Thyroid and Parathyroid Surgery Center
| | - Zhihui Li
- Department of Thyroid and Parathyroid Surgery Center
| | - Jingqiang Zhu
- Department of Thyroid and Parathyroid Surgery Center
| | - Tao Wei
- Department of Thyroid and Parathyroid Surgery Center
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Wang H, Wang B, Wang T, Fan R. A genetic variant in the promoter region of miR-877 is associated with an increased risk of hepatocellular carcinoma. Clin Res Hepatol Gastroenterol 2020; 44:692-698. [PMID: 32113822 DOI: 10.1016/j.clinre.2020.01.006] [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] [Received: 12/14/2019] [Revised: 01/17/2020] [Accepted: 01/29/2020] [Indexed: 02/04/2023]
Abstract
INTRODUCTION Genome wide association study has identified chromosome 6p21.33 as a risk locus of hepatocellular carcinoma (HCC). MiR-877 is located on this region, functioning as a tumor suppressor. The aim of this study was to investigate the association between rs1264440 in the promoter of miR-877 and HCC risk. MATERIALS AND METHODS A total of 352 HCC patients and 359 age, gender, ethnicity and living area matched controls were enrolled in this study. The rs1264440 was genotyped using the TaqMan allelic discrimination assay. MiR-877 expression in HCC tissues was examined using quantitative PCR. RESULTS After Adjustment for age, sex, smoking status, drinking status and HBsAg status, this study showed a significant association between the rs1264440 and HCC risk. Subjects with the rs1264440 TT genotype and T allele showed a 2.20- and 1.44-fold increased risk to develop HCC, respectively (TT vs. CC: 95% CI, 1.18-4.11, P=0.01;T vs. C: 95% CI, 1.07-1.94, P=0.02). The increased risk was also observed in smokers and nondrinkers subgroup. The rs1264440 TT carriers had lower levels of miR-877. CONCLUSION The rs1264440 in the promoter region of miR-877 may regulate miR-877 expression and serve as an independent biomarker for the risk of HCC.
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Affiliation(s)
- Hongtu Wang
- Department of Infections Disease, the First Affiliated Hospital of Kunming Medical University, 650032 Kunming, Yunnan, China
| | - Bo Wang
- Department of Neurosurgery, the First Affiliated Hospital of Kunming Medical University, 650032 Kunming, Yunnan, China
| | - Tao Wang
- Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital of Kunming Medical University, 650101 Kunming, Yunnan, China
| | - Ruixuan Fan
- Department of Infections Disease, the First Affiliated Hospital of Kunming Medical University, 650032 Kunming, Yunnan, China.
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Ogawa K, Noda A, Ueda J, Ogata T, Matsuyama R, Nishizawa Y, Qiao S, Iwata S, Ito M, Fujihara Y, Ichihara M, Adachi K, Takaoka Y, Iwamoto T. Forced expression of miR-143 and -145 in cardiomyocytes induces cardiomyopathy with a reductive redox shift. Cell Mol Biol Lett 2020; 25:40. [PMID: 32855642 PMCID: PMC7444248 DOI: 10.1186/s11658-020-00232-x] [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: 12/20/2019] [Accepted: 08/10/2020] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Animal model studies show that reductive stress is involved in cardiomyopathy and myopathy, but the exact physiological relevance remains unknown. In addition, the microRNAs miR-143 and miR-145 have been shown to be upregulated in cardiac diseases, but the underlying mechanisms associated with these regulators have yet to be explored. METHODS We developed transgenic mouse lines expressing exogenous miR-143 and miR-145 under the control of the alpha-myosin heavy chain (αMHC) promoter/enhancer. RESULTS The two transgenic lines showed dilated cardiomyopathy-like characteristics and early lethality with markedly increased expression of miR-143. The expression of hexokinase 2 (HK2), a cardioprotective gene that is a target of miR-143, was strongly suppressed in the transgenic hearts, but the in vitro HK activity and adenosine triphosphate (ATP) content were comparable to those observed in wild-type mice. In addition, transgenic complementation of HK2 expression did not reduce mortality rates. Although HK2 is crucial for the pentose phosphate pathway (PPP) and glycolysis, the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) was unexpectedly higher in the hearts of transgenic mice. The expression of gamma-glutamylcysteine synthetase heavy subunit (γ-GCSc) and the in vitro activity of glutathione reductase (GR) were also higher, suggesting that the recycling of GSH and its de novo biosynthesis were augmented in transgenic hearts. Furthermore, the expression levels of glucose-6-phosphate dehydrogenase (G6PD, a rate-limiting enzyme for the PPP) and p62/SQSTM1 (a potent inducer of glycolysis and glutathione production) were elevated, while p62/SQSTM1 was upregulated at the mRNA level rather than as a result of autophagy inhibition. Consistent with this observation, nuclear factor erythroid-2 related factor 2 (Nrf2), Jun N-terminal kinase (JNK) and inositol-requiring enzyme 1 alpha (IRE1α) were activated, all of which are known to induce p62/SQSTM1 expression. CONCLUSIONS Overexpression of miR-143 and miR-145 leads to a unique dilated cardiomyopathy phenotype with a reductive redox shift despite marked downregulation of HK2 expression. Reductive stress may be involved in a wider range of cardiomyopathies than previously thought.
