POH1与TGF-β信号交互调控对肝癌细胞恶性表型的影响及分子机制

TGF-β signaling plays essential roles in the development and progression of hepatocellular carcinomas (HCC), mainly through its implications in the processes of EMT induction, the acquisition of stemness properties and drug resistance, as well as pro-angiogenesis. Our previous data indicates that a reciprocal regulation of TGF-β signaling and POH1, a deubiquitinase aberrantly elevated in HCC tissues, may occur in HCC cells. POH1 positively regulates TGF-β signaling and contributes to TGF-β-induced EMT, whereas TGF-β can increase the abundance of the nuclear POH1. In addition, the analyses of whole-genome transcriptional profiles and LC-MASS show that several POH1-regulated genes and -interacted proteins identified are related to TGF-β signaling, indicating the association between POH1 and TGF-β signaling. In the present study, we will address the following questions:1) how POH1 regulates TGF-β signaling and thereby promotes TGF-β-induced malignant phenotypes in HCC cells; 2) how TGF-β signaling enhances POH1 abundance in nuclear compartment and whether the upregulation of the nuclear POH1 contributes to TGF-β-promoted malignance in HCC; 3) whether there is a clinical relevance of the mutual regulation of POH1 and TGF-β signaling in HCC patients. The study will provide insight into the regulation of POH1-TGF-β signaling in malignant diseases and help develop novel therapeutic strategies.

TGF-β信号通路的异常在肝癌的发生发展过程中起重要作用。我们的初步研究数据提示，在肝癌组织中异常高表达的去泛素化酶POH1与TGF-β信号通路之间可能存在交互调控关系：POH1能够促进TGF-β信号通路的活化，参与TGF-β诱导的EMT等恶性表型；TGF-β信号活化可上调核POH1蛋白水平；此外，利用高通量分析发现，POH1所调控的基因群和其相互作用蛋白中均含TGF-β信号通路的相关分子。本项目将在此基础上进一步研究：1)POH1如何调控TGF-β信号并影响肝癌细胞的恶性表型；2)TGF-β信号如何上调核POH1蛋白水平，有何生理学意义；3)临床肝癌标本中POH1表达与TGF-β信号通路状态是否存在相关性及其生物学意义。本研究将揭示POH1-TGF-β信号交互调控效应和机制，为阐明肝癌发生发展及相关治疗策略设计提供理论线索。

TGF-β信号通路的高度活化促进肝癌的进展，但是其分子机制，尤其是转录后的调节机制尚不明确。通过分析肝癌的表达谱数据库及对临床肝癌样本的检测。本研究发现，POH1的表达与肝癌中TGF-β信号的活化程度及肝癌的进展程度正相关。功能实验结果表明，POH1促进TGF-β信号的传导并增强肝癌细胞在体内和体外的转移能力。在POH1缺失的小鼠肝脏组织中，TGF-β受体的表达水平显著下调。在机制上，本研究发现POH1通过调控TGF-β受体及CAV1蛋白的泛素化水平，抑制溶酶体介导的TGF-β受体降解，从而影响其蛋白稳定性。本项研究揭示了POH1在肝癌细胞中的高表达可促进TGF-β信号通路活化并促进肝癌进展及其潜在的分子机制，为临床上抑制肝癌转移策略的研究提供了新的思路和线索。