Coulouarn C, Factor V M, Andersen J B, Durkin M E, Thorgeirsson S S
Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda 20892-4262, MD, USA.
Oncogene. 2009 Oct 8;28(40):3526-36. doi: 10.1038/onc.2009.211. Epub 2009 Jul 20.
Growing evidence indicates that microRNAs have a significant role in tumor development and may constitute robust biomarkers for cancer diagnosis and prognosis. In this study, we evaluated the clinical and functional relevance of microRNA-122 (miR-122) expression in human hepatocellular carcinoma (HCC). We report that miR-122 is specifically repressed in a subset of primary tumors that are characterized by poor prognosis. We further show that the loss of miR-122 expression in tumor cells segregates with specific gene expression profiles linked to cancer progression, namely the suppression of hepatic phenotype and the acquisition of invasive properties. We identify liver-enriched transcription factors as central regulatory molecules in the gene networks associated with loss of miR-122, and provide evidence suggesting that miR-122 is under the transcriptional control of HNF1A, HNF3A and HNF3B. We further show that loss of miR-122 results in an increase of cell migration and invasion and that restoration of miR-122 reverses this phenotype. In conclusion, miR-122 is a marker of hepatocyte-specific differentiation and an important determinant in the control of cell migration and invasion. From a clinical point of view, our study emphasizes miR-122 as a diagnostic and prognostic marker for HCC progression.
越来越多的证据表明，微小RNA在肿瘤发展中发挥着重要作用，并且可能构成癌症诊断和预后的有力生物标志物。在本研究中，我们评估了微小RNA - 122（miR - 122）表达在人类肝细胞癌（HCC）中的临床和功能相关性。我们报告称，miR - 122在一部分预后不良的原发性肿瘤中被特异性抑制。我们进一步表明，肿瘤细胞中miR - 122表达的缺失与与癌症进展相关的特定基因表达谱相关，即肝表型的抑制和侵袭特性的获得。我们确定肝脏富集转录因子是与miR - 122缺失相关的基因网络中的核心调节分子，并提供证据表明miR - 122受HNF1A、HNF3A和HNF3B的转录控制。我们进一步表明，miR - 122的缺失导致细胞迁移和侵袭增加，而miR - 122的恢复则逆转了这种表型。总之，miR - 122是肝细胞特异性分化的标志物，也是控制细胞迁移和侵袭的重要决定因素。从临床角度来看，我们的研究强调miR - 122作为HCC进展的诊断和预后标志物。
