Bmi1驱动肝癌发生发展的新机制：TGFβ/SMAD信号通路介导的细胞周期调控研究

Bmi1是肝癌发生的一个重要驱动基因及潜在治疗靶点。但由于Bmi1也为肝脏祖细胞增殖所必需，因此有必要研究Bmi1调控肝癌生长分子机制并据此进行针对性治疗。前期研究中发现，Bmi1通过抑制Ink4A/Arf维持肝脏祖细胞增殖，但并不通过Ink4A/Arf驱动肝癌发生发展。在肝癌细胞中沉默Bmi1会显著上调TGFβ2及其下游分子，在Bmi1敲除小鼠肝细胞中TGFβ/SMAD信号分子也普遍上调。同时我们发现Bmi1通过推进细胞周期促进肝癌发生发展，文献亦报道TGFβ/SMAD途径可以在肿瘤中调控细胞周期。这些结果都提示TGFβ/SMAD信号通路可能介导了Bmi1对肝癌的生长调控。在本研究中，我们将研究TGFβ/SMAD信号通路在介导Bmi1驱动肝癌发生发展中的作用和分子机制。本研究的开展将有助于阐明Bmi1在肝癌发生发展中的作用机制，并促进针对Bmi1靶点的肝癌生物治疗研究。

Bmi1 is a driver oncogene and potential therapeutic target of hepatocellular carcinoma (HCC). Since Bmi1 is also essential for the proliferation of hepatic progenitor cells in livers, uncovering the molecular mechanisms underlying hepatic carcinogenesis driven by Bmi1 will favor the gene therapy targeting Bmi1. In our previous study, we found that Bmi1 maintains the proliferation of liver progenitor cells (oval cells) by repressing Ink4A/Arf. However, Bmi1 promotes the hepatic carcinogenesis and HCC growth independent of Ink4A/Arf. We also found that knockdown of Bmi1 in HCC cells will significantly up-regulate the expression level of TGFβ2 and its downstream molecules. In Bmi1 knockout mice, the TGFβ/SMAD signaling is comprehensively up-regulated as well. These results suggest that TGFβ/SMAD signaling plays an important role in mediating the growth of HCC cells drived by Bmi1. Here, in this proposal, we are trying to uncover the role and mechanism of TGFβ/SMAD signaling for the HCC formation and growth promoted by Bmi1. This study will promote our understanding of the function and mechanism of Bmi1 signaling during HCC initiation and progression, and also accelerate the therapeutic study targeting Bmi1 in HCC.