CD147 mediates epidermal malignant transformation through the RSK2/AP-1 pathway.
CD147 mediates epidermal malignant transformation through the RSK2/AP-1 pathway.
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CD 147通过RSK 2/AP-1途径介导表皮恶性转化。
DOI：
10.1186/s13046-022-02427-w
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发表时间：
2022-08-13
影响因子：
11.3
通讯作者：
Peng, Cong
中科院分区：
文献类型：
--
作者：
Zhang, Xu;Guo, Yeye;Xiao, Ta;Li, Jie;Guo, Aiyuan;Lei, Li;Jin, Chong;Long, Qi;Su, Juan;Yin, Mingzhu;Liu, Hong;Chen, Chao;Zhou, Zhe;Zhu, Susi;Tao, Juan;Hu, Shuo;Chen, Xiang;Peng, Cong
表皮恶变是皮肤鳞状细胞癌(CSCC)发病过程中的重要环节。尽管已有证据表明CD147在多种肿瘤中起关键作用，但CD147在体内表皮恶性转化中的作用尚不清楚。建立表皮CD147过表达或敲除(EpiCD147-OE或EpiCD147-KO)转基因小鼠模型，用于体内研究。对差异表达基因进行RNA测序和定量聚合酶链式反应分析。免疫组织化学和流式细胞术检测CD147在髓系抑制细胞(MDSCs)中的作用。采用免疫沉淀法、EMSA法和芯片法研究CD147在细胞转化中的作用机制。我们发现在EpiCD147-OE转基因小鼠中，CD147在表皮中的特异性过表达可诱导自发的肿瘤形成，此外，在MDSC募集中起重要作用的一系列趋化因子和细胞因子，包括CXCL1，显著上调。正如预期的那样，在DMBA/TPA小鼠模型中，通过增加肿瘤起始率以及肿瘤的数量和大小，CD147在表皮的过表达显著促进了肿瘤的发生。有趣的是，在EpiCD147-OE转基因小鼠中，CXCL1的表达和MDSCs的渗透显著增加。我们的研究结果还表明，CD147的敲除可以减轻EGF诱导的HaCaT细胞的恶性转化以及CXCL1的表达。CD147在皮肤鳞状细胞癌(CSCC)中高表达，且与髓系相关标志物CD33的表达呈正相关。我们进一步鉴定了丝氨酸/苏氨酸激酶RSK2是CD147在CD147D207-230结合部位的相互作用伙伴。CD147和RSK2的相互作用激活了RSK2，从而增强了AP-1的转录激活。此外，EMSA和芯片检测表明AP-1可以与CXCL1启动子结合。重要的是，RSK2抑制剂通过抑制MDSCs的募集而抑制了DMBA/TPA小鼠模型的肿瘤生长。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MDSCs，在体内表皮恶性转化过程中发挥关键作用。网上版载有补充材料，可在10.1186/s13046-022-02427-w查阅。
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 (EpiCD147-OE or EpiCD147-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. We found that specific overexpression of CD147 in the epidermis (EpiCD147-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 EpiCD147-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 EpiCD147-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 CD147D207-230. 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. 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. The online version contains supplementary material available at 10.1186/s13046-022-02427-w.
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影响因子：
82.9
作者：
Nagaraj, Srinivas;Gupta, Kapil;Gabrilovich, Dmitry I.
通讯作者：
Gabrilovich, Dmitry I.
影响因子：
1.1
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Eckert RL;Adhikary G;Young CA;Jans R;Crish JF;Xu W;Rorke EA
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作者：
ASHMAN, LK;MURRAY, AW;KOTLARSKI, I
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KOTLARSKI, I
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Hattori, N;Komine, M;Tamaki, K
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Tamaki, K