SASH1和MAP4K4合谋引起乳腺癌增殖的机制研究

乳腺癌是严重威胁妇女健康第一大肿瘤，但发病机制尚未完全清楚。我们前期发现：在121例乳腺癌组织和30例癌旁组织中MAP4K4和SASH1的表达变化趋势一致；SASH1结合MAP4K4 ，而且二者均能诱导对方的泛素化修饰降解；shRNA干扰MAP4K4和MAP4K4抑制剂(GNE-495)均能下调SASH1和阻止SASH1的泛素化修饰；干扰SASH1的表达能下调总MAP4K4却上调phospho-MAP4K4水平。本项目拟通过体外细胞实验和裸鼠移植瘤模型及大样本乳腺癌组织验证： SASH1作为Cul4A/4B-DDB1-DWD assembly的一个新的底物蛋白被泛素化修饰降解；SASH1与MAP4K4之间相互诱导对方的磷酸化和泛素化修饰。本研究将发现一条新的Cul4A/4B-DDB1-DWD-SASH1-MAP4K4级联调节乳腺癌增殖，为利用GNE-495治疗乳腺癌提供新的治疗方案。

The morbidity of breast cancer assumes the trend of escalation year by year and become a serious threat to the first major cancer of women's health. However, the pathogenesis is completely clear. Our current study reveals that :(1) MAP4K4 and SASH1 show similar trend of change in breast carcinoma tissues of 121cases and adjacent tissues of 30 cases. (2)SASH1 binds to MAP4K4 and SASH1 and MAP4K4 induce the other party’s ubiquitination degradation. (3)MAP4K4-shRNA-mediated silencing and MAP4K4 inhibitor (GNE-495) both can down-regulate SASH1 and block SASH1 ubiquitination modification. (4) SASH1-shRNA-mediated silencing down-regulates total MAP4K4 and upregulates phospho-MAP4K4 levels.In this study, through in vitro cellular assays, xenograft models in nude mice and large samples’ breast cancer tissue, we intend to identify that SASH1,being as a novel substrate receptor of Cul4A/4B-DDB1-DWD assembly can be polyubiquinated and degradated.SASH1 and MAP4K4 can induce the other party’s ubiquitination modification and phosphorylation modification.The study will reveal a novel Cul4A/4B-DDB1-DWD-SASH1-MAP4K4 cascade to mediate breast cancer proliferation,which will provide a novel treatment perscription for breast carcinoma using GNE-495.