p85β细胞核转位导致PIK3CA螺旋域突变肿瘤发生发展的机制研究

PI3K信号通路在多种肿瘤中异常活跃。PI3K通常是由催化亚基p110和调节亚基p85组成的异源二聚体。我们之前的研究证实，p110α螺旋域热点突变蛋白直接与IRS1蛋白互作并促进肿瘤发生，然而此类肿瘤细胞中p85蛋白的功能和作用机制仍然未知。在前期工作基础中我们发现在p110α螺旋域突变细胞中，p85β可以从PI3K蛋白复合体中解离而此机制不适用于p85α；p85β入核后能够促进肿瘤发生；核定位信号是介导p85β细胞核转位的条件之一。本项目将进一步研究在PIK3CA/p110α螺旋域突变细胞中，p85β细胞核转位的分子机制；核定位p85β在肿瘤发生过程中的功能和作用机制；靶向p85β细胞核转位治疗PIK3CA螺旋域突变肿瘤的可能性。我们希望通过阐明p85β细胞核转位与肿瘤发生的关系，挖掘PIK3CA螺旋域突变促进肿瘤发生的机制，并探索PIK3CA螺旋域突变肿瘤靶向治疗的思路和方案。

PI3K signaling pathway is hyperactive in most human cancers. PI3K normally consists of two subunits, the catalytic subunit p110 and the regulatory subunit p85. In our previous study, we found that p110α helical domain hot spot mutant protein directly interacted with IRS1 protein, therefore promoting tumor growth. However, the function of p85 in p110α-helical-domain-mutant cells is largely unknown. In this project, we discovered that p85β, but not p85α, disassociated from PI3K complex and translocated into nucleus specifically in p110α-helical-domain-mutant cells. The nuclear p85β, but not cytoplasmic p85β, plays an important role in tumorigenesis. The nuclear localization signal (NLS) of p85β is one critical condition for its nuclear translocation. Furthermore, we will demonstrate the mechanisms of (1) how p85β translocates into nucleus; (2) how p85β regulates downstream signaling pathway to affect tumorigenesis; (3) and whether p85β nuclear translocation would be an effective therapeutic target for PIK3CA helical domain mutated tumors. By demonstrating the mechanisms of p85β nuclear translocation and its role in tumorigenesis, we would like to reveal the specific mechanism of PIK3CA helical domain mutant proteins promoting tumorigenesis, therefore discover novel therapeutic strategy to target PIK3CA helical domain mutated tumors.