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Affiliation(s)
- Kota Ogawa
- Department of Biomedical Sciences, Chubu University Graduate School of Life and Health Sciences, Kasugai, Aichi Japan
| | - Akiko Noda
- Department of Biomedical Sciences, Chubu University Graduate School of Life and Health Sciences, Kasugai, Aichi Japan
| | - Jun Ueda
- Center for Education in Laboratory Animal Research, Chubu University, Kasugai, Aichi Japan
- Present address: Center for Advanced Research and Education, Asahikawa Medical University, Asahikawa, Hokkaido Japan
| | - Takehiro Ogata
- Department of Pathology and Cell Regulation, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Rumiko Matsuyama
- Department of Biomedical Sciences, Chubu University Graduate School of Life and Health Sciences, Kasugai, Aichi Japan
| | - Yuji Nishizawa
- Department of Biomedical Sciences, Chubu University Graduate School of Life and Health Sciences, Kasugai, Aichi Japan
| | - Shanlou Qiao
- Department of Biomedical Sciences, Chubu University Graduate School of Life and Health Sciences, Kasugai, Aichi Japan
| | - Satoru Iwata
- Department of Biomedical Sciences, Chubu University Graduate School of Life and Health Sciences, Kasugai, Aichi Japan
- Center for Education in Laboratory Animal Research, Chubu University, Kasugai, Aichi Japan
- College of Bioscience and Biotechnology, Chubu University, Kasugai, Aichi Japan
| | - Morihiro Ito
- Department of Biomedical Sciences, Chubu University Graduate School of Life and Health Sciences, Kasugai, Aichi Japan
| | - Yoshitaka Fujihara
- Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
- Present address: Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center, Osaka, Japan
| | - Masatoshi Ichihara
- Department of Biomedical Sciences, Chubu University Graduate School of Life and Health Sciences, Kasugai, Aichi Japan
| | - Koichi Adachi
- Radioisotope Research Center Medical Division, Nagoya University Graduate School of Medicine, Nagoya, Aichi Japan
| | - Yuji Takaoka
- Department of Biomedical Sciences, Chubu University Graduate School of Life and Health Sciences, Kasugai, Aichi Japan
| | - Takashi Iwamoto
- Department of Biomedical Sciences, Chubu University Graduate School of Life and Health Sciences, Kasugai, Aichi Japan
- Center for Education in Laboratory Animal Research, Chubu University, Kasugai, Aichi Japan
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Yang J, Qin T, Liu S, Tang H, Liu M, Wang Q. Interaction analysis of miR-1275/IGF2BP1/IGF2BP3 with the susceptibility to hepatocellular carcinoma. Biomark Med 2020; 14:283-292. [PMID: 32134323 DOI: 10.2217/bmm-2019-0332] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Aim: The aim of this study was to investigate the association of miR-1275 rs16759, IGF2BP1 rs11079850 and IGF2BP3 rs34414305 with hepatocellular carcinoma (HCC) risk. Materials & methods: Genotyping of the rs16759 and rs11079850 was performed using a Taqman assay and genotyping of the rs34414305 was performed using PCR. Relative expression of miR-1275, IGF2BP1 and IGF2BP3 was examined using quantitative PCR. Results: Comparison of the rs16759GG, CG/GG and CC genotype showed an increased risk of HCC. When comparing G with C allele, a significantly increased risk of HCC was also found. The rs16759, rs11079850 and rs34414305 had combined the interactive effects on the carcinogenesis of HCC. Moreover, the rs34414305 Del/ATT-Del/Del carriers displayed lower levels of IGF2BP3. Conclusion: The rs16759, rs11079850 and rs34414305 may singly and interactively contribute to carcinogenesis of HCC.
