CTNNA1 promotes invasion and migration in clear cell renal cell carcinoma via N-cadherin-dependent adhesion and RhoA modulation

Background and Objectives Clear cell renal cell carcinoma (ccRCC) frequently exhibits amplification of chromosome 5q31.2; however, the biological impact of this alteration remains unclear. CTNNA1, which is located in this region, regulates cell-cell adhesion, but its function in ccRCC has not been fully characterized. This study aimed to clarify the role CTNNA1 in ccRCC progression and its association with cadherin-mediated adhesion and invasive potential. Methods Whole-transcriptome data from 57 metastatic ccRCC cases treated at Yamagata University were analyzed to assess CTNNA1 expression and its correlation with 5q copy number variation. TCGA data were used to compare cadherin expression profiles. Human ccRCC cell lines (A-498, 786-O, 769-P) underwent CTNNA knockdown using small interfering RNA (siRNA). Expression levels were verified by quantitative real-time PCR (qRT-PCR) and western blotting. Cell invasion and migration were measured by trans well assays, and protein localization was examined by immunofluorescence microscopy. Results CTNNA1 expression was elevated in ccRCC cases with 5q amplification and correlated with increased invasive potential. Despite low E-cadherin expression, CTNNA1 formed a complex and co-localized with N-cadherin, contributing to intercellular adhesion. CTNNA1 silencing significantly reduced invasion, while overexpression enhanced it. Immunofluorescence revealed alphaE-catenin localization at cell-cell junctions in adherent cells and a perinuclear redistribution in isolated cells. RhoA localization mirrored CTNNA1 and was disrupted following CTNNA1 knockdown, suggesting its involvement in regulating polarity and migration through RhoA signaling. Conclusions CTNNA1 promotes ccRCC cell invasion and migration through N-cadherin-mediated adhesion and modulation of RhoA signaling regulation. CTNNA1 may represent a potential therapeutic target for metastasis prevention in ccRCC.