TFAP2A/AKR1B10 axis promotes clear cell renal cell carcinoma metastasis by facilitating anoikis resistance

Abstract Background: Clear cell renal cell carcinoma (ccRCC) is characterized by a high propensity for metastasis, which critically depends on the acquisition of anoikis resistance (AR), but the molecular drivers of AR remain undefined. This study aims to elucidate the functional role and regulatory mechanisms of AKR1B10 in AR and metastatic progression in ccRCC. Methods: Anoikis‑resistant ccRCC sublines were established using prolonged suspension culture. RNA sequencing and bioinformatic analyses identified differentially expressed genes. Clinical significance of AKR1B10 and its upstream transcription factor TFAP2A was assessed using TCGA‑KIRC dataset and tissue microarrays. Biological functions of the TFAP2A/AKR1B10 axis were investigated through in vitro assays including Western blotting, qRT‑PCR, flow cytometry, wound healing, and transwell migration/invasion assays. Regulatory relationship was confirmed via dual‑luciferase reporter and ChIP assays. In vivo metastatic potential was evaluated using a tail‑vein lung metastasis model in nude mice. Results: AKR1B10 was identified as one of the upregulated genes in AR cells. High AKR1B10 expression was correlated with advanced TNM (Tumor-Node-Metastasis) staging, and poor prognosis in ccRCC. Functionally, AKR1B10 knockdown suppressed epithelial-mesenchymal transition (EMT), induced apoptosis, and significantly inhibited the migration, invasion, and in vivo metastatic capacity of ccRCC, while its overexpression produced the opposite effects. Mechanistically, TFAP2A was identified as a direct upstream transcription factor that binds to the AKR1B10 promoter, activating its transcription. Rescue experiments confirmed that AKR1B10 is a critical mediator of TFAP2A-driven malignant phenotypes. The oncogenic role of the TFAP2A/AKR1B10 axis was validated in both cell lines and an in vivo metastatic model. Conclusions: The TFAP2A/AKR1B10 axis is a novel driver of AR and metastasis in ccRCC. TFAP2A upregulates AKR1B10 to promote EMT and survival of detached cells. AKR1B10 serves as a prognostic biomarker and potential therapeutic target for metastatic ccRCC.