Integrin beta 4 promotes colorectal cancer progression by upregulating Ezrin and activating the Wnt/β‑catenin signaling pathway.

Abstract

Colorectal cancer (CRC) is a major cause of cancer‑related mortality worldwide. Integrin beta 4 (ITGB4) has been previously identified as being overexpressed in CRC; however, its precise oncogenic mechanism remains unclear. The present study aimed to elucidate the functional role of ITGB4 in CRC progression and identify its downstream molecular effectors to provide new insights for targeted therapy. The biological functions of ITGB4 were investigated in CRC cell lines (SW480 and HCT116) using a series of in vitro assays, including Cell Counting Kit‑8, colony formation, Transwell migration and invasion, and flow cytometry for apoptosis following ITGB4 knockdown. An in vivo xenograft mouse model was used to evaluate the effect of ITGB4 on tumor growth. Downstream targets were screened using RNA sequencing (RNA‑seq) and validated by co‑immunoprecipitation and co‑immunofluorescence. The underlying signaling pathway was investigated by western blotting and functional rescue experiments. The results demonstrated that knockdown of ITGB4 significantly suppressed CRC cell proliferation, migration and invasion, while promoting apoptosis in vitro. Similarly, silencing ITGB4 markedly inhibited tumor growth in the in vivo xenograft model. RNA‑seq analysis identified Ezrin (EZR) as a key downstream target of ITGB4, and a direct protein‑protein interaction was confirmed between them. Mechanistically, ITGB4 knockdown decreased the expression of EZR at both the mRNA and protein levels. ITGB4 was demonstrated to exert its pro‑tumorigenic effects through the regulation of EZR, which subsequently activated the Wnt/β‑catenin signaling pathway. Interestingly, EZR overexpression partially restored ITGB4 levels, suggesting a hypothetical positive feedback loop via Wnt/β‑catenin signaling that could amplify this oncogenic axis. Notably, the malignant phenotypes suppressed by ITGB4 silencing were significantly rescued by the overexpression of EZR. In conclusion, the present study identified a novel ITGB4/EZR/Wnt/β‑catenin signaling axis in CRC. ITGB4 promotes CRC progression by modulating EZR expression and subsequently activating the Wnt/β‑catenin pathway. These findings highlight ITGB4 as a potential prognostic biomarker and a promising therapeutic target for CRC.