Claudin-1 Interacts with CD81 and Promotes the Progression of Colorectal Cancer

Objectives: Although claudin-1 (CLDN1) interacts with Cluster of Differentiation 81 (CD81) in various cell types, the specific mechanism underlying this interaction and its functional implications in colorectal cancer (CRC) cells remain poorly understood. This study outlines the regulatory role of CLDN1 in CRC cell tumorigenicity through its interaction with CD81, elucidating the underlying signaling cascade. Methods: Changes in the expression of CLDN1 and CD81, as well as their correlation with the survival of CRC patients, were analyzed using samples from The Cancer Genome Atlas database, the Kaplan‒Meier plotter database, and tissue microarrays. CLDN1 and CD81 were silenced in CRC cell lines to examine their effects on cell viability, migration, and invasion. The interaction between CLDN1 and CD81, as well as the regulation of CD81, was examined via coimmunoprecipitation and ubiquitination analysis. CLDN1-overexpressing SW620 cells and a xenograft tumor model were cotreated with the anti-CD81 monoclonal antibody (mAb) 5A6 to investigate the role of the CLDN1/CD81 axis in CRC tumor growth. Results: CLDN1 expression was enhanced in CRC tissue and was correlated with poor survival in patients. Analysis revealed a significant upregulation of CLDN1 in all examined CRC cell lines relative to normal intestinal epithelial controls. Silencing of CLDN1 and CD81 reduced the CRC cell viability, invasion and migration. CLDN1 interacted with CD81 and promoted CD81 expression by suppressing CD81 ubiquitination. The anti-CD81 mAb 5A6 reversed the functions of CLDN1 overexpression in CRC malignant phenotypes and tumor xenograft growth. Conclusion: This study establishes CLDN1 as a promising therapeutic target in CRC and reveals that disrupting the CLDN1/CD81 axis might represent a novel treatment strategy.