PSMD10通过p53对膀胱癌侵袭进展的调控作用及机制研究

Bladder cancer is a common urological malignancy. Most newly diagnosed bladder cancers are non-muscle invasive bladder cancers, which are easy to recur and develop into muscle invasive bladder cancers. Studies have shown that the tumor suppressor gene p53 plays a key role in the progression of bladder cancer, but the related molecular mechanisms and the key genes regulating the up-stream of p53 have not been elucidated. In this study, we screened out the key gene PSMD10 which regulated bladder cancer progression through the whole transcriptome sequencing, and found that PSMD10 expression level correlated with muscle invasion and was negatively correlated with p53 expression level. Furthermore, PSMD10 promoted the degradation of p53 by up-regulating the expression of MDM2, which promoted the progression of bladder cancer. Therefore we propose our hypothesis: PSMD10 directly binds with MDM2, the important regulatory protein of p53, which inhibits the self-ubiquitination and degradation of MDM2. This change results in promoting the degradation of p53 by MDM2 and the functional inactivation of p53, which ultimately promotes the progression of bladder cancer. This project intends to study the regulatory roles and molecular mechanisms of PSMD10 on the progression of bladder cancer, through four aspects including clinical specimens, humanized orthotopic tumor transplantation model, transgenic animal models and tumor cell lines. We also plans to elucidate the clinical significance of PSMD10 in the molecular classification, progression prediction and targeted therapy of patients with bladder cancer.

膀胱癌是泌尿系最常见的恶性肿瘤之一，初诊时多为非肌层浸润性膀胱癌，术后易复发或进展为肌层浸润性膀胱癌。研究表明抑癌基因p53在膀胱癌进展中发挥关键作用，但相关分子机制以及调控p53上游的关键基因尚未阐明。课题组前期通过全转录组测序筛选出调控膀胱癌侵袭进展的关键基因PSMD10，其高表达和肌层浸润正相关，和P53表达负相关，且PSMD10上调MDM2表达导致p53降解，从而促进膀胱癌侵袭进展。故我们提出科学假设：PSMD10与p53上游的重要调节蛋白MDM2直接结合，抑制MDM2的自身泛素化降解，从而促进MDM2对p53蛋白的降解，使p53的功能失活，最终促进膀胱癌侵袭进展。本项目拟通过临床标本、人源化原位肿瘤移植模型、转基因动物模型、肿瘤细胞系四个层面研究PSMD10对膀胱癌侵袭进展的调控作用及分子机制，并明确PSMD10在膀胱癌患者分子分型、进展风险预测及靶向治疗中的临床意义。

膀胱尿路上皮癌可分为非肌层浸润性膀胱癌（non-muscle invasive bladder cancer, NMIBC）和肌层浸润性膀胱癌（muscle invasive bladder cancer, MIBC），其中MIBC预后明显较差，容易进展和复发。而NMIBC进展为MIBC的具体机制仍不明确，有研究指出P53通路的改变是MIBC的特征性分子标志。前期我们通过转录组测序发现PSMD10基因在膀胱癌中表达明显上调。后续我们通过研究发现PSMD10/Gankyrin在肿瘤组织中高表达，其与肿瘤的级别、浸润深度等明显相关，并且其表达与MDM2表达成正相关，与P53表达成负相关的关系。通过查阅文献及前期研究基础后我们产生以下推测：该基因作为P53通路的上游基因能与MDM2结合并促进其泛素化降解，从而使得细胞内MDM2增多，促进对p53的降解，最终可促进膀胱癌进展。在本项研究中我们通过临床标本验证、生物信息学分析、细胞生物学实验、动物模型构建等方法对PSMD10在膀胱癌中的作用加以阐释和验证，为膀胱癌进展标志物及靶向药物筛选提供理论和实践基础。