Wip1在肾透明细胞癌中转录调控及转录后修饰机制及其临床意义研究

Clear cell renal cell carcinoma（CCRCC） has a strong latency, the early symptoms are not obvious, and CCRCC in later stage is not sensitive to Radiation and chemotherapy and easy for transfer. If tumor markers of renal carcinoma early stage are found, and those tumor markers could be cancer gene for treating CCRCC, then the above two problems can be solved, and the cure rate of CCRCC will be improve significantly. The applicant does a study recently to find that Wip1 in CCRCC tissue and CCRCC cell lines shows a high expression, and the high expression of Wip1 is closely related to malignant of CCRCC and the prognosis of patients. Combined with our recent research progress about Wip1 and P53, therefore, the project firstly imagines that from intervention of Wip1 transcriptional regulation and Wip1 post-translational modifications to improve the diagnosis and treatment of CCRCC strategy. The project proposes to discuss Wip1 in CCRCC, P53 mechanism and Wip1 transcriptional regulation mechanism from molecular level, cellular level and animal mode of level, then to design and build wip1 transcription factors specific inhibitors. Finally, CCRCC - Wip1 database is established and Wip1 in CCRCC diagnosis and treatment and prognostic value is analyzed. Our findings will not only further uncover the role of Wip1 in clear cell renal cell carcinoma progression, but also offer a potential therapeutic target for clear cell renal cell carcinoma.

肾透明细胞癌隐秘性强，早期症状不明显；肾癌晚期对放化疗不敏感且容易转移。如果找到既能作为肾癌早期癌标，又能作为肾癌治疗靶点的癌基因，以上两个问题能得到解决，则肾癌的治愈率明显提高。申请人新近的研究首次发现Wip1在肾癌组织及肾癌细胞株均呈高表达，并且Wip1的高表达与肾癌的恶性程度、肾癌病人的预后密切相关。结合我们近期有关于Wip1与P53的研究进展，本项目首次设想：从干预wip1转录调控及Wip1转录后修饰两方面来提高肾癌的诊疗策略。本课题拟从分子细胞水平、动物模型层面，探讨肾癌中Wip1与P53作用机制及wip1转录调控机理。再设计与构建wip1转录因子特异性抑制剂。最后建立肾透明细胞癌-Wip1数据库，分析Wip1在肾透明细胞癌诊疗与预后的价值。结果不仅将进一步阐明Wip1在肾透明细胞癌发生、发展及侵袭转移中的作用，同时还可能为寻找肾透明细胞癌的新的治疗靶点提供重要的理论依据。

野生型p53诱导的磷酸酶1（Wip1）在乳腺癌、肾细胞癌等癌组织中存在扩增和过表达，前期实验中我们发现Wip1在肾透明细胞癌（ccRCC）组织中过表达，且与ccRCC的恶性进展及转移密切相关。但是Wip1在ccRCC中被如何调控尚未可知，是否存在有效的调控机制仍有待进一步明确。非编码RNA是一类由基因组转录却无蛋白质编码潜能的RNA，如microRNA，具有分布广泛、种类繁多和功能丰富等特点。首先，在项目实施过程中我们逐步建立并完善了肾癌的临床生物样本库，目前已搜集了超过400例肾透明细胞癌癌组织、癌旁组织和血液样本，定期随访并收集了完善的预后数据，为申请项目的实施提供了有力支持。其次，课题组最新研究发现非编码微小RNA-23b可靶向调控Wip1抑制肾透明细胞癌细胞的侵袭及转移，联合miR-23b和Wip1可作为预测肾透明细胞癌预后的有效指标。最后，前期研究中我们发现Wip1在部分ccRCC组织中异常高表达，且伴随肿瘤血管生成显著增加。为探究Wip1异常高表达的原因，我们综合检测分析该部分临床标本中Wip1的DNA、RNA及蛋白水平，最终确定Wip1异常高表达是因Wip1基因截短突变所致。 我们的研究为开发临床治疗肾细胞癌癌的新方法提供了分子新靶点、新通路与实验数据， 有潜在的应用价值。