Abstract
BACKGROUND: STRIP2 is a key regulator of cytoskeletal dynamics, yet its precise role in hepatocellular carcinoma (HCC) remains unclear. This study aimed to elucidate the mechanistic function of STRIP2 in HCC progression. METHODS: STRIP2 expression was analyzed using public databases. The prognostic significance and predictive value of STRIP2 were assessed through Kaplan-Meier survival analysis, receiver operating characteristic (ROC) curves, univariate and multivariate Cox regression, and nomogram models. Enrichment analysis was performed to explore STRIP2-related signaling pathways. Immune infiltration analysis was conducted to examine the relationship between STRIP2 and the tumor immune microenvironment. Tumor Immune Dysfunction and Exclusion (TIDE) scores and drug sensitivity analyses were used to evaluate the therapeutic relevance of STRIP2. Finally, immunohistochemistry (IHC) and immunofluorescence (IF) staining were performed to validate STRIP2 expression and its prognostic significance in a clinical cohort, while its functional role in HCC cells was investigated through knockout experiments. RESULTS: STRIP2 expression was found to be significantly upregulated in HCC tissues based on public database analysis, enrichment and immune infiltration analyses indicated that high STRIP2 expression was linked to an immunosuppressive tumor microenvironment, characterized by increased Th2 cell infiltration and reduced CD8(+) T-cell activity. Mechanistically, STRIP2 may regulate ion channel activity to mediate cytoskeletal remodeling and cell adhesion, thereby enhancing HCC cell migration and invasion. Additionally, elevated STRIP2 expression was associated with reduced sensitivity to immunotherapy, as indicated by higher TIDE scores. Immunohistochemical and IF staining demonstrated that STRIP2 is predominantly localized in the cytoplasm of HCC cells. In clinical cohort analysis, STRIP2 overexpression was associated with poor prognosis in HCC patients. Cox regression analyses confirmed that it was an independent prognostic factor for HCC. Functional experiments further revealed that STRIP2 knockout significantly inhibited HCC cell proliferation, migration, and invasion. CONCLUSIONS: STRIP2 functions as a tumor-promoting factor in HCC, facilitating tumor progression, immune evasion, and therapy resistance. STRIP2 may serve as a novel biomarker and a promising target for precision treatment in HCC.