USF1介导膀胱癌奥沙利铂耐药的分子机制研究

Drug resistance of bladder cancer is the major cause for chemotherapy failure. Oxaliplatin induces apoptosis by activating p38 MAPK to exert its antitumor effect. However, p38 MAPK pathway was activated in drug-resistant bladder cancer without the onset of apoptosis. Previously, we found that downstream transcription factor USF1 is the key gene mediating the drug resistance induced by p38 MAPK signaling, but the underlying mechanism is elusive. Further study revealed that USF1 expression is positively associated with GSTP1 and survivin, and GSTP1 and survivin promoters contain several potential USF1 binding sites, suggesting they may be regulated by USF1.We proposed that the transcription of GSTP1 and survivin induced by p38 MAPK/USF1 pathway is one of the mechanism by which bladder cancer develop resistance against Oxaliplatin. This study is aimed to employ technology of molecular and cellular biology, in combination with clinical samples and documents, to prove that aberrant expression of USF1 promotes the transcription of GSTP1 and survivin to contribute to drug resistance of bladder cancer.This study may identify potential target of reversing drug resistance,and provide molecular marker for clinical diagnosis and prognosis.

膀胱癌产生耐药性是导致化疗失败的重要原因。化疗药奥沙利铂通过激活p38 MAPK通路诱导凋亡是其抗肿瘤效应的关键途径之一。膀胱癌耐药细胞株p38 MAPK通路同样激活却无法诱导凋亡，反而促进耐药性的产生。我们前期发现膀胱癌耐药细胞异常表达的p38 MAPK通路下游转录因子USF1是耐药性产生的关键基因，但其作用机制不详。进一步研究表明USF1表达量与耐药关键酶GSTP1和抗凋亡因子survivin呈现出正相关，而且GSTP1和survivin的启动子存在多个USF1潜在结合位点，提示他们转录很可能受USF1调控。我们认为p38 MAPK/USF1通路激活促进GSTP1和survivin转录表达是膀胱癌产生奥沙利铂耐药的机制之一。本项目拟采用分子生物学和细胞生物学技术，结合对临床膀胱癌患者标本和资料的分析，证明异常表达的USF1通过促进GSTP1和survivin的转录诱导膀胱癌产生耐药性。

膀胱癌产生耐药性是导致化疗失败的重要原因。化疗药奥沙利铂通过激活p38 MAPK通路诱导凋亡是其抗肿瘤效应的关键途径之一。本项目拟采用分子生物学和细胞生物学技术，结合对临床膀胱癌患者标本和资料的分析，证明异常表达的USF1通过促进GSTP1survivin的转录诱导膀胱癌产生耐药性。我们通过一系列的实验，确定了 USF1 在膀胱癌细胞奥沙利铂耐药性的产生过程中所发挥的关键作用；确定了 USF1 通过促进 GSTP1 和 survivin 的转录表达得以参与膀胱癌奥沙利铂耐药性的产生；确定了 USF1 的高表达确实是造成膀胱癌患者对奥沙利铂耐药性的分子机制之一，使 USF1 成为临床奥沙利铂治疗诊断预后分子标记。