EGFR异常活化与皮肤鳞癌发生发展密切相关，其异常活化与下游信号通路及内吞异常有关，但机制仍不明确。深入研究EGFR异常活化机制有助于开发治疗皮肤鳞癌的新药物。我们前期研究发现，肿瘤侵袭转移相关重要分子CD147与EGFR存在直接相互作用，并参与EGFR信号通路异常活化；CD147功能发挥依赖TRAF6介导的K-63链类型泛素化；敲降TRAF6后可显著减弱CD147与EGFR相互作用，并抑制EGFR信号通路活化。综合我们前期数据，因此提出科学假说：“CD147经由TRAF6介导的K-63泛素化加强与EGFR直接相互作用，激活下游信号通路和抑制EGFR内吞，导致EGFR信号通路异常活化，并最终促进上皮细胞恶性转化以及皮肤鳞癌的发生发展”。本项目拟通过细胞体外及动物体内实验结合临床标本分析证明该假说，项目的实施有望阐明EGFR信号通路调控的新机制，为开发治疗皮肤鳞癌新药物提供新靶点。

Abnormal activation of EGFR is related to the development of cutaneous squamous cell carcinoma. The abnormal activation of EGFR is caused by dysregulation of downstream signal pathway and endocytosis, but the mechanism is still unclear. Exploring the mechanism of EGFR abnormal activation will help develop new drugs for treatment of cutaneous squamous cell carcinoma. Our preliminary results found that CD147, a key molecule involved in tumor invasion and metastasis, directly interact with EGFR and is involved in the abnormal activation of EGFR. CD147 function is dependent on TRAF6 and its K-63 ubiquitination. Knocking down TRAF6 attenuates CD147 and EGFR interaction, inhibits EGFR signaling pathway at the same time. Based on our previous research results, we present the following scientific hypothesis that "TRAF6-mediated K-63 ubiquitination of CD147 enhances the interaction of CD147 with EGFR , and activates downstream signaling pathways and inhibits EGFR endocytosis, resulting in abnormal activation of EGFR signaling pathways and promotes epithelial cell malignant transformation and cutaneous squamous cell carcinoma development " .This hypothesis will be demonstrated by the in vitro and in vivo experiments and combined with the analysis of clinical samples, which will elucidate the new mechanism of dysregulation of EGFR signaling pathway and provide a new target for the development of new drugs for the treatment of cutaneous squamous cell carcinoma.