卵巢高级别浆液性癌（HGSOC）发病机制不清和缺乏靶向治疗是临床上治疗失败的重要原因。本课题组前期研究已证实MAP3K3是HGSOC潜在癌基因，其表达和功能受micro RNA和Lnc RNA的表观遗传学调控，但调控其蛋白动态表达的分子网络仍待补充。经预实验，我们初步发现MAP3K3具有被K63连接的多聚泛素化链修饰现象，NEDD4L与MAP3K3蛋白稳定性负相关，过表达NEDD4L可下调MAP3K3蛋白表达并降低卵巢癌细胞增殖、侵袭力。因此提出假说：NEDD4L可能作为E3连接酶介导MAP3K3通过蛋白酶体途径降解，下调其蛋白表达，降低HGSOC细胞的增殖、侵袭能力。本课题拟1、证实MAP3K3 的K63多聚泛素化修饰调控其在HGSOC中的生物学功能；2、阐明NEDD4L调控MAP3K3泛素化降解的作用机制；以期为解析MAP3K3的分子调控网络和探究HGSOC演进的分子机制提供理论依据。

Unclear pathogenesis and lack of targeted therapy are the important reasons for failure in clinical treatment of high-grade serous ovarian carcinoma (HGSOC). In our preliminary studies, MAP3K3 (mitogen-activated protein kinase/extracellular signal-regulated kinase kinasekinase3) has been identified as a potential oncogene of HGSOC. MAP3K3 function could be modulated via its gene expression or association with micro RNA and Lnc RNA. However, the molecular network regulating expression of MAP3K3 still needs to be explored. Our preliminary experimental date demonstrated that: MAP3K3 could be modified by Lys63-linked polyubiquitination, NEDD4L may mediate the degradation of MAP3K3 via its E3 ubiquitin ligase activity, which could reduce the proliferation and invasion ability of HGSOC. Thus, we proposed the hypothesis that, NEDD4L may act as E3 ubiquitin ligase, mediate Lys63-linked polyubiquitination of MAP3K3 to proteasomal degradation, and suppress the proliferation, invasion and metastatic of HGSOC. Ultimately, we will focus on 1. Confirm the correlation in the midst of the polyubiquitination modification of MAP3K3 and the biological behavior of HGSOC; 2. Analyze the role and regulation mechanism between NEDD4L and ubiquitin degradation of MAP3K3; provide experimental evidence for the analysis molecular mechanism and regulatory network of MAP3K3 in HGSOC development.