Parietal cell-Specific SLC26A9 Deletion induces spontaneous Gastric Carcinogenesis in Mice

Previous study showed that Slc26a9 loss impairs parietal cell function and survival. We investigated whether Slc26a9 loss causes spontaneous gastric carcinogenesis in mice and plays a role in the development and progression in human gastric cancer (GC). Gastric histopathology and potential molecular mechanism were explored in Slc26a9 knockout mice and wild-type littermates as well as Slc26a9fl/fl/Atp4b-Cre and Slc26a9fl/fl mice from 8 days to 18 months by histological and immunohistochemical analyses, quantitative PCR, in situ hybridization, and RNA microarray analysis, respectively. We demonstrated that loss of parietal cell expression of Slc26a9 is the key event to induce spontaneous gastric carcinogenesis in mice, and clarified the sequence of events leading to malignant transformation, including Slc26a9 deficiency in parietal cells resulted in dysregulated differentiation of stem cells in an inflammatory environment, activated Wnt signaling pathway to induce gastric epithelia cell hyperproliferation and apoptosis inhibition, as well as spontaneous epithelial to mesenchymal transition-induced cancer stem cell phenotypes. Downregulation of SLC26A9 correlated with GC patient’s short survival. Graphical Abstract Loss of parietal cell expression of Slc26a9 is the key event to induce spontaneous gastric carcinogenesis in transgenic mice. ![Figure][1] * AG : atrophic gastritis AIF : apoptosis-inducing factor AREG : amphiregulin CAG : chronic atrophic gastritis CCND1 : Cyclin D1 CHIA : acidic chitinase Cyt-C : cytochrome C EGFR : epidermal growth factor receptor EMT : epithelial-mesenchymal transition Endo G : endonuclease G GC : gastric cancer GCS : gastric cancer stem cell GSC : gastric stem cell HGIN : high-grade intraepithelial neoplasia HB-EGF : heparin-binding EGF IM : intestine metaplasia ISH : in situ hybridization ITLN1 : intelectin 1 KM : knockout mice SPEM : spasmolytic polypeptide-expressing metaplasia TGF-α : transforming growth factor-α TUNEL : transferase dUTP Nick End Labelling WM : wild type mice [1]: pending:yes