Downregulation of KRTAP2-3 Suppresses Proliferation and Tumor Formation of Oral Cancer Cells via Inactivation of KRAS Signals.

The progression and metastasis of oral squamous cell carcinoma (OSCC), the most common type of head and neck squamous cell carcinoma (HNSCC), are driven by complex molecular mechanisms, including proliferative signaling pathways such as KRAS signaling and epithelial-mesenchymal transition (EMT). 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-associated protein 2-3 (KRTAP2-3), 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 KRTAP2-3 in the proliferation and tumor formation of OSCC cells. Using multiple OSCC cell lines, we demonstrated that downregulation of KRTAP2-3 not only induced mesenchymal-epithelial transition (MET) but also reduced cell proliferation. Furthermore, RNA sequencing analyses of OSCC cells and HNSCC tumor tissues revealed that KRTAP2-3 downregulation suppressed KRAS signaling accompanied by decreased expressions of fibroblast growth factor-5 (FGF-5) and Fos-like antigen 1 (FOSL1), poor prognostic factors in HNSCC. Knockdown of either FGF-5 or FOSL1 significantly reduced OSCC cell proliferation, highlighting their critical roles in KRTAP2-3-mediated tumor progression. Furthermore, downregulation of KRTAP2-3 significantly suppressed tumor formation of OSCC cells. These findings suggest that KRTAP2-3 promotes OSCC progression by maintaining mesenchymal and proliferative traits via pathways related to FGF-5, FOSL1, and KRAS signaling. Targeting the KRTAP2-3 may represent a promising therapeutic strategy for OSCC, addressing the dual challenge of suppressing both proliferation and metastasis.