FOXM1‐Cx31 Axis Drives Pancreatic Cancer Stem Cell‐Like Properties and Chemoresistance

Pancreatic cancer is a highly lethal malignancy with few effective treatment options. Connexin 31 (Cx31) is a membrane protein capable of forming hexameric channels to facilitate the exchange of metabolites and signaling molecules. Yet, the contribution of Cx31 to the onset and progression of pancreatic cancer remains to be understood. We analyzed Cx31 expression in pancreatic cancer tissues and cell lines using public databases and experimental models. The correlation between Cx31 expression and clinical outcomes was evaluated. The effects of Cx31 on pancreatic cancer cell proliferation, stemness, migration, chemoresistance, and immune infiltration were investigated. Transcriptome analysis and bioinformatics tools were employed to explore the underlying mechanisms. Cx31 was found to be upregulated in pancreatic cancer tissues compared to normal tissues, and its high expression correlated with shorter overall survival and higher mortality risk. Cx31 promoted acinar-to-ductal metaplasia (ADM), stemness, proliferation, migration, metastasis, and chemoresistance in pancreatic cancer cells. Bioinformatics analysis suggested a positive correlation between Cx31 and stemness-related genes. Cx31 knockdown altered the expression of genes involved in stemness and chemoresistance pathways, such as Wnt and Notch. Additionally, Cx31 was identified as a direct target of the transcription factor FOXM1, which upregulated its expression. Cx31 plays a multifaceted role in pancreatic cancer, influencing processes from initiation to metastasis and chemoresistance. It may serve as a potential therapeutic target to combat the aggressive nature of pancreatic cancer. The FOXM1-Cx31 axis could be a promising target for overcoming treatment resistance in pancreatic cancer.