TSC/mTORC1 mediates mTORC2/AKT1 signaling in c-MYC-induced murine hepatocarcinogenesis via centromere protein M. TSC/mTORC1 mediates mTORC2/AKT1 signaling in c-MYC-induced murine hepatocarcinogenesis via centromere protein M

Activated mTORC2/AKT signaling plays a role in hepatocellular carcinoma (HCC). Research has shown that TSC/mTORC1 and FOXO1 are distinct downstream effectors of AKT signaling in liver regeneration and metabolism. However, the mechanisms by which these pathways mediate mTORC2/AKT activation in HCC are not yet fully understood. Amplification and activation of c-MYC is a key molecular event in HCC. In this study, we explored the roles of TSC/mTORC1 and FOXO1 as downstream effectors of mTORC2/AKT1 in c-MYC-induced hepatocarcinogenesis. Using various genetic approaches in mice, we found that manipulating the FOXO pathway had minimal impact on c-MYC-induced HCC. In contrast, loss of mTORC2 inhibited c-MYC-induced HCC, an effect that was completely reversed by ablating TSC2, which activated mTORC1. Additionally, we discovered that p70/RPS6 and 4EBP1/eIF4E act downstream of mTORC1, regulating distinct molecular pathways. Notably, the 4EBP1/eIF4E cascade is crucial for cell proliferation and glycolysis in c-MYC-induced HCC. We also identified centromere protein M (CENPM) as a downstream target of the TSC2/mTORC1 pathway in c-MYC-driven hepatocarcinogenesis, and its ablation entirely inhibited c-MYC-dependent HCC formation. Our findings demonstrate that the TSC/mTORC1/CENPM pathway, rather than the FOXO cascade, is the primary signaling pathway regulating c-MYC-driven hepatocarcinogenesis. Targeting CENPM holds therapeutic potential for treating c-MYC-driven HCC. Overall design: Comparative gene expression profiling analysis of RNA-seq data for the mouse c-MYC/MCL1 HCCs treated with MLN0128, everolimus, vehicle as well as C57BL/6 wild-type normal livers

激活的mTORC2/AKT信号通路（mTORC2/AKT signaling）在肝细胞癌（hepatocellular carcinoma, HCC）中发挥重要作用。已有研究证实，TSC/mTORC1与FOXO1是AKT信号通路（AKT signaling）在肝再生与代谢进程中的两类不同下游效应分子。然而，上述通路介导肝细胞癌中mTORC2/AKT激活的具体分子机制尚未完全阐明。c-MYC基因的扩增与激活是肝细胞癌发生发展中的关键分子事件。本研究旨在探讨TSC/mTORC1与FOXO1作为mTORC2/AKT1下游效应分子，在c-MYC诱导的肝细胞癌变过程中的调控作用。本研究通过小鼠体内多种遗传学操作手段，发现干预FOXO通路对c-MYC诱导的肝细胞癌几乎无显著影响。与之相反，mTORC2缺失可抑制c-MYC诱导的肝细胞癌，而该效应可通过敲除TSC2以激活mTORC1而完全逆转。此外，本研究还发现p70/RPS6与4EBP1/eIF4E均作用于mTORC1下游，分别调控不同的分子通路。值得注意的是，4EBP1/eIF4E信号级联在c-MYC诱导的肝细胞癌中，对细胞增殖与糖酵解过程至关重要。本研究同时鉴定出着丝粒蛋白M（centromere protein M, CENPM）是c-MYC驱动的肝细胞癌变过程中TSC2/mTORC1通路的下游靶标，敲除CENPM可完全抑制c-MYC依赖型肝细胞癌的形成。本研究结果表明，调控c-MYC驱动的肝细胞癌变的核心信号通路为TSC/mTORC1/CENPM通路，而非FOXO信号级联。靶向CENPM有望为c-MYC驱动的肝细胞癌治疗提供新的潜在策略。【整体实验设计】：对经MLN0128、依维莫司（everolimus）、溶剂（vehicle）处理的小鼠c-MYC/MCL1肝细胞癌样本，以及C57BL/6野生型正常肝组织的RNA测序（RNA-seq）数据开展比较基因表达谱分析。