lncRNA-MEG3调控MET表达介导肝细胞癌索拉非尼耐药的作用机制研究

索拉非尼是治疗肝癌的一线靶向药物，但是因为肝癌对其耐药而疗效远不理想。我们前期研究表明，肝癌组织中MET表达与索拉非尼耐药相关，但具体机制不清。近期我们通过基因芯片筛选索拉非尼耐药和敏感肝癌组织中差异表达的mRNA和lncRNA，发现耐药肝癌组织中MET高表达的同时伴有lncRNA-MEG3(MEG3) 低表达；RNA pull-down实验提示MEG3可能与MET直接结合；在肝癌细胞中过表达MEG3可抑制MET表达，并抑制肝癌细胞增殖迁移。由此，我们推测MEG3通过与MET结合，调控MET及其下游肝癌增殖相关通路，从而影响肝癌对索拉非尼的敏感性。本项目拟进一步从分子、细胞和动物水平，通过RIP、缺失定位等实验方法证实MEG3调控MET表达介导肝癌索拉非尼耐药的具体机制，并探讨索拉非尼联合MEG3过表达对克服肝癌靶向耐药的可行性。项目的开展有望为肝癌靶向治疗耐药机制的阐明提供新的科学依据。

Although sorafenib has been used as the first-line choice in targeting treatment of hepatocellular carcinoma (HCC), its efficiency is limited because of drug resistance. Our previous studies have demonstrated that the MET expression is associated with sorafenib resistance in HCC, however, the molecular mechanisms remains unclear. Recently, we detected the differential expressions of mRNAs and long noncoding RNAs(lncRNAs) between sorafenib-resistant HCC tissues and sorafenib-sensitive HCC tissues by lncRNAs microarray technology. Results showed that high-expression of MET is associated with reduced lncRNA-MEG3 expression in sorafenib-resistant HCC tissues. Further RNA pull-down experiments suggested that lncRNA-MEG3 combined with MET. Over-expression of lncRNA-MEG3 inhibits the MET expression and inhibits the proliferation and invasion of HCC cells. Thus, we speculate that lncRNA-MEG3 combines with MET and inhibits its expression, then inhibits its downstream pathways that associated with HCC viability, and finally reduces the treatmental efficiency of sorafenib to HCC. The current study will confirm that lncRNA-MEG3 regulates MET expression and prompts sorafenib resistance in hepatocellular carcinoma. Furthermore, the efficency of combined treatmet of sorafenib and lncRNA-MEG3 over-expression will also be determined. This study will facilitate to clarify the novel mechanism of sorafenib resistance in the treatment of HCC, thus provide more scientific basis for the targeting therapy of HCC.