TET1/exosome-derived miR-22-3p/BTG1信号轴在膀胱癌化疗耐药中的作用与分子机制

膀胱癌化疗耐药是临床中亟待攻克的难题。我们研究发现miR-22-3p在膀胱癌耐药细胞及其外泌体中异常高表达，显著促进化疗耐药。但是机制尚不清楚。进一步研究发现：（1）TET1在耐药膀胱癌组织中高表达；（2）耐药细胞中pri-miR-22启动子区羟甲基化水平升高；敲低TET1后，miR-22-3p的表达显著下降；（3）miR-22-3p潜在靶向结合耐药相关基因BTG1。据此，我们推测：在耐药细胞中，TET1催化pri-miR-22启动子区羟甲基化，促进miR-22-3p的胞内表达和胞外分泌，靶向抑制自身和周围细胞的BTG1基因，促进微环境肿瘤细胞群体耐药。项目拟：(1)探索TET1/exosome-derived miR-22-3p/BTG1信号轴的分子机制及其在膀胱癌化疗耐药中的作用；（2）分析该信号轴与膀胱癌临床特征的相关性。研究结果将为揭示膀胱癌耐药新机制和寻找治疗新靶点提供理论依据。

Bladder cancer chemotherapy resistance is an urgent problem to be overcome in clinical practice. Our research found that miR-22-3p was abnormally highly expressed in bladder cancer resistant cells and exosomes, which significantly promoted chemotherapy resistance. However, the mechanism is unclear. Further research found that: (1) TET1 was highly expressed in drug-resistant bladder cancer tissues; (2) the level of hydroxymethylation in the pri-miR-22 promoter region in drug-resistant cells increased; after knocking down TET1, the expression of miR-22-3p decreased significantly; (3) miR-22-3p potentially targeted the drug resistance related gene-BTG1. Based on these, we speculate that in drug-resistant bladder cancer cells, TET1 catalyzes hydroxymethylation of the pri-miR-22 promoter region, promotes intracellular expression and extracellular secretion of miR-22-3p, and targets self- and surrounding cells’ BTG1 gene, promotes drug resistance in microenvironmental tumor cell populations. The project is intended to: (1) explore the molecular mechanism of the TET1 / exosome-derived miR-22-3p / BTG1 signal axis and the role in chemotherapy resistance of bladder cancer; (2) analyze the correlation between this signal axis and the clinical characteristics of bladder cancer. The research results will provide a theoretical basis for revealing the new mechanism of bladder cancer resistance and finding new therapeutic targets.