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

Xu Zhang; Yeye Guo; Ta Xiao; Jie Li; Aiyuan Guo; Li Lei; Chong Jin; Qi Long; Juan Su; Mingzhu Yin; Hong Liu; Chao Chen; Zhe Zhou; Susi Zhu; Juan Tao; Shuo Hu; Xiang Chen; Cong Peng

doi:10.1186/s13046-022-02427-w

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

J Exp Clin Cancer Res. 2022 Aug 13;41(1):246. doi: 10.1186/s13046-022-02427-w.

Authors

Xu Zhang^#^{1

2}, Yeye Guo^#^{1

2}, Ta Xiao³, Jie Li^{1

2}, Aiyuan Guo⁴, Li Lei⁴, Chong Jin⁵, Qi Long⁵, Juan Su^{1

2}, Mingzhu Yin^{1

2}, Hong Liu^{1

2}, Chao Chen^{1

2}, Zhe Zhou^{1

2}, Susi Zhu^{1

2}, Juan Tao⁶, Shuo Hu⁷, Xiang Chen^{8

9}, Cong Peng^{10

11}

Affiliations

¹ 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.
² National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, 41008, China.
³ Institute of Dermatology, Chinese Academy of Medical Science & Peking Union Medical College, Nanjing, 210042, China.
⁴ Department of Dermatology, The 3rd Xiangya Hospital, Central South University, Changsha, 410000, China.
⁵ Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA, 19104, USA.
⁶ Department of Dermatology, Affiliated Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
⁷ Department of Nuclear Medicine, XiangYa Hospital, Central South University; Key Laboratory of Biological Nanotechnology of National Health Commission, Changsha, 410000, Hunan, China.
⁸ 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. chenxiangck@126.com.
⁹ National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, 41008, China. chenxiangck@126.com.
¹⁰ 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. pengcongxy@csu.edu.cn.
¹¹ National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, 41008, China. pengcongxy@csu.edu.cn.

^# Contributed equally.

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.

Keywords: CD147, Keratinocyte, Malignant transformation, RSK2.

MeSH terms

Animals
Basigin / metabolism*
Carcinoma, Squamous Cell* / genetics
Cell Transformation, Neoplastic / metabolism
Epidermis / metabolism
Epidermis / pathology
Mice
Ribosomal Protein S6 Kinases, 90-kDa / metabolism
Skin Neoplasms* / genetics
Transcription Factor AP-1 / genetics

Substances

Bsg protein, mouse
Transcription Factor AP-1
Basigin
Ribosomal Protein S6 Kinases, 90-kDa
ribosomal protein S6 kinase, 90kDa, polypeptide 3

Abstract

MeSH terms

Substances

Grants and funding