IGF/FOXO信号轴调控蛋白酶体活性参与肝癌干细胞自我更新维持的机制研究

It has been demonstrated that the activity of proteasomes is down-regulated in multiple Cancer Stem Cells (CSCs), but the mechanisms have not been elucidated yet. Our previous study has shown that proteasomes is low activity in liver CSCs, which participate in maintaining the self-renewal of CSCs through JNK/Smad3L/Nanog pathway.With literature research and chip screening as well as our previous work, we propose: "IGF signaling pathways down-regulate the proteasome activity by negatively regulating the expression of FOXO transcription factor, which cause the lower expression of multiple proteasome components, and eventually benefits the maintenance of self-renewal status of liver cancer stem cells". This study will extend the finding of our previous work, and unfold the detail mechanism of IGF signal maintaining the self-renewal of liver CSCs by regulating the activity of proteasome. This work is meaningful for uncovering the role and mechanism of the extensively proteasome low-activity in CSCs, extending the knowledge about the self-renewal mechanisms of CSCs, guiding the clinical application of proteasome inhibitor, and development of new strategies for tumor therapy.

新近研究发现蛋白酶体在多种肿瘤干细胞中活性降低，但作用未知。前期在青年基金的支持下，我们率先证明肝癌干细胞中蛋白酶体呈低活性状态，且可通过JNK/Smad3L/Nanog信号通路的活化，参与肝癌干细胞自我更新的维持。但目前肿瘤干细胞中蛋白酶体活性为何会下调，其上游调控机制尚不清楚。我们的前期研究发现，在肝癌干细胞中IGF信号通路参与自我更新的维持，且与蛋白酶体的活性调控有关。结合文献检索与芯片筛查，我们提出："在肝癌干细胞中IGF信号通路可通过负调控FOXO的活性，进而降低蛋白酶体系统中多个组分的表达，诱发蛋白酶体的低活性状态，维持肝癌干细胞的自我更新"。本研究将延续前一课题，打通IGF信号借由调控蛋白酶体活性，参与肝癌干细胞自我更新维持的完整机制。该研究将丰富人们对肿瘤干细胞自我更新调节机制的认识，指导蛋白酶体抑制剂的临床应用，推动新肿瘤治疗策略的开发，具有重要的理论和实践意义。

随着人们对肿瘤干细胞自我更新机制研究以及肿瘤微环境研究的持续深入，两者之间的协同作用被逐步发掘出来。本项目从微环境IGF信号入手，发现在肝癌干细胞中IGF信号通路可通过调控FOXO的活性，进而降低蛋白酶体系统中关键组分POMP的表达，诱发蛋白酶体的低活性状态，维持肝癌干细胞的自我更新。在研究过程中，结合课题方向，对IGF信号及其下游分子STAT3，以及肿瘤自我更新关键基因LSD1的蛋白酶体代谢调控等内容开展拓展研究。研发结果表明微环境IGF信号可能通过多条途径调节Nanog的表达，而多种微环境信号也可以通过AKT、STAT3等关键中间分子调控Nanog的表达，这些分子本身受到泛素蛋白酶体系统的代谢调控，而Nanog又可反过来负反馈调控蛋白酶体活性，从而形成一个微环境调控细胞自我更新的复杂网络。该研究将丰富人们对肿瘤干细胞自我更新调节机制的认识，指导蛋白酶体抑制剂的临床应用，推动新肿瘤治疗策略的开发，具有重要的理论和实践意义。