肝细胞MEN1/Sirt1调控NAFLD相关肝细胞癌发生的关键作用

代谢异常和衰老导致的NAFLD日益成为肝癌的重要风险因素。肝细胞内特定抑癌基因是代谢异常和肝脏肿瘤发生之间的关键调控者。我们前期发现肝细胞内抑癌基因MEN1维持肝脏脂代谢平衡并随着衰老而减少，肝细胞特异MEN1敲除小鼠（LMKO）发生NAFLD并在老年自发肝癌。长寿基因Sirt1是MEN1调节脂代谢的重要相互作用分子，并能抑制肿瘤发生。因此我们推测MEN1/Sirt1协同维持肝脏代谢平衡抑制肿瘤发生，拟通过LMKO小鼠模型表型研究及大样本临床分析明确MEN1在肝癌发生中作用；并基于前期RNAseq结果，探索MEN1/Sirt1通过直接组蛋白去乙酰化或抑制β-catenin活性调控脂代谢通路关键因子SCD1和轴突导向通路关键因子Ephrins的精确机制；旨在阐明MEN1对肝癌发生的关键作用机制，从分子水平解释衰老、脂代谢异常和肿瘤发生之间的关键联系，为防治NAFLD相关肝癌提供新的干预靶点。

Metabolism disorder and aging related NAFLD is becoming an important risk factor of liver malignancy worldwide. It’s been established that specific tumor suppressors in hepatocyte play vital role in metabolism disorder and hepatocarcinogensis. Our previous study have revealed tumor suppressor MEN1 is critical for hepatic lipid metabolism homeostasis and tapered with aging. Mice with liver-knockout of MEN1 (LMKO) suffer from NAFLD and thus HCC during aging. The “longevity gene” Sirt1 is an established interacting factor of MEN1in preventing liver steatosis, and reported to suppress carcinogenesis. Accordingly, we speculate MEN1/Sirt1 cooperatively maintain hepatic lipid metabolism homeostasis and inhibit hepatocarcinogensis. We aim to clarify the role of MEN1 in HCC development through comprehensive phenotype study in LMKO mice along with analysis in large clinical samples. Furthermore, we will explore the precise mechanism of MEN1/Sirt1in regulating lipid metabolism pathway and axon guidance pathway, focusing on the effect of histone deacetylation and β-catenin activity inhibition on expression of two genes, SCD1 and Ephrins . Our findings will clarify the critical metabolic mechanism of MEN1 in hepatocarcinogensis, as well as molecular connection among aging, lipid metabolism and hepatocarcinogensis, thus providing new target for prevention of NAFLD related liver cancer.