GLI2异常活化激活驱动蛋白表达促进肝癌细胞恶性增殖的分子机制研究

转录因子GLI2是Hedgehog（Hh）信号通路的关键节点，起着枢纽作用。近年研究表明Hh信号通路异常活化与多种肿瘤的发生相关，但其分子机制还有待明晰。我们前期研究发现：肝癌组织中GLI2基因启动子区甲基化程度低于癌旁组织；特异性抑制Hh信号通路降低肝癌细胞的增殖能力；基因芯片检测发现抑制GLI2导致多个与有丝分裂相关的驱动蛋白基因（如KIF20A等）的表达显著降低。这提示GLI2启动子区去甲基化可引起Hh通路异常活化，另外， GLI2可能通过调控驱动蛋白基因（簇）在肝癌细胞增殖中起重要作用。本项目将以GLI2为重点,研究导致GLI2异常活化的表观遗传学机制；发掘受GLI2调控的新靶基因；利用GLI2基因敲除小鼠研究Hh信号通路在肝癌形成中的作用；从分子、细胞、模式动物和临床队列四个层面，阐明"GLI2-驱动蛋白"信号轴调控肝癌细胞恶性增殖的分子机制，为寻找肝癌诊疗相关的新靶点奠定基础。

Aberrant activation of Hedgehog(Hh) signaling plays a critical role in the tumorigenesis of various malignant tumors. GLIs are primary transcriptional regulators that mediate Hh signaling activation.In our preliminary studies, we found that GLI2 exhibited lower DNA methylation at its promoter region in hepatocellular cancer (HCC) tissues, when compared with that in adjacent normal tissues. Blockade of Hh signaling attenuated cell proliferation of HCC. Furthermore, Knockdown of GLI2 resulted in decreased expression of multiple kinesins associated with cell proliferation, such as KIF20A. These findings indicate that demethylation of GLI2 at promoter region may contribute to aberrant activation of Hh signaling pathway. Moreover,the kinesin genes (or gene clusters) regulated by GLI2 may be pivotal in HCC proliferation. In this study, we will utilize several approaches including molecular and cellular biology, animal model, and clinical cohont to investigate the epigenetic mechanisms of the aberrant activation of GLI2 and the new target genes regulated by GLI2. These findings will provide the insights into the processing of GLI2-kinesin signaling axis in HCC maligancy, as well as new targets for therapy.