MSH2/circLIFR复合体通过DNA损伤信号通路调控膀胱癌铂类化疗敏感性的作用及其机制研究

基于顺铂（CDDP）的化疗是转移性膀胱癌的标准治疗，但是大部分患者会短期内出现CDDP耐药。研究已证实DNA错配修复（MMR）系统中的关键蛋白MSH2，在膀胱癌CDDP耐药中扮演重要角色。我们前期发现环状RNA circLIFR在膀胱癌中低表达，且在细胞核内富集；初步检测显示circLIFR可与MSH2结合，过表达circLIFR可提高膀胱癌细胞对CDDP的敏感性。本研究拟进一步观测膀胱癌circLIFR与MSH2蛋白的相互作用；通过建立circLIFR及MSH2稳定过表达/抑制体系，探讨MHS2/circLIFR复合体对DNA损伤信号通途ATM/P73及膀胱癌生物学功能的影响。本项目旨在阐明MSH2/circLIFR复合体调控DNA损伤修复信号通路影响肿瘤细胞化疗敏感性的全新作用方式，为晚期膀胱癌治疗提供新靶点。

Bladder cancer is one of the most common cancer in the world and the most costly cancer to treat on a per patient basis due to required clinical surveillance and multiple therapeutic interventions. Clinically, cisplatin (CDDP)-based gemcitabine and cisplatin (GC) regimen has become a standard-of-care treatment for muscle-invasive bladder cancer (MIBC). The DNA mismatch repair (MMR) system guards against genomic instability and mutations. MMR genes MutS homolog 2 (MSH2) plays a crutial role in chemoresistance of baldder cancer cells. we discovered that circLIFR, a circRNA generated from the circularization of LIFR gene, is significantly downregulated in bladder cancer patients. Subsequent studies showed that circLIFR could interact with MSH2 to mediate CDDP-sensitivity in bladder cancer cell lines. In the project, we intend to confirm the interaction of MSH2 with circLIFR. Furthermore, we will establish MSH2 and circLIFR stable.overexpression/restraint system, and explore the role of MSH2/circLIFR complex onmediate CDDP-sensitivity through MutSα/ATM-p73 axis in bladder cancer. This work will provide a systematic elucidation into the regulation of circLIFR on the function of MSH2, and indicate that circLIFR and MSH2 may be act as promising therapeutic targets for CDDP-resistant bladder cancer.