Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong, China; State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong, China; State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
Cancer Lett. 2015 Jun 28;362(1):97-105. doi: 10.1016/j.canlet.2015.03.023. Epub 2015 Mar 23.
Nearly 50% of known miRNAs are found in clusters and transcribed as polycistronic transcripts. In this study, we showed that over-expression of miR-183/96/182 cluster is frequent in hepatocellular carcinoma (HCC), a highly aggressive malignancy that is commonly fatal. In a cohort of HCC patients (n = 81), miR-183/96/182 up-regulation correlated with metastatic features including presence of microvascular invasion, advanced tumor differentiation, and shorter recurrence-free survival. Univariate and multivariate analyses further showed miR-183/96/182 over-expression represented an independent prognostic factor (Relative Risk: 2.0471; P = 0.0289). Functional investigation using siRNA against miR-183/96/182 in two invasive HCC cells indicated significant inhibition on cell migration and invasion without affecting cell viability. Forkhead boxO1 (FOXO1) was further validated as a downstream target of these three miRNAs. In investigating the regulatory mechanism underlining miR-183/96/182 over-expression, a direct interaction of CTNNB1 on the promoter region was confirmed by ChIP-PCR and luciferase reporter validations. Knockdown of CTNNB1 also showed concordant down-regulations of miR-183, -96 and -182, and the re-expression of FOXO1. Our findings demonstrated that over-expression of miR-183/96/182 confers an oncogenic function in HCC cell dissemination, and could serve as an independent prognostic predictor for HCC patients.
近 50%的已知 miRNA 存在于簇中，并作为多顺反子转录本转录。在这项研究中，我们表明 miR-183/96/182 簇的过表达在肝细胞癌 (HCC) 中很常见，HCC 是一种侵袭性很强的恶性肿瘤，通常是致命的。在一组 HCC 患者 (n=81) 中，miR-183/96/182 的上调与转移性特征相关，包括微血管侵犯、肿瘤分化程度较高以及无复发生存时间较短。单因素和多因素分析进一步表明，miR-183/96/182 的过表达代表了一个独立的预后因素 (相对风险：2.0471；P=0.0289)。使用针对这三种 miRNA 的 siRNA 在两种侵袭性 HCC 细胞中进行功能研究表明，细胞迁移和侵袭显著受到抑制，而不影响细胞活力。叉头框 O1 (FOXO1) 进一步被验证为这三种 miRNA 的下游靶标。在研究miR-183/96/182 过表达的调控机制时，通过 ChIP-PCR 和荧光素酶报告验证证实了 CTNNB1 对启动子区域的直接作用。CTNNB1 的敲低也显示了 miR-183、-96 和 -182 的下调以及 FOXO1 的重新表达。我们的研究结果表明，miR-183/96/182 的过表达赋予 HCC 细胞扩散中的致癌功能，并可作为 HCC 患者的独立预后预测因子。
