Hippo信号通路和EZH2在黄曲霉素B1诱导肝脏祖细胞恶性转化为肝细胞癌中相互作用及机制研究

黄曲霉素B1（AFB1）是引起肿瘤的主要环境因素之一，肝脏祖细胞（LPCs）可能是肝细胞癌（HCC）起源细胞。Hippo信号通路和EZH2在肿瘤发生发展和干细胞发育等方面起着重要作用。申请者前期研究发现：AFB1在体内外均诱导LPCs异常增殖和恶性转化；AFB1通过抑制Lats1的磷酸化，激活转录共刺激因子Yap1/Taz和下游因子的合成；EZH2抑制Taz的蛋白降解 ，维持Taz的激活状态。基于前期研究结果，本课题将研究Hippo信号通路和EZH2介导的组蛋白甲基化在HCC中的异常表达及在LPCs内的激活；建立AFB1作用于LPCs的体内外模型，观察AFB1诱导LPCs异常增殖和恶性转化为HCC的过程，探讨Hippo信号通路和EZH2在其中的相互作用和分子机制。本课题将进一步揭示HCC发病的细胞和分子机制，加深HCC发生及其机制的了解，为HCC的防治提供新的靶点和思路。

Aflatoxin B1(AFB1) has been identified as the most harmful hepatocarcinogen leading to the development of hepatocellular carcinoma (HCC) in humans and animals. The studies demonstrated that liver progenitor cells (LPCs) might be the cellular origin of HCC and AFB1 exposure produced LPCs proliferation in animal models. However, the precise mechanism responsible for regulation of LPCs proliferation and how its deregulation contributes to HCC development induced by AFB1remains poorly understood. Previous work from our laboratory demonstrated that AFB1 exposure induced oval cell response in murine models. In previous studies, we also found that: (1) In vitro model, AFB1 induced the proliferation of both hepatocytes and LPCs, also induced the cell death of hepatocytes while had minimal effects on LPCs, which was consistent with the findings on AFB1 ingestion model in vivo. (2) AFB1 exhibited the stimulative effects on the dedifferentiation and invasion of LPCs. There is now a growing body of evidence showing that the Hippo pathway and EZH2 plays a vital role in modulating organ size, cellular proliferation, differentiation, tissue homeostasis, tumor progression. We found that AFB1 induced Yap1/Taz activation by reducing phosphorylation of Lats1 in LPCs. And when EZH2 was inhibited, the expression and function of Taz was reduced. Based on these previous data, we suggest that Hippo signaling pathway and EZH2 is involved in neoplastic transformation of LPCs to HCC induced by AFB1.So we will detect aberrant activation of Yap1/Taz and EZH2 in human HCC samples and location of them in LPCs. We would use the AFB1-treated models in vivo and in vitro, to confirm whether LPCs treated with AFB1 will give rise to HCC, clarify the different effects of AFB1 on hepatocytes and LPCs. And we would explore the role of cross-talk between Hippo signaling pathway and EZH2 in this course. Moreover, we would determine whether knockout of Lats1,Yap1/Taz and EZH2 leads to inhibition of LPCs’ growth and HCC development induced by AFB1.If these studies were finally finished, the results will be useful for us to better understand AFB1-induced hepatocarcinogenesis, and help us to develop new potential therapies targeting of Hippo signaling pathway and EZH2 for HCC.