The IQGAP3-Myc Axis Regulates Stomach Tissue Repair and Pre-cancerous Metaplasia Development
Authors
Junichi Matsuo1, Douchi Daisuke1,2, Mitsuhiro Shimura1,2, Linda Shyue Huey Chuang1, Yoshiaki Ito1
Affiliations
- Cancer Science Institute of Singapore, National University of Singapore
- Department of Surgery, Tohoku University Graduate School of Medicine
Abstract
Two types of stem cells located in the isthmus and base have been identified as essential for maintenance of the stomach corpus. The isthmus of gastric glands is enriched with actively proliferating stem cells that express Iqgap3. At the base where the terminally differentiated chief cells reside, a rare subset of Pgc-expressing dormant stem cells can be found. Stem cell-derived tissue repair and carcinogenesis share similar molecular pathways, suggesting that dysregulation of tissue repair mechanisms may initiate carcinogenesis. Following tissue injury, we observed concordant upregulation of Iqgap3 expression and Myc pathways, along with increased stem cell activity, especially in the chief cell population. To further explore the role of Iqgap3 in stem cell-derived tissue repair and carcinogenesis, we developed a mouse model capable of conditionally depleting Iqgap3 in Pgc-expressing stomach epithelial cells. Ablation of Iqgap3 expression in the adult mouse stomach was associated with decreased cell proliferation and chief cell population one month after injury. Transcriptomic analysis showed a suppression of the Myc pathway and stem cell activity in Iqgap3-depleted stomachs, suggesting that Iqgap3 potentially governs tissue repair through the Myc pathway. We also investigated the role of Iqgap3 in precancerous metaplasia. Inducing KrasG12D in mice with a conditional knockout of Iqgap3 revealed a reduced frequency of metaplasia at the gland base. Therefore, Iqgap3 contributes to the stem cell