LPM1调控Capn4促进鼻咽癌转移的机制研究

Capn4属于 Calpain家族，是Calpain家族中的调节性小亚基，参与细胞增殖分化、细胞骨架重构、凋亡及肿瘤转移等过程，但促进肿瘤发生发展（特别是转移）的机制尚不明确。我们前期研究发现Capn4在鼻咽癌中高表达，并且与鼻咽癌的转移密切相关；机制研究发现Capn4通过磷酸化NF-κB p65上调MMP2的表达进而促进鼻咽癌转移。进一步分析发现Capn4的表达与EB病毒感染密切相关，在LMP1阳性的鼻咽癌组织中Capn4阳性表达率高达82.2%；荧光素酶报告基因实验提示：LMP1诱导Capn4的表达并呈剂量依赖性。本项目拟在前期研究基础上，通过基因芯片、免疫共沉淀、基因干扰、阻断剂等实验，深入研究LMP1调控Capn4促进鼻咽癌转移的分子机理，为阐明Capn4在鼻咽癌中的生物学功能及为鼻咽癌转移防治的分子靶标筛选奠定基础。

Capn4 is a small regulatory subunit of the calpain proteolytic system, mainly involved in the processes of cell proliferation and differentiation, backbone rearrangement, apoptosis and cancer cell metastasis etc. However, its roles and underlying mechanisms for promoting tumorigenesis and progression remain unclear. Our previous study has demonstrated that Capn4 was highly expressed in nasopharyngeal carcinoma (NPC) samples from patients, an event closely correlated to the metastasis of NPC. We have also found that Capn4 promoted NPC metastasis by the upregulation of MMP2 expression via phosphorylation of the p65 subunit of NF-κB. Immunohistochemistry results have further revealed that the expression of Capn4 was significantly correlated with EB virus infection and the expression rate of Capn4 is about 82.2% in the LMP1 positive NPC samples. Moreover, Luciferase reporter gene assay suggested that LMP1 could increase the promoter activity of Capn4 in a dose-dependent manner in NPC cells. Based on these preliminary findings, the present project is designed to explore deeper insights into the molecular mechanism(s) by which LMP1 contributes to the metastasis of NPC via regulation of Capn4, using genetic and pharmacological approaches including genechip microarray, co-immunoprecipitation, RNA interference, small molecule inhibitors,etc. It is expected that the proposed studies will lay down the foundation for understanding whether and by which mechanisms Capn4 promotes NPC metastasis, and thus seeking the potential molecular targets for prevention and treatment of metastasis NPC.