TWA1 Promotes the Progression of Esophageal Squamous Cell Carcinoma via the p38/CXCL2/CXCR2/ERK Signaling Axis

Background Esophageal squamous cell carcinoma (ESCC) remains a leading cause of cancer-related deaths in East Asia, and its molecular mechanisms are not fully understood. Two-hybrid-associated protein 1 (TWA1/GID8), a scaffold protein involved in cell-cycle regulation and stress responses, has been implicated in tumor progression; however, its role in ESCC remains unclear. This study aimed to investigate the expression, biological function, and underlying molecular mechanisms of TWA1 in ESCC. Methods TWA1 expression was evaluated using proteomic analysis, public datasets, and two independent ESCC cohorts. Functional roles of TWA1 were examined through gain- and loss-of-function assays in vitro and in vivo. RNA sequencing, pathway enrichment analysis, biochemical assays, and pharmacological interventions were performed to identify downstream signaling mechanisms. Results TWA1 was significantly overexpressed in ESCC tissues and associated with advanced stage and poor overall survival. TWA1 promoted ESCC cell proliferation, cell-cycle progression, migration, invasion, and tumor growth while inhibiting apoptosis. Mechanistically, TWA1 activated p38 signaling to enhance CXCL2 expression. Increased CXCL2 subsequently stimulated ERK1/2 activation, contributing to malignant phenotypes. Inhibition of p38 or CXCL2/CXCR2 signaling attenuated TWA1-driven ESCC progression. Conclusion This study elucidates TWA1 as an upstream regulator of the p38–CXCL2–CXCR2–ERK1/2 signaling cascade in ESCC and provides mechanistic evidence connecting TWA1 to crosstalk between MAPK and chemokines during tumor progression. Furthermore, it underscores the potential of TWA1 as a prognostic biomarker and candidate target in ESCC. However, the study is limited by the retrospective nature of clinical cohorts, the limited size of the initial discovery cohort, and the use of subcutaneous xenograft models that may not fully recapitulate the tumor microenvironment.