TROP2 suppresses pyroptosis via the PI3K/AKT pathway to drive tumor progression in hypopharyngeal squamous cell carcinoma

Hypoopharyngeal squamous cell carcinoma (HPSCC) is one of the most aggressive cancers and is characterized by an extremely poor prognosis. We screened TROP2 to be highly expressed in HPSCC, but its effect on HPSCC remains unclear. This study is intended to determine the underlying mechanism by which TROP2 regulates HPSCC. Detecting TROP2 expression in HPSCC and normal tissues to clarify its distribution in tumor epithelial cells. Using TROP2 overexpression/knockdown to assess its effects on HPSCC cell progression phenotypes and pyroptosis. Applying molecular biology techniques to analyze TROP2’s regulation of the NLR signaling pathway, pyroptosis-related proteins and the PI3K/AKT pathway. And verifying via chromatin immunoprecipitation (ChIP) the binding of transcription factor JUND to the TROP2 promoter and its role in activating TROP2 expression. We showed that TROP2 is significantly upregulated in HPSCC, particularly in tumor epithelial cell. Our study revealed that TROP2 promotes HPSCC progression by suppressing pyroptosis. Mechanistically, TROP2 was found to regulate NOD-like receptor (NLR) signaling pathway and downregulate key pyrotosis-related protein, including GSDMD-N, Cleaved Caspase-1 (p20), IL18 and IL-1β. Additionally, we identified that PI3K/AKT signaling pathway is critically involved in TROP2-mediated inhibition of pyroptosis. Upstream analysis further revealed that the transcription factor JUND directly binds to and activates the TROP2 promoter, thereby contributing to its overexpression in HPSCC. Our findings highlight the JUND-TROP2-PI3K/AKT-pyrotosis axis as a potential therapeutic target for the treatment of HPSCC.