肿瘤相关巨噬细胞TAM与miR-132甲基化的交叉对话在肝癌索拉非尼耐药中的机制研究

肿瘤相关巨噬细胞（TAM）在HCC发生发展中起着重要作用，但在HCC耐药中的作用及机制尚不清楚。我们前期研究发现，TAM及miR-132甲基化失活参与了肝癌细胞对索拉非尼耐药。结合相关文献推测，索拉非尼长期作用于肝癌细胞诱导了miR-132高甲基化，从而激活β-catenin信号通路，同时也会使TAM内EGF大量释放，激活EGFR信号通路，β-catenin与EGFR之间的cross-talk促进了HCC耐药。为证实此假设，我们将分析临床肝癌标本中TAM分布及miR-132表达与HCC索拉非尼耐药之间的关系；通过体外共培养TAM及肝癌细胞，探析miR-132表达与肝癌细胞β-catenin通路激活及EGFR通路之间的关系及机制；通过肝癌动物模型，证实TAM及miR-132对HCC索拉非尼耐药的作用及机制。本课题将有助于深入了解索拉非尼耐药的机制，为探索更有效的生物靶向治疗提供新的依据。

Tumor-associated macrophages(TAM) palys an important roles in the development of hepatocellular carcinoma, yet its role in resistence of HCC remains uncertain. Our preliminary studies suggest that TAM and miR-132 methylation implicated progression on sorafenib resistance of HCC. Based on our preliminary data, we hypothesized that β-catenin/EGFR signaling pathway cross-talk on TAM and miR-132 methylation induced sorafenib resistance of HCC. In this application, by in vitro and in vivo experiments, we plan to validate TAM expression and miR-132 methylation status in sorafenib-resistant tumor tissues, and investigate how TAM and miR-132 impacted turmor resistant, particularly the mechanism involving the β-catenin/EGFR pathway cross-talk. The outcome will help to identify molecular mechanism of sorafenib resistance of HCC, and therapeutic targets for drug discovery against HCC.