上海交通大学学报（医学版）

›› 2012, Vol. 32 ›› Issue (9): 1264-.doi: 10.3969/j.issn.1674-8115.2012.09.026

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非编码小RNA在肝癌发生中的作用及机制研究进展

何祥火, 梁琳慧, 丁 洁, 黄胜林   

  1. 上海交通大学 医学院附属仁济医院 上海市肿瘤研究所, 上海 200032
  • 出版日期:2012-09-28 发布日期:2012-09-29
  • 作者简介:何祥火（1972—）, 男, 研究员, 博士, 博士生导师, 上海市肿瘤研究所癌基因及相关基因国家重点实验室功能基因组课题组长；电子信箱: xhhe@shsci.org。
  • 基金资助:

    国家杰出青年科学基金（81125016）；国家自然科学基金重大研究计划（91029728）；国家自然科学基金面上项目（81071637）；上海市科委重大基础研究项目（07DJ14006）；上海市科委重点基础研究项目（10JC1414200）

Advances in research on the role and mechanism of microRNAs in hepatic carcinogenesis

HE Xiang-huo, LIANG Lin-hui, DING Jie, HUANG Sheng-lin   

  1. Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China
  • Online:2012-09-28 Published:2012-09-29

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摘要：

MicroRNA（miRNA）是一类约 22 个核苷酸组成的小分子非编码RNA，主要在转录后水平通过促进靶基因mRNA的降解或抑制其翻译过程而发挥负调控作用。miRNA不但参与生命活动的一些基本过程，如细胞分化、细胞增殖、细胞凋亡和细胞代谢等，而且与人类疾病，尤其与恶性肿瘤的发生发展密切相关，可作为一类新的癌基因及抑癌基因，在癌症的发生发展中起重要作用。近年，我们首次在肝癌染色体变异区内发现新的肝癌转移促进因子miR-151并阐明了其分子作用机制，即RhoGDIA是miR-151下游靶基因，介导了miR-151的促肝癌转移功能；miR-151与其宿主基因FAK协同作用，活化Rac, cdc42及Rho GTPase，进而促进肝癌细胞的迁移、侵袭与转移，为阻断肝癌转移提供了新的治疗靶点。研究发现多个用于肝癌诊断及转移、复发、预后预测的miRNA分子标志物，建立了肝癌诊断、转移、复发及预后的miRNA预测模型；鉴定miR-125b为肝癌侯选抑癌基因，主要通过抑制癌基因LIN28B发挥抑癌作用；发现miR30d为肝癌转移促进基因，转移抑制基因GNAI2为其功能靶基因；另外，发现miRNA不仅与mRNA的3’非翻译区结合，而且能与基因家族的蛋白编码区结合从而调控基因表达，为研究miRNA在肿瘤中的调控机制提供了新的思路；采用实验方法论证了单个基因能同时被多个miRNA所调控，为建立miRNA与mRNA复杂的相互作用调控网络提供了良好的实验基础。

关键词: microRNA, 肝癌, miR-151, miR-125b, miR-30d

Abstract:

MicroRNAs (miRNAs) are small, non-coding RNAs that can act as oncogenes or tumor suppressors in human cancer. Recently we identified 129 known miRNA genes in the recurrent chromosomal aberration regions of hepatocellular carcinoma (HCC). Further analysis showed that 22 miRNAs are often amplified or deleted in HCC. MicroRNA-151 (miR-151), a frequently amplified miRNA on 8q24.3, is often expressed together with its host gene FAK, and significantly increases HCC cell migration and invasion in vitro and in vivo by directly targeting RhoGDIA, a putative metastasis suppressor in HCC, thus leading to the activation of Rac1, Cdc42 and Rho GTPases. In addition, we analyzed the miRNA profiles in HCC and found that 69 miRNAs were differentially expressed between HCC and corresponding noncancerous liver tissues. The set of differentially expressed miRNAs could distinctly classify HCC and noncancerous liver tissues. Moreover, some of these differentially expressed miRNAs were related to the clinical features of HCC patients such as metastasis and recurrence. Importantly, the expression level of individual miRNA miR-125b was correlated with the survival time of HCC patients. These results revealed the diagnostic and prognostic implications of miRNAs in HCC. Furthermore, we showed that miR-125b could function as a candidate tumor suppressor in HCC through directly targeting oncogene LIN28B, thus resulting in the increase of p21Cip1/Waf1 expression and cell cycle arrest at G1/S transition. Moreover, we analyzed the function and mechanism of metastasis-related miR-30d in HCC and found that miR-30d could promote HCC cell migration and invasion by downregulating Galphai2 (GNAI2) expression. Intriguingly, we found that miRNA can target the coding region of mRNA other than its 3’ UTR; and experimentally showed that one mRNA could be simultaneously regulated by multiple miRNAs.

Key words: MicroRNA, hepatocellular carcinoma, miR-151, miR-125b, miR-30d