角质形成细胞中CD147通过PLCγ1信号通路趋化MDSCs促进皮肤鳞癌的作用机制研究

皮肤鳞状细胞癌（cSCC）是致死率仅次于黑素瘤的转移性皮肤肿瘤，其中角质形成细胞（KC）能够分泌一系列细胞因子和趋化因子，募集MDSCs等免疫抑制细胞形成肿瘤微环境，促进肿瘤发生。CD147与KC的增殖分化密切相关，但其调控MDSCs的具体机制仍未阐明。在预实验中我们通过表皮过表达CD147的基因鼠证实CD147能趋化MDSCs，促进cSCC的发生；RNA-seq证实CD147能促进CXCL1和CXCL2的表达，CXCL1/2为MDSCs重要的趋化因子；抗体芯片证实CD147能促进PLCγ1活化从而调控AP-1；同时CXCL1/2启动子区域存在AP-1结合位点。因此我们提出CD147能通过PLCγ1信号通路调控CXCL1/2的表达并趋化MDSCs，从而促进cSCC发生发展的假说。本项目将探讨KC中CD147在cSCC肿瘤微环境中的作用及趋化MDSCs的分子机制，为探索新的治疗手段提供依据。

Cutaneous squamous cell carcinoma (cSCC) is a metastatic skin cancer with a high lethal rate, which is only less than melanoma. During the tumorigenesis of cSCC, keratinocytes secrete various cytokines and chemokines to recruit and regulate the differentiation of immunosuppressive cells, such as MDSCs, therefore altering the tumor microenvironment (TME) and promoting the development of cSCC. CD147 is well-known to associated with the proliferation and differentiation of keratinocytes. However, the specific mechanism of CD147 in regulating MDSCs has not been elucidated yet. As our data shows, in transgenic mice with epidermal-specific overexpression of CD147, CD147 significantly increased the recruitment of MDSCs, thereby promoting the occurrence and development of cSCC. Subsequent transcriptome sequencing confirmed that CD147 increased the expression of chemokines such as CXCL1 and CXCL2, which are reported to be the essential factors to recruit MDSCs. The antibody microarray showed the activation of PLCγ1 after the over-expression of CD147. Interestingly, we found the bind of CXCL1/CXCL2 promoter and AP-1, a transcription factor which was regulated by PLCγ1. Based on the above results, we propose the hypothesis that CD147 in keratinocytes recruit MDSCs by up-regulating the expression of CXCL1 and CXCL2 through the PLCγ1 signaling pathway, thereby promoting the development of cSCC. This study aims to reveal the role of CD147 in cSCC TME and the molecular mechanism of that in chemotaxis of MDSCs, ultimately to provide the evidence for new therapeutic approaches.