Department of Dermatology, Xiangya Hospital, Central South University; Hunan Key Laboratory of Skin Cancer and Psoriasis and Hunan Engineering Research Center of Skin Health and Disease; National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Xiangya Road #87, Changsha, 410008, Hunan, China.
National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, 41008, China.
J Exp Clin Cancer Res. 2022 Aug 13;41(1):246. doi: 10.1186/s13046-022-02427-w.
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.
Epidermal CD147-overexpression or knockout (Epi or Epi) 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.
We found that specific overexpression of CD147 in the epidermis (Epi) 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 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 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. 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.
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.
表皮的恶性转化是皮肤鳞状细胞癌（cSCC）发病机制中的一个重要过程。虽然有证据表明 CD147 在各种肿瘤中发挥关键作用，但 CD147 在体内表皮恶性转化中的作用尚不清楚。
生成表皮 CD147 过表达或敲除（Epi 或 Epi）转基因小鼠模型进行体内研究。进行 RNA 测序和 qPCR 以鉴定差异表达基因。进行免疫组织化学和流式细胞术以研究 CD147 调节髓样来源抑制细胞（MDSCs）的作用。进行免疫沉淀、EMSA 和 ChIP 测定以研究 CD147 转化细胞的机制。
我们发现表皮中 CD147 的特异性过表达（Epi）诱导自发性肿瘤形成；此外，一组趋化因子和细胞因子，包括在 MDSC 募集中起重要作用的 CXCL1，在 Epi 转基因小鼠中显着上调。正如预期的那样，表皮中 CD147 的过表达通过增加肿瘤起始率以及 DMBA/TPA 小鼠模型中肿瘤的数量和大小，显著促进了肿瘤发生。有趣的是，在 Epi 转基因小鼠中，CXCL1 的表达和 MDSC 的浸润显着增加。我们的研究结果还表明，CD147 的敲低可减弱 EGF 诱导的恶性转化以及 HaCaT 细胞中 CXCL1 的表达。一致地，CD147 在皮肤鳞状细胞癌（cSCC）中过表达，并与髓样相关标志物 CD33 的表达呈正相关。我们进一步鉴定出丝氨酸/苏氨酸激酶 RSK2 是 CD147 结合位点的 CD147 的相互作用伙伴。CD147 与 RSK2 的相互作用激活了 RSK2，从而增强了 AP-1 转录激活。此外，EMSA 和 ChIP 测定表明，AP-1 可以与 CXCL1 启动子结合。重要的是，RSK2 抑制剂通过抑制 MDSC 的募集抑制 DMBA/TPA 小鼠模型中的肿瘤生长。
我们的研究结果表明，CD147 通过激活角质形成细胞并通过 RSK2/AP-1 途径募集 MDSC，在体内表皮恶性转化中发挥关键作用。
