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Despite advances in cancer research, the dual challenge of suppressing both proliferation and metastasis of OSCC cells remains unresolved. As a poor prognostic factor in HNSCC, we recently identified the keratin\u2010associated protein 2\u20133 (KRTAP2\u20103), which induces EMT and metastasis of OSCC cells. However, its involvement in OSCC progression has not yet been fully elucidated. In the present study, we aimed to examine the roles of endogenous KRTAP2\u20103 in the proliferation and tumor formation of OSCC cells. Using multiple OSCC cell lines, we demonstrated that downregulation of KRTAP2\u20103 not only induced mesenchymal\u2010epithelial transition (MET) but also reduced cell proliferation. Furthermore, RNA sequencing analyses of OSCC cells and HNSCC tumor tissues revealed that KRTAP2\u20103 downregulation suppressed KRAS signaling accompanied by decreased expressions of fibroblast growth factor\u20105 (FGF\u20105) and Fos\u2010like antigen 1 (FOSL1), poor prognostic factors in HNSCC. Knockdown of either FGF\u20105 or FOSL1 significantly reduced OSCC cell proliferation, highlighting their critical roles in KRTAP2\u20103\u2010mediated tumor progression. Furthermore, downregulation of KRTAP2\u20103 significantly suppressed tumor formation of OSCC cells. These findings suggest that KRTAP2\u20103 promotes OSCC progression by maintaining mesenchymal and proliferative traits via pathways related to FGF\u20105, FOSL1, and KRAS signaling. Targeting the KRTAP2\u20103 may represent a promising therapeutic strategy for OSCC, addressing the dual challenge of suppressing both proliferation and metastasis.<\/jats:p>","DOI":"10.1111\/cas.70355","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T05:32:52Z","timestamp":1784698372000},"page":"2752-2768","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Downregulation of\n                    <scp>KRTAP2<\/scp>\n                    \u20103 Suppresses Proliferation and Tumor Formation of Oral Cancer Cells via Inactivation of\n                    <scp>KRAS<\/scp>\n                    Signals"],"prefix":"10.1111","volume":"117","author":[{"given":"Qianqian","family":"Miao","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Graduate School of Medical and Dental Sciences Institute of Science Tokyo  Tokyo 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