Downregulation of MUC6 improves esophageal epithelial barrier dysfunction and inhibits epithelial-mesenchymal transition in reflux esophagitis

Reflux esophagitis (RE) is a chronic inflammatory condition resulting from the reflux of gastric contents. Mucin 6 (MUC6), a member of the mucin family, has been found to have dysregulated expression in various esophageal diseases. However, the specific role of MUC6 in RE remains largely unclear. MUC6 levels were detected in esophageal tissues between RE patients and non-RE patients using RT-qPCR and western blot assays. Additionally, to stimulate RE in vitro, human esophageal epithelial cells (HEEC) were exposed to hydrochloric acid (HCl) with a pH of 3.0. To mimic RE in vivo, hemipyloric ligation combined with cardiomyotomy was performed. MUC6 levels were significantly higher in esophageal tissues of RE patients compared to non-RE patients. Meanwhile, elevated MUC6 levels were also observed in HCl-stimulated HEEC cells and in esophageal tissues of rats with RE. Downregulation of MUC6 notably attenuated the inflammatory response both in vitro and in vivo, as evidenced by a reduced production of IL-6. Additionally, silencing MUC6 remarkably improved esophageal epithelial barrier dysfunction in vitro and in vivo through upregulating tight junction protein ZO-1. Meanwhile, MUC6 knockdown resulted in increased levels of E-cadherin, and decreased levels of N-cadherin, vimentin, transforming growth factor-beta 1 (TGF-β1) and Smad3 in RE models both in vitro and in vivo. Collectively, MUC6 knockdown could improve esophageal epithelial barrier dysfunction and inhibit epithelial-mesenchymal transition in HCl-stimulated HEEC cells and in esophageal tissues of RE rats, potentially via modulation of the TGF-β1/Smad3 signaling pathway. These data suggested that MUC6 may be a promising target for diagnosis and treatment of RE.