Deoxycholic Acid Drives ATP4A-Dependent Growth and Migration of Vocal Fold Leukoplakia Epithelial Cells via TGR5/JAK2/STAT3 Signaling

作者：Jia-Yu Zhang, Tkachenko Bi, Qinying Wang, Jiang-Tao Zhong, Yang‐Yang Bao, Z. Fu, Zhe Chen, Heng-Chao Chen, Zai-Zai Cao, Shui‐Hong Zhou · 发表于：Journal of Voice · 年份：2025 · DOI：10.1016/j.jvoice.2025.11.012 · 被引用次数：1 · 研究领域：Drug Transport and Resistance Mechanisms、Helicobacter pylori-related gastroenterology studies、Barrier Structure and Function Studies

PURPOSE: Vocal fold leukoplakia (VFL) is the most common precancerous lesion of laryngeal carcinoma, with variable malignant potential. The pathogenesis of VFL remains incompletely understood. Increasing evidence indicates that laryngopharyngeal reflux, especially bile acid reflux, may drive epithelial transformation. METHODS: ATP4A and ATP4B expression were assessed by immunohistochemistry in 58 VFL and 15 laryngeal squamous cell carcinoma (LSCC) specimens. Primary VFL epithelial cells were treated with graded concentrations of deoxycholic acid (DCA, 50-400 μM). Small interfering RNAs targeting ATP4A and TGR5, as well as the JAK2/STAT3 inhibitor AG490, were employed to delineate signaling mechanisms. Proliferation and migration were measured by cell counting kit (CCK)-8 and Transwell assays, respectively, while mRNA and protein levels were analyzed using quantitative real-time-PCR and Western blotting. RESULTS: ATP4A positivity was significantly higher in LSCC than in VFL (47.57 ± 15.75% vs 33.47 ± 21.22%, (P = 0.018), whereas ATP4B showed no significant difference. In vitro, DCA at 0-200 μM dose-dependently increased proliferation, migration, ATP4A expression, and TGR5/JAK2/STAT3 phosphorylation, while higher concentrations (300-400 μM) suppressed cell activity. ATP4A knockdown reversed DCA-induced proliferation and migration. Similarly, TGR5 silencing or AG490 treatment abrogated DCA-mediated upregulation of ATP4A and functional enhancement. CONCLUSIONS: DCA activates the ...