肾癌(RCC)产生耐药以致复发转移是其致死率高的根本原因。已报道Yes相关蛋白(YAP)在肿瘤发展和耐药过程中发挥着重要作用。申请者前期研究发现YAP可增加肾癌细胞对靶向药物的抵抗，并且YAP上调RCC发生、发展及产生耐药过程中的关键蛋白：低氧诱导因子-2α(HIF-2α)，对HIF-1α无影响。我们科学假设YAP通过调控HIF-2α增加肿瘤干细胞(CSCs)特性从而促进RCC耐药。本课题拟通过染色质免疫共沉淀等技术确定YAP对HIF-2α的调控机制，利用基因转染或封闭等技术明确YAP/HIF-2α信号通路调控细胞生长和CSCs特性的分子机制，在体内外水平探讨阻断YAP对肾癌耐药的影响，并结合临床样本检测、分析癌症基因组图谱数据库等方法明确YAP表达水平与靶向药物疗效的关系，为改善患者预后和靶向药物的临床治疗效果提供基因诊断依据和潜在干预靶点。

Renal cell carcinoma (RCC) is a common urology tumor with refractory to chemotherapy, relapses frequently and results in mortality of patients. Studie have shown Yes-associated protein(YAP) plays an important role in tumor develop and drug resistance. Our preliminary study found that YAP improve RCC targeted drug resistance. Further experiments have shown that YAP increase hypoxia inducible factor-2α(HIF-2α) expression,but no effect on HIF-1α, which is a key factor in the process of RCC occurrence, development and drug resistance. Here, we suspect that YAP could potentiate RCC drug resistance through activation of HIF-2α to increase oncogene c-myc expression, which potentiate RCC proliferation, and cancer stem cells(CSCs) properties. The objective of this study is to clarify the molecular mechanism of YAP regulates the HIF-2α by chromatin immune precipitation assay and ect, and YAP/HIF-2α signaling regulates cell proliferation and CSCs properties by using gain of function or knock-down strategies. Furthermore, we will use YAP knock-down or overexpression cell model, RCC tissue and The Cancer Genome Atlas to confirm the phenomenon and mechanism described above, in vivo and in vitro. Taken together, this study will provide genetic diagnosis for prognosis of RCC patients and potential intervention targets in the targeted drug treatment.