RAPTOR Silencing Inhibits Head and Neck Squamous Cell Carcinoma Progression via Regulation of S100A8/A9 and Urokinase Plasminogen Activator

BACKGROUND Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive malignancy with limited prognostic biomarkers and therapeutic targets. This study aims to develop a robust protein-based prognostic model and investigate the functional role of RAPTOR in HNSCC progression. MATERIAL AND METHODS Proteomic data from The Cancer Proteome Atlas and transcriptomic data from The Cancer Genome Atlas were integrated to identify prognosis-related proteins, and a multivariable Cox regression model was developed. Functional studies, including lentiviral knockdown, proliferation and invasion assays, RNA sequencing, and xenograft models, were conducted to evaluate the role of RAPTOR (encoded by the RPTOR gene). Since RAPTOR is an essential component of mTORC1 and lacks a direct inhibitor, the mTORC1 inhibitor rapamycin was used as a pharmacological surrogate to assess the therapeutic potential of targeting RAPTOR-mediated signaling. RESULTS A 7-protein prognostic model (CD45, RAPTOR, SETD2, MERIT40_pS29, HER3_pY1289, Hexokinase-I, and BETACATENIN) stratified patients into high- and low-risk groups with significantly different overall survival, and the risk score remained an independent prognostic factor. RAPTOR was markedly upregulated in HNSCC and correlated with immune infiltration. Functional assays revealed that RAPTOR silencing inhibited proliferation, migration, and invasion, suppressed PI3K/AKT/mTOR signaling and uPA expression, and upregulated both S100A8/A9 levels. Rapamycin treatment recapitulated these effects in vitro and in vivo. CONCLUSIONS This study identifies a novel protein-based prognostic model for HNSCC and demonstrates that RAPTOR promotes tumor progression through mTOR signaling and S100A8/A9-uPA regulation. Targeting RAPTOR-mediated pathways may offer new strategies for precision therapy in HNSCC.