野生型IDH1促进非小细胞肺癌发生发展的机制研究及其对预后预测效果的评价

Our recent studies have found that the overexpressed wild type IDH1 (IDH1wt) in non-small cell lung cancer (NSCLC) tissue could promote tumor progression and was one of the independent factor for shorter survival. Additionally, in preliminary research, we have also found that the over-expression of IDH1wt could be regulated by TRIB3 and then potentially activate the serine metabolism pathway by regulating PSAT1 which is one of most key serine biosynthesis enzyme. Based on these findings, we will carry out research as followed in the preset study. firstly, to explore the mechanism of TRIB3 maintaining high expression of IDH1wt in NSCLC from transcription and protein stability. Secondly, to exlpore the mechanism of PSAT1 expression and Serine activity regulated by IDH1wt by knockdown and recovery tests. Thirdly, to explore the mechanism of TRIB3-IDH1wt-PSAT1-Serin pathway in the induction and/or maintenance of NSCLC stem cell characteristics. Finally, to establish the statistical model for prognosis prediction of NSCLC based on the molecular characteristics of TRIB3-IDH1wt-PSAT1-Serin pathway. The study will demonstrate the key mechanism that IDH1wt regulated by TRIB3 and then activate PSAT1 to affect the serine metabolic pathway, which would promote the NSCLC stem cell characteristic and then drive NSCLC development. In addition, the findings of this study will establish statistical model for prognosis prediction of NSCLC and provide scientific evidence for new strategies of NSCLC diagnosis and treatment.

项目组前期发现野生型IDH1(IDH1wt)高表达于非小细胞肺癌(NSCLC)，是预后不良指标；进一步预实验发现IDH1wt高表达受接头蛋白TRIB3调节，且IDH1wt正调控丝氨酸(Serine)代谢通路关键酶PSAT1表达。本项目在此基础上，拟①从转录和蛋白稳定性两方面，探索NSCLC中TRIB3维持IDH1wt高表达的机制；②经敲降和回复试验，解析IDH1wt正调控PSAT1表达和上调Serine的机制；③探索TRIB3-IDH1wt-PSAT1-Serine通路在肿瘤干细胞特性诱导和维持中的作用；④统计学方法构建通路分子特征为核心的预后预测模型。通过上述研究，阐明NSCLC中IDH1wt受TRIB3调控维持高表达，继而上调PSAT1-serine通路，促进肿瘤干细胞特性，发挥促癌作用的关键机制；建立能指导临床的预后预测分子模型，从而为开发新的NSCLC诊治策略提供科学依据。

肿瘤干细胞（cancer stem cells, CSCs）是肿瘤发生转移、复发和耐药的根源，肿瘤干细胞显出与非干细胞不同的代谢特征，用于维持干细胞运转所需能量和可塑性潜力。除了糖代谢和谷氨酰胺代谢以外，丝氨酸、甘氨酸一碳代谢对于维持非小细胞肺癌（Non-small cell lung cancer, NSCLC）的干细胞特性也至关重要,因此靶向CSCs的代谢重编程有望成为有效抑制NSCLC的新策略和新方法。我们的早期工作证实：野生型IDH1高表达于NSCLC，是预后不良指标。在本项目中，我们进一步证实了①野生型IDH1正调控丝氨酸从头合成途径代谢关键酶PHGDH和PSAT1的表达，激活丝氨酸从头合成途径；②野生IDH1与PHGDH相互作用阻碍PHGDH泛素化和蛋白降解；③野生型IDH1通过维持FXR1稳定性，增强PAST1的转录活性；④野生型IDH1通过激活丝氨酸代谢维持NSCLC干细胞特性；⑤靶向IDH1-丝氨酸从头合成途径调控通路使NSCLC对化疗敏感。该工作拓展了我们对NSCLC肿瘤代谢重编程的认识。此外我们自主设计了多肽类先导物阻断野生型IDH1-丝氨酸代谢调节信号，并证实靶向IDH1-PHGDH和IDH1-FXR1的多肽先导物能够有效抑制野生型IDH1对丝氨酸从头合成途径的激活效应，有望成为治疗NSCLC的新型药物，为高表达野生型IDH1的NSCLC患者提供全新的诊疗策略。