The role of STRA6 induced by ONECUT2 drives malignant progression and radioresistance in rectal cancer through activating the Wnt/β-Catenin signaling pathway.

Stimulated by retinoic acid 6 (STRA6) is widely recognized for its roles in the pathogenesis and progression of multiple cancers. However, its biological functions and molecular mechanisms in rectal cancer (RC) remain poorly understood. This study aims to elucidate the functional roles of STRA6 and investigate the mechanisms underlying its dysregulation in RC. We employed RNA-seq to identify differentially expressed genes. STRA6 expression levels and activation of the Wnt/β-catenin pathway in RC were assessed using reverse transcription-quantitative PCR and Western blotting. Functional implications of these genes were investigated through a series of assays, such as CCK-8, flow cytometry and transwell assays. Potential upstream transcription factors regulating STRA6 were predicted bioinformatically and validated using a dual-luciferase reporter assay. Finally, the in vivo relevance of these findings was evaluated in a xenograft mouse model. A marked increase in STRA6 and One cut domain family member 2 (ONECUT2) expression was observed in RC tissues, with particularly elevated levels detected in radiation -resistant RC tissues. Functionally, STRA6 overexpression enhanced RC cell proliferation, migration and invasion, while reducing apoptosis. Rescue experiments demonstrated that the oncogenic effects of ONECUT2 were partially reversed upon STRA6 knockdown. Mechanistically, ONECUT2 was identified as a transcription factor that binds directly to the STRA6 promoter and upregulates its expression, thereby activating the Wnt/β-catenin pathway to facilitate RC progression and radiation resistance. ONECUT2/STRA6 axis exerts an oncogenic function in RC through activation of Wnt/β-catenin pathway, suggesting its potential as a therapeutic target. STRA6 is widely recognized for its roles in the pathogenesis and progression of multiple cancers. but its role in rectal cancer (RC) remains unclear. This study clarified STRA6's function in RC and identified ONECUT2 as its upstream transcription factor regulating the Wnt/β-catenin pathway to facilitate RC progression and radiation resistance. The findings provide novel insights into the prognostic and functional role of STRA6 in RC and underscore its potential as a promising therapeutic target.