TRAF6泛素化修饰CD147对黑素瘤细胞侵袭转移调控的分子机制研究

黑素瘤细胞的自分泌及间质成纤维细胞的旁分泌基质金属蛋白酶（MMPs）对肿瘤的侵袭转移有着重要意义。CD147能够调控黑素瘤细胞及间质成纤维细胞MMPs的表达及活性，被认为是侵袭转移过程中的一个关键分子，然而其活化机制未能完全阐明。前期实验结果显示CD147与泛素化酶TRAF6 存在相互作用并介导泛素化修饰CD147；同时TRAF6在黑素瘤临床样本中高表达，敲降TRAF6表达能够明显抑制黑素瘤细胞的侵袭转移及MMP-9的表达。鉴于肿瘤微环境在侵袭转移中的重要作用，我们提出不仅对于黑素瘤细胞，而且在间质成纤维细胞中，TRAF6能够通过泛素化修饰调控CD147活性，影响MMPs的表达分泌，从而参与黑素瘤的侵袭转移。本项目将阐明TRAF6调控CD147活化的作用机制，探讨TRAF6/CD147信号轴对黑素瘤细胞及间质成纤维细胞功能包括两种细胞之间相互作用的影响，揭示该信号轴在黑素瘤侵袭转移中的作用

Melanoma cells and fibroblasts in stroma express and secrete MMPs which plays critical role in invasion and metastasis.CD147 is regarded as a crucial molecule in melanoma invasion and metastasis through regulation MMPs function, such as MMP-2,9,in tumor cells and fibroblasts，but the process of CD147 activation remains unclear.K63 linked ubiquitination is a key post-transcriptional modification for protein function. Our preliminary results showed that CD147 interacts with TRAF6, a E3 ligase,and TRAF6 induces CD147 of K63 linked ubiquitination,furthermore,TRAF6 is highly expressed in metastatic melanoma clinical tissue and knock down of TRAF6 expression significantly attenuates invasion and metastasis in melanoma cells and MMP-9 expression. In consideration of role of tumor microenvironment in invasion and metastasis, we propose, not only in tumor cells but also in stromal fibroblast cells, that TRAF6 regulates CD147 activation through ubiquitination for MMPs expression and secrete which plays a critical role in melanoma invasion and metastasis. Our study will investigate mechanism about activation of CD147 by TRAF6 and discover the role of TRAF6/CD147 axis in invasion and metastasis contributed to understand the metastatic mechanism in melanoma.