microRNA-122调控肝癌上皮-间叶转换的机制及意义

MiR-122 is the liver-specific abundant miRNA, which is down-regulated in hepatocellular carcinoma (HCC). Cytokine TGF-b?is a potent inducer of epithelial-to-mesenchymal transition (EMT) and promotes tumor metastasis. In the pilot study, we found that miR-122 was down-regulated upon TGF-b stimulaiton. Re-expression of miR-122 significantly inhibited the EMT and migration of HCC cells. In contrast, attenuation of miR-122 markedly elevated the expression of mesenchymal marker in HCC cells. These data suggested that the decline of miR-122 induced by TGF-b may participate in the induction of EMT and metastasis of HCC cells. With these findings as backgroud, we plan: 1、to verify the regulation of miR-122 on EMT and metastasis of HCC cells via detecting the conversion of cell type markers and evaluating invasion ability in vitro and metastasis in vivo. 2、to identify the target genes and the pathway through which miR-122 modulates EMT. 3、to investigate the mechanism underlying the regulation of miR-122 expression by TGF-b, and further to integrate both upstream and downstream pathway of miR-122 in EMT procedure. These results will expand our knowledge on the implication of miR-122 in the EMT and metastasis of HCC cells, and provide novel target for HCC therapy.

miR-122在肝脏特异性高表达、且在肝细胞肝癌中显著下调。细胞因子TGF-b促进肿瘤细胞发生上皮?间叶转换以及肿瘤转移。前期研究中，我们发现TGF-b能诱导miR-122表达下调；回复miR-122表达水平能抑制肝癌细胞EMT及其迁移能力；抑制内源miR-122能显著诱导肝癌细胞表达间叶细胞标记。提示TGF-b诱导miR-122表达下调可能介导了肝癌细胞EMT过程以及肿瘤转移。以此为基础，我们拟开展以下工作：1、通过体外的分子标记检测及细胞迁移侵袭实验，并结合裸鼠体内模型，验证miR-122对肝癌细胞EMT及侵袭转移的调控作用。2、鉴定介导miR-122调控作用的靶基因及信号网络。3、研究TGF-b调控miR-122表达的分子机制，并整合miR-122上游表达调控及下游功能网络。研究结果将加深人们对于miR-122调控通路及其在肝癌EMT和侵袭转移中作用的认识，并为肝癌治疗提供新的靶标。

miR-122是肝脏高表达的miRNA。本项目研究了miR-122在肝纤维化中的作用，并阐述了miR-122表达失调的机制。我们揭示一条新的TGF-b-miR-122-fibronectin/SRF信号通路，发现miR-122可通过直接抑制fibronectin和SRF的表达，阻断肝脏纤维化及硬化，而肝炎微环境的TGF-b可导致miR-122表达降低，继而促进了肝纤维化的进展。我们进一步阐述了miR-122下调的原因，发现：TGF-b通路相关分子可通过与C/EBPa 相互作用，阻断其转录活性，从而抑制miR-122的表达。.本项目研究结果提示miR-122与蛋白分子共同构成的细胞信号回路精确调控着肝纤维化过程，扩展了人们对于肝纤维化发生机制的认识。miR-122有望成为治疗肝纤维化的新靶标。