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Affiliation(s)
- Jun Yang
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Tao Qin
- Department of Laboratory Medicine, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, China
| | - Shanshan Liu
- Department of Laboratory Medicine, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, China
| | - Hui Tang
- Department of Laboratory Medicine, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, China
| | - Mengqing Liu
- The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, China
| | - Qian Wang
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong 510515, China
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Tu H, Chen D, Cai C, Du Q, Lin H, Pan T, Sheng L, Xu Y, Teng T, Tu J, Lin Z, Wang X, Wang R, Xu L, Chen Y. microRNA-143-3p attenuated development of hepatic fibrosis in autoimmune hepatitis through regulation of TAK1 phosphorylation. J Cell Mol Med 2020; 24:1256-1267. [PMID: 31808606 PMCID: PMC6991639 DOI: 10.1111/jcmm.14750] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 09/12/2019] [Accepted: 09/24/2019] [Indexed: 12/11/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic liver disease due to autoimmune system attacks hepatocytes and causes inflammation and fibrosis. Intracellular signalling and miRNA may play an important role in regulation of liver injury. This study aimed to investigate the potential roles of microRNA 143 in a murine AIH model and a hepatocyte injury model. Murine AIH model was induced by hepatic antigen S100, and hepatocyte injury model was induced by LPS. Mice and AML12 cells were separated into six groups with or without the treatment of miRNA-143. Inflammation and fibrosis as well as gene expression were examined by different cellular and molecular techniques. The model was successfully established with the elevation of ALT and AST as well as inflammatory and fibrotic markers. Infection or transfection of mir-143 in mice or hepatocytes significantly attenuated the development of alleviation of hepatocyte injury. Moreover, the study demonstrated phosphorylation of TAK1-mediated miRNA-143 regulation of hepatic inflammation and fibrosis as well as hepatocyte injury. Our studies demonstrated a significant role of miRNA-143 in attenuation of liver injury in AIH mice and hepatocytes. miRNA-143 regulates inflammation and fibrosis through its regulation of TAK1 phosphorylation, which warrants TAK1 as a target for the development of new therapeutic strategy of autoimmune hepatitis.
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Affiliation(s)
- Hanxiao Tu
- Department of Infectious DiseasesWenzhou Key Laboratory of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityHepatology Institute of Wenzhou Medical UniversityWenzhouChina
| | - Dazhi Chen
- Department of GastroenterologyThe First Hospital of Peking UniversityBeiJingChina
| | - Chao Cai
- Department of Infectious DiseasesWenzhou Key Laboratory of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityHepatology Institute of Wenzhou Medical UniversityWenzhouChina
| | - Qianjing Du
- Department of Infectious DiseasesWenzhou Key Laboratory of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityHepatology Institute of Wenzhou Medical UniversityWenzhouChina
| | - Hongwei Lin
- Department of Infectious DiseasesWenzhou Key Laboratory of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityHepatology Institute of Wenzhou Medical UniversityWenzhouChina
| | - Tongtong Pan
- Department of Infectious DiseasesWenzhou Key Laboratory of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityHepatology Institute of Wenzhou Medical UniversityWenzhouChina
| | - Lina Sheng
- Department of Infectious DiseasesWenzhou Key Laboratory of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityHepatology Institute of Wenzhou Medical UniversityWenzhouChina
- Department of Infectious DiseasesThe Affiliated Yiwu Central Hospital of Wenzhou Medical UniversityYiwuChina
| | - Yuedong Xu
- Department of Infectious DiseasesWenzhou Key Laboratory of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityHepatology Institute of Wenzhou Medical UniversityWenzhouChina
| | - Teng Teng
- Department of Infectious DiseasesWenzhou Key Laboratory of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityHepatology Institute of Wenzhou Medical UniversityWenzhouChina
| | - Jingjing Tu
- Department of Infectious DiseasesWenzhou Key Laboratory of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityHepatology Institute of Wenzhou Medical UniversityWenzhouChina
| | - Zhuo Lin
- Department of Infectious DiseasesWenzhou Key Laboratory of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityHepatology Institute of Wenzhou Medical UniversityWenzhouChina
| | - Xiaodong Wang
- Department of Infectious DiseasesWenzhou Key Laboratory of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityHepatology Institute of Wenzhou Medical UniversityWenzhouChina
| | - Rui Wang
- Department of Infectious DiseasesWenzhou Key Laboratory of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityHepatology Institute of Wenzhou Medical UniversityWenzhouChina
| | - Lanman Xu
- Department of Infectious DiseasesWenzhou Key Laboratory of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityHepatology Institute of Wenzhou Medical UniversityWenzhouChina
- Department of Infectious Diseases and Liver DiseasesNingbo Medical Center Lihuili HospitalNingboChina
- Department of Infectious Diseases and Liver DiseasesThe Affiliated Lihuili Hospital of Ningbo UniversityNingboChina
| | - Yongping Chen
- Department of Infectious DiseasesWenzhou Key Laboratory of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityHepatology Institute of Wenzhou Medical UniversityWenzhouChina
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Kotarac N, Dobrijevic Z, Matijasevic S, Savic-Pavicevic D, Brajuskovic G. Analysis of association of potentially functional genetic variants within genes encoding miR-34b/c, miR-378 and miR-143/145 with prostate cancer in Serbian population. EXCLI JOURNAL 2019; 18:515-529. [PMID: 31423132 PMCID: PMC6694712 DOI: 10.17179/excli2019-1257] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 07/12/2019] [Indexed: 12/11/2022]
Abstract
MiRNA-associated genetic variants occurring in regulatory regions can affect the efficiency of transcription and potentially modify pri-miRNA or pre-miRNA processing. Since miRNA-based mechanisms are shown to be involved in the pathogenesis of prostate cancer (PCa), the aim of the present study was to evaluate the effect of rs4938723, rs1076064 and rs4705343 occurring in regulatory regions of miR-34b/c, miR-143/145 and miR-378, respectively, on PCa risk and progression in Serbian population. We examined a total of 1060 subjects, of which 350 were patients with PCa, 354 were patients with benign prostatic hyperplasia (BPH), while 356 healthy volunteers were included in the control group. Genotyping of rs4938723, rs1076064 and rs4705343 was performed by using Taqman® SNP Genotyping Assays. Allele C of rs4705342 was found to increase the risk of PCa (P=0.031 for codominant model, P=0.0088 for recessive model). Rs1076064 minor allele G was found to associate with serum PSA score, as well as with PCa T category and disease aggressiveness. For rs4938723 minor allele C was shown to be associated with the lower PCa T category (Pdom=0.0046; OR=0.36, 95 % CI 0.17-0.76) in T2 vs. T1 comparison. Rs4705342 was identified as PCa susceptibility variant in Serbian population, while for rs1076064 and rs4938723 association with PCa progression parameters was found.
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Affiliation(s)
- Nevena Kotarac
- Centre for Human Molecular Genetics, Faculty of Biology, University of Belgrade, Belgrade, Serbia
| | - Zorana Dobrijevic
- Centre for Human Molecular Genetics, Faculty of Biology, University of Belgrade, Belgrade, Serbia
| | - Suzana Matijasevic
- Centre for Human Molecular Genetics, Faculty of Biology, University of Belgrade, Belgrade, Serbia
| | - Dusanka Savic-Pavicevic
- Centre for Human Molecular Genetics, Faculty of Biology, University of Belgrade, Belgrade, Serbia
| | - Goran Brajuskovic
- Centre for Human Molecular Genetics, Faculty of Biology, University of Belgrade, Belgrade, Serbia
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