The ITGA6-AEBP2 Complex Promotes Transcriptional Activation of GSK3β to Augment Wntβ-Catenin Signaling and Stemness in Pancreatic Cancer

Background Pancreatic cancer (PC) remains one of the most lethal malignancies in the digestive system, posing a significant threat to human health due to the critical lack of therapeutic targets. While integrin α6 (ITGA6) has been implicated as a key regulator in multiple cancer types, its precise functional role and molecular mechanisms in pancreatic tumorigenesis remain poorly understood. Methods We first identified differentially expressed genes (DEGs) with prognostic significance in PC using TCGA database analysis. ITGA6 expression was validated at protein and mRNA levels through immunohistochemistry (IHC), quantitative real-time PCR (qRT-PCR), and western blotting. Lentiviral-based overexpression and knockdown systems were established to modulate ITGA6 expression in PC cells. Cellular phenotypes were assessed using CCK-8 proliferation assays, flow cytometry, Transwell migration/invasion chambers, and wound healing assays. In vivo validation was performed using subcutaneous xenograft mouse models. The underlying molecular mechanism was investigated through co-immunoprecipitation (Co-IP), dual-luciferase reporter assays, and chromatin immunoprecipitation (ChIP) to delineate the ITGA6-AEBP2-GSK3β regulatory axis. Results This study revealed significantly elevated ITGA6 expression in PC tissues, with high ITGA6 levels correlating with poor patient survival outcomes. Genetic knockdown of ITGA6 effectively suppressed malignant phenotypes, including proliferation and migration in PC cells. Mechanistically, we identified that ITGA6 physically interacted with the transcription factor AEBP2 to enhance transcriptional activation of GSK3β. Importantly, the ITGA6-AEBP2-GSK3β axis was found to promote PC progression and chemoresistance through Wnt/β-catenin pathway-mediated augmentation of cancer stem cell properties. Conclusion ITGA6 promoted PC progression and conferred treatment resistance through the AEBP2/GSK3-β/β-catenin signaling axis. These results not only elucidated a novel molecular mechanism underlying PC aggressiveness but also identified ITGA6 as a promising therapeutic target for this lethal malignancy.