CD147 mediates epidermal malignant transformation through the RSK2/AP-1 pathway

Abstract

Abstract Background Malignant transformation of the epidermis is an essential process in the pathogenesis of cutaneous squamous-cell carcinoma (cSCC). Although evidence has demonstrated that CD147 plays key roles in various tumors, the role of CD147 in epidermal malignant transformation in vivo remains unclear. Methods Epidermal CD147-overexpression or knockout (Epi CD147-OE or Epi CD147-KO ) transgenic mouse models were generated for in vivo study. RNA-sequencing and q-PCR were performed to identify the differentially expressed genes. Immunohistochemistry and flow cytometry were performed to investigate the role of CD147 in regulating myeloid-derived suppressor cells (MDSCs). Immunoprecipitation, EMSA and ChIP assays were performed to investigate the mechanism of CD147 in cell transformation. Results We found that specific overexpression of CD147 in the epidermis (Epi CD147-OE ) induces spontaneous tumor formation; moreover, a set of chemokines and cytokines including CXCL1, which play essential function in MDSC recruitment, were significantly upregulated in Epi CD147-OE transgenic mice. As expected, overexpression of CD147 in the epidermis remarkably facilitated tumorigenesis by increasing the rate of tumor initiation and the number and size of tumors in the DMBA/TPA mouse model. Interestingly, the expression of CXCL1 and the infiltration of MDSCs were dramatically increased in Epi CD147-OE transgenic mice. Our findings also showed that knockdown of CD147 attenuated EGF-induced malignant transformation as well as CXCL1 expression in HaCaT cells. Consistently, CD147 was found overexpressed in cutaneous squamous cell carcinoma (cSCC), and positively related with the expression of CD33, a myeloid-associated marker. We further identified RSK2, a serine/threonine kinase, as an interacting partner of CD147 at the binding site of CD147 D207-230 . The interaction of CD147 and RSK2 activated RSK2, thus enhancing AP-1 transcriptional activation. Furthermore, EMSAs and ChIP assays showed that AP-1 could associate with the CXCL1 promoter. Importantly, RSK2 inhibitor suppressed the tumor growth in DMBA/TPA mouse model by inhibiting the recruitment of MDSCs. Conclusion Our findings demonstrate that CD147 exerts a key function in epidermal malignant transformation in vivo by activating keratinocytes and recruiting MDSCs via the RSK2/AP-1 pathway.