化学致癌是膀胱癌明确的致病因素，正常的DNA修复功能是预防突变和肿瘤发生的重要机制。以往多项研究发现DNA修复蛋白XPC表达缺失是膀胱癌的高频事件，它不仅直接影响DNA修复能力，而且在DNA损伤应答（DDR）中起潜在的信号作用,影响膀胱癌的发生，耐药和高异质性的生物学行为。最近我们发现XPC缺失在顺铂介导的DNA损伤应答中促进自噬的发生,细胞表现为耐药和染色体畸变增高。同时发现DDR关键分子GADD45a 不能诱导表达和p-ATM(ser1981)过度活化并与自噬关系密切。我们推测XPC缺失促进自噬可能通过GADD45a或ATM的活化诱导新的基因组毒性诱导的靶向自噬实现的，最终改变细胞命运。本研究采用现代生物技术重点探索膀胱癌XPC缺失促进自噬的分子机制，为确立XPC在DDR中新的信号功能调控自噬发生提供直接证据。理论的突破将有助于我们更深入全面地理解肿瘤耐药和高遗传不稳定性的关系。

The chemical carcinogen is the established risk factors of bladder cancer. DNA repair plays an essential role in preventing deleterious DNA damage-induced effects, such as mutation accumulation and bladder tumor occurrence.We previously reported that some bladder cancers, which were characterized by the attenuated expression of XPC, not only appeared to have reduced DNA repair capability, but also influenced carcinogenesis and biological behavior of high heterogenesity via its’ potiential signal transduction in DNA damage response(DDR).We also found that XPC deficiency in baldder cancer cell could promoted autophgy process in response to cisplatin-mediated DDR.The procession was tightly related to the events of both down regulated expression of GADD45a and over active ATM phosphated. These finding give rise the hypothesis that defect of XPC in bladder cancer could inpact the autophagy via inducing canonical pathway or a new genotoxin-induced target autophay pathway, and eventually change damaged cells biological behavior and fate. The project is expected to provide new evidence for new function of XPC in modulating auophgy occurrence in DDR.It also will provide new insight into understand molecular mechanism of chemoresistance and higher genetic instability in human bladder cancer.