COL6A2 drives clear cell renal cell carcinoma progression via integrin-dependent modulation of Wnt/β-catenin signaling.

Introduction: The mechanistic role of COL6A2, an extracellular matrix protein, in clear cell renal cell carcinoma (ccRCC) is largely unexplored. This study aimed to investigate COL6A2 expression, its prognostic value, biological functions, and underlying molecular mechanisms in ccRCC. Methods: COL6A2 expression was analyzed in ccRCC tissues and cell lines using public datasets and Western blotting on clinical samples and cell lines. Prognostic associations were evaluated using TCGA-KIRC data via clinicopathological correlations, Kaplan-Meier survival, and Cox regression analyses. Functional effects of COL6A2 knockdown in ccRCC cells were assessed by CCK-8, wound healing, Transwell, and Western blot analysis of EMT-associated proteins. Mechanistic investigations involved bioinformatic analysis, co-immunoprecipitation, Western blotting for Wnt/β-catenin pathway proteins, integrin blockade, and rescue experiments with the Wnt/β-catenin activator. Results: COL6A2 mRNA and protein were significantly upregulated in ccRCC tissues and cell lines. High COL6A2 expression correlated with aggressive clinicopathological features and independently predicted poorer prognosis. COL6A2 knockdown significantly inhibited ccRCC cell proliferation, migration, invasion, and reversed epithelial-mesenchymal transition (EMT). Mechanistically, COL6A2 was found to physically interact with integrin β1, thereby activating the Wnt/β-catenin signaling pathway to induce EMT. Rescue experiments confirmed the role of this signaling axis in mediating the malignant phenotypes. Conclusion: COL6A2 promotes ccRCC aggressiveness and modulates Wnt/β-catenin signaling in an integrin-dependent manner. These findings nominate the COL6A2-integrin interface as a potential therapeutic and biomarker axis in ccRCC.