Dumin Yuan1,2,Taolang Li3, Zhiyuan Ma3, Chunli Hu1,2, Jiaxing Zhu2, Jiaxing An2 , Guorong Wen2, Hai Jin2, Biguang Tuo1,2 and Xuemei Liu1,2
1Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, China, 2Digestive Disease Institute of Guizhou Province, Zunyi, China,3Department of Thyroid and Breast Surgery, Affiliated Hospital of Zunyi Medical University, China
Background/Aims: Slc26a9 is a member of Slc26a family with high expression in the stomach. Our previous study showed that Slc26a9 functions as a tumor suppressor in the gastrointestinal epithelium. However, the molecular and cellular basis of the tumor suppressor function remains unknown.
Methods: Gene microarray analysis together with histopathological and immunohistochemical (IHC) analysis, as well as In Situ Hybridization (ISH) with specific markers were performed in Slc26a9 wild type mice (WM) and knockout mice (KM) from 8 days to 18 months after birth.
Results: Compared with Slc26a9 WM at different age, Slc26a9 KM displayed nearly atrophic corpus mucosa accompanied by mucous cell metaplasia, hyperplasia and epithelial defects with increased cell proliferation but suppressed apoptosis, finally, moderately differentiated gastric cancer formation. ISH and IHC analysis showed that loss of Slc26a9 not only significantly altered multiple lineage markers of gastric epithelial cell differentiation, but also progressively downregulated the expression of gastric stem cell (GSC) markers at different age. Additionally, spontaneous inflammation was observed in Slc26a9 KM. Gene microarray analysis showed that multiple genes of tight junction and SHH signaling pathways was defectiveness, demonstrating that loss of Slc26a9 impairs epithelial barrier function and mucosal homeostasis, and induces gastric epithelial cell transformation. Moreover, Slc26a9 deficiency resulted in epithelial marker significantly decreased, but upregulation of the mesenchymal marker in gastric mucosa at 14 months after birth, followed with enhancement of gastric cancer stem cell (CSC) phenotypes, suggesting that the loss of Slc26a9 promotes spontaneous EMT. The phenomenon is due to the compounding effects of the dysregulation of the TGF-α and WNT pathways.
Conclusion: Slc26a9 deficiency results in tumorigenesis as a consequence of dysregulated GSC cell differentiation in inflammatory environment, mucosa barrier dysfunction and EMT-induced CSC phenotypes. Slc26a9 function as a protective role in safeguarding gastric epithelial cells against aberrant growth factor signalling and the resultant cellular plasticity and stemness.