Targeting TMPRSS11B by Daphnoretin as a promising therapeutic strategy for oral squamous cell carcinoma

Objective : Oral squamous cell carcinoma (OSCC) is a common cancer with a grim outlook, emphasizing the urgent requirement for novel treatment approaches. This study investigated the expression profile and functional mechanisms of transmembrane serine protease 11B (TMPRSS11B) in OSCC, and for the first time, identifies the natural compound Daphnoretin as exerting anti-tumor effects through targeting TMPRSS11B. Tumorigenicity was assessed by subcutaneous injection of CAL27 cells into nude mice, with tumor growth monitored over three weeks. Histological analysis was performed using H&E and Ki67 immunohistochemical staining. Cellular proliferation was examined using EdU staining, CCK-8, and colony formation assay. GROMACS was utilized for molecular docking and dynamics simulations. Employing Western blotting and quantitative PCR techniques, we have verified that TMPRSS11B is significantly downregulated in OSCC cells. A subcutaneous tumor xenograft mouse model was developed, with tumor malignancy evaluated via hematoxylin and eosin (H&E) staining and Ki67 immunostaining. Functional analyses involved modulating TMPRSS11B expression in SCC15 and CAL27 cell lines using lentiviral vectors, revealing that TMPRSS11B overexpression inhibits cell proliferation, whereas its knockdown facilitates a proliferative phenotype. Molecular docking analysis demonstrated a high-affinity interaction between Daphnoretin and TMPRSS11B. Mechanistic validation studies indicated that knocking down TMPRSS11B significantly reduces the suppressive impact of Daphnoretin on tumor cell proliferation. These findings confirm TMPRSS11B as a critical target for the anti-cancer action of Daphnoretin. The research explains the key regulatory function of TMPRSS11B in OSCC development and identifies Daphnoretin as a novel agent that upregulates TMPRSS11B expression. Consequently, it provides new theoretical insights and identifies a promising lead compound for the development of targeted therapies against OSCC.