三氧化二砷降解HER2蛋白的机制研究

Many studies demonstrated that the human epidermal growth factor receptor(HER) 2 tyrosine kinase receptor was overexpressed in many cancers.Elevated HER2 levels correlated strongly with the pathogenesis and prognosis of breast cancer.In previous studies,our findings suggested that arsenic trioxide (ATO) could significantly down-regulate the expression of HER2 receptor proten in HER2-overexpressing breast and gastric cancer cells.Further experiment indicated that the ubiquitin-proteasome pathway was involved in ATO-induced degadation of HER2 portein.However,the exact mechanisms of regulation of the HER2 protrein by E3-ubiquitin ligase is unclear,which this program seeks to explore.With the aim of better elucidating the mechanisms of ATO-induced degradation of HER2 protein,the research will be conducted in several HER2-overexpressing tumor cells.This study may offer a new insight into the understanding of the mechanisms of ATO.

研究表明，HER2基因在多种恶性肿瘤中均有不同程度的扩增和蛋白过表达，HER2过表达成为临床上判断预后的独立因素。本课题前期筛选实验发现：三氧化二砷可明显下调HER2蛋白表达水平，通过抑制下游PI3K-AKT信号通路，诱导HER2过表达细胞凋亡。免疫共沉淀证实，泛素蛋白酶体降解通路参与砷剂诱导的HER2下调。本课题拟通过：在多种HER2过表达细胞株中，考察三氧化二砷如何介导HER2降解及诱导凋亡的过程，筛选相关的关键E3泛素连接酶，进一步明确泛素化降解系统在砷剂诱导HER2下调中的具体分子机制，为今后治疗HER2过表达肿瘤提供新的药物选择和重要线索。