Hippo信号通路调控肝脏糖原代谢平衡而抑制肝癌发生的功能与机制研究

The occurrence and development of hepatocellular carcinoma are closely related to various metabolic disorders. Studies have shown that the occurrence of hepatocellular carcinoma is accompanied by a variety of metabolic disorders, including glycogen metabolic disorders, but the relationship between metabolic disorders and hepatocellular carcinoma and regulatory mechanisms are not fully known. The applicant previous publications have shown that The Hippo signaling pathway plays an essential role in liver homeostasis and tumorigenesis. The preliminary data of the applicant showed that there were glycogen accumulation areas in the liver of Mst1/2 liver specific deficiency. Moreover, Glycogen storage disease mouse show liver enlargement and the inactivation of the Hippo pathway. Short-term intervention of glycogen synthesis in Mst1/2 DKO mice could alleviate the liver enlargement caused by the gene deficiency. This grant will analyze the correlationship of glycogen accumulation, the activity of Hippo signaling and tumorigenesis level in Mst1/2 DKO hepatocellular carcinoma model at the molecular, biochemical and whole animal level, clarify The function and molecular mechanism of Hippo signaling in regulating glycogen metabolism to inhibit liver tumorigenesis. Which will further elucidate the pathogenesis of liver cancer and establish theoretical basis of liver cancer drug design.

肝癌发生发展与机体各种代谢失调紧密相关。研究表明肝癌的发生伴随着糖原代谢失调，但糖原代谢紊乱和肝癌的关系及调控机制尚不清晰。申请人已发表数据表明Hippo信号通路的调控在肝脏稳态维持和肿瘤发生中具有重要作用。而前期未发表数据显示在Hippo通路核心激酶Mst1/2肝脏特异性缺失的小鼠肝癌中，与其对照小鼠肝脏组织相比均存在局部糖原累积区域；而糖原累积症模型G6PC肝脏特异性敲除小鼠会出现肝脏肿大和Hippo通路下游的Yap激活；更重要的是，利用糖原合成抑制剂喂饲Mst1/2 DKO小鼠，短期干预即可缓解该基因缺失造成的肝脏肿大。本基金项目中，我们将在实验动物、分子生物学及生物化学等层面分析糖原累积、Hippo信号通路活性与肝癌发生发展的相关性；明确糖原代谢紊乱对肝癌发生发展的作用和影响并初步探索糖原累积调控肝细胞增殖及肝癌发生的机制，为我国肝癌的防治提供一定的新思路。

肝癌发生发展与机体各种代谢失调紧密相关。研究表明肝癌的发生伴随着糖原代谢失调，但糖原代谢紊乱和肝癌的关系及调控机制尚不清晰。申请人数据显示在Hippo通路核心激酶Mst1/2肝脏特异性缺失的小鼠肝癌中，与其对照小鼠肝脏组织相比均存在局部糖原累积区域；而糖原累积症模型G6PC肝脏特异性敲除小鼠会出现肝脏肿大和Hippo通路下游的Yap激活；更重要的是，利用糖原合成抑制剂喂饲Mst1/2 DKO小鼠，短期干预即可缓解该基因缺失造成的肝脏肿大。本项目执行中，我们在实验动物、分子生物学及生物化学等层面分析了糖原累积、Hippo信号通路活性与肝癌发生发展的相关性；明确了糖原代谢紊乱对肝癌发生发展的作用和影响并初步探索糖原累积调控肝细胞增殖及肝癌发生的机制，为我国肝癌的防治提供一定的新思路。