Rox8/TIAL1调控Hippo信号通路的机制研究

Hippo信号通路从果蝇到人高度保守,其异常与肿瘤的发生发展密切相关，但其调控机制尚未完全明晰。我们利用黑腹果蝇作为模式生物进行遗传筛选，发现RNA结合蛋白Rox8是Hippo通路的一个新调控因子，通过直接结合yki3'UTR，促进ykimRNA降解,进而降低Yki蛋白的水平。经生物信息分析，在脑癌LGG患者中TIAL1（Rox8的同源基因）与YAP（Yki的同源基因）在表达水平和病人生存率两个层面呈现显著负相关。本项目拟在前期研究基础上，深入研究以下三个科学问题: 1）Rox8促进ykimRNA降解的分子机制？2）该调控机制从果蝇（Rox8-Yki）到人(TIAL1-YAP)是否保守？3）临床上，TIAL1是否通过调控YAP的表达参与肿瘤发生与发展？本项目将进一步完善Hippo信号通路调控网络，揭示Rox8/TIAL1在癌症中的作用，为相关疾病的治疗提供新的方案及潜在的药物靶点。

The Hippo signaling is highly conserved from Drosophila to human. Dysregulation of the Hippo pathway has been implicated in various cancers, whereas the underlying mechanism remains poorly unveiled. Utilizing Drosophila melanogaster as a model organism, we performed a genetic screen and characterized the RNA binding protein Rox8 as a new regulator of the Hippo pathway. Mechanistically, Rox8 inactivates the Hippo pathway by directly binding to yki mRNA 3'UTR and decreasing Yki protein level via mRNA decay. Bioinformatics analysis showed that TIAL1 (the human ortholog of Rox8) displayed a significant negative correlation with YAP (Yki counterpart in human) at both expression level and clinical survival rate in LGG brain cancer patients. Based on these preliminary data, we will further elaborate the following three scientific questions: 1）What is the mechanism whereby Rox8 promotes yki mRNA degradation? 2) Whether the above mechanism is conserved from Drosophila to human? 3) Clinically, whether TIAL1 contributes to cancer progression by regulating YAP expression? This project aims to improve the regulatory network of the Hippo pathway, elucidate the role of Rox8/TIAL1 in the development of cancers, and provide novel therapeutic strategies and potential drug targets against the diseases.