Cutaneous squamous cell carcinoma (cSCC) is the second most common type of skin cancer. NPTX2, a member of the neuronal pentraxin family, is reported to play inconsistent roles in different cancers. The role and mechanism of NPTX2 in cSCC remain unclear. In this study, we found that NPTX2 was overexpressed in both skin lesions and cell lines of cSCC. In vitro studies showed that NPTX2 facilitated cell proliferation, migration, invasion, colony formation, and epithelial‒mesenchymal translation in A431 and SCL-1 cells. NPTX2 interacted with METTL3, increased METTL3 expression, and improved N6-methyladenosine modification in cSCC cell lines. Mechanistically, NPTX2 facilitated epithelial‒mesenchymal translation by promoting METTL3-mediated N6-methyladenosine of SNAIL. METTL3 knockdown and N6-methyladenosine inhibition reversed the impacts of NPTX2 overexpression on cSCC cells. In vivo studies verified the role of NPTX2 as an oncogene in cSCC. Therefore, NPTX2 may be a potential therapeutic target for cSCC.
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