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首页> 外文期刊>Cell & Bioscience >A novel miR-0308-3p revealed by miRNA-seq of HBV-positive hepatocellular carcinoma suppresses cell proliferation and promotes G1/S arrest by targeting double CDK6/Cyclin D1 genes
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A novel miR-0308-3p revealed by miRNA-seq of HBV-positive hepatocellular carcinoma suppresses cell proliferation and promotes G1/S arrest by targeting double CDK6/Cyclin D1 genes

机译：通过HBV阳性肝细胞癌MiRNA-SEQ揭示的新型miR-0308-3P抑制细胞增殖，并通过靶向双CDK6 / cyclin D1基因来促进G1 / S逮捕

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Persistent infection with hepatitis B virus (HBV) accounts for the majority of hepatocellular carcinoma (HCC), but the molecular mechanisms underlying liver carcinogenesis are still not completely understood. Increasing evidence demonstrates that microRNAs (miRNAs) play significant functional roles in virus–host interactions. The aim of this study was to explore differentially expressed miRNA profiles and investigate the molecular mechanism of miR-0308-3p in HBV-positive HCC carcinogenesis. High-throughput sequencing was used to detect novel miRNAs in three samples of HBV-positive HCC tissue compared to matched HBV-negative HCC tissue. The Cancer Genome Atlas (TCGA) database was used to mine miRNAs related to HBV-positive HCC. Bioinformatics analyses were conducted to predict the miRNAs’ possible biological and pathway regulatory functions. Quantitative polymerase chain reaction (qPCR) was then applied to evaluate the expression levels of randomly selected miRNAs. CCK-8 was used to measure cell proliferation and cell cycles were analyzed using flow cytometry. A dual luciferase reporter gene assay was used to confirm the downstream targets of miR-0308-3p. In total, there were 34 overlapping miRNAs in both our miRNA-seq data and the TCGA database. We found two overlapping miRNAs in both the HBV-positive HCC samples and the TCGA database, and 205 novel pre-miRNA sequences were predicted. miR-522 and miR-523 were markedly overexpressed in HBV-positive HCC and were associated with a significantly poorer long-term prognosis (miR-522, HR 2.19, 95% CI 1.33–3.6, p?=?0.0015; miR-523HR 1.5, 95% CI 1–2.44, p?=?0.0047). Of note, we found that the novel miR-0308-3p was markedly downregulated in HBV-positive HCC samples and HCC cancer cell lines compared with HBV-negative HCC samples and adjacent normal hepatic tissue. Moreover, elevated expression of miR-0308-3p was found to inhibit proliferation of cancer cells by promoting G1/S cell cycle arrest but did not influence the apoptosis of cancer cells. A dual luciferase reporter activity assay identified that miR-0308-3p acted directly on the target sequence of the CDK6?and?Cyclin D1 mRNA 3?UTR to suppress CDK6?and?Cyclin D1 expression. MiR-0308-3p upregulation dramatically suppressed HCC cell proliferation and induced G1/S cell cycle arrest by directly targeting CDK6/Cyclin D1. These findings reveal a novel molecular mechanism for activation of G1/S arrest in HCC and may prove clinically useful for developing new therapeutic targets.
机译：耐久性感染乙型肝炎病毒（HBV）占大多数肝细胞癌（HCC），但肝脏致癌作用的分子机制仍未完全理解。越来越多的证据表明MicroRNA（miRNA）在病毒宿主交互中发挥着显着的功能作用。本研究的目的是探讨差异表达的miRNA谱，并研究HBV阳性HCC癌中miR-0308-3P的分子机制。与匹配的HBV阴性HCC组织相比，使用高通量测序在HBV阳性HCC组织的三个样品中检测新的miRNA。癌症基因组Atlas（TCGA）数据库用于挖掘与HBV阳性HCC相关的miRNA。进行生物信息学分析以预测MiRNA可能的生物和途径调节功能。然后施用定量聚合酶链反应（QPCR）以评估随机选择的miRNA的表达水平。 CCK-8用于测量细胞增殖，使用流式细胞术分析细胞循环。使用双荧光素酶报告基因测定法确认miR-0308-3p的下游靶标。总共，我们的miRNA-SEQ数据和TCGA数据库中有34个重叠的miRNA。我们在HBV阳性HCC样品和TCGA数据库中发现了两种重叠的miRNA，并且预测了205个新的预先进行的预先预先序列。 MIR-522和MIR-523在HBV阳性HCC中显着过表达，与显着较差的长期预后（MIR-522，HR 2.19,95％CI 1.33-3.6，P？= 0.0015; miR-523hr 1.5,95％CI 1-2.44，P？= 0.0047）。值得注意的是，与HBV阴性HCC样品和相邻的正常肝组织相比，新型MIR-0308-3P在HBV阳性HCC样品和HCC癌细胞系中显着下调。此外，发现MIR-0308-3P的升高表达通过促进G1 / S细胞循环捕获来抑制癌细胞的增殖，但未影响癌细胞的凋亡。双荧光素酶报告活性测定结果确定miR-0308-3p直接作用于CDK6的靶序列α和α细胞蛋白D1 mRNA 3？UTR以抑制CDK6？和？Cyclin D1表达。 MiR-0308-3P上调通过直接靶向CDK6 / Cyclin D1显着抑制了HCC细胞增殖和诱导G1 / S细胞周期捕获。这些发现揭示了一种新的分子机制，用于激活HCC的G1 / S停止，并可在临床上证明临床上用于开发新的治疗靶标。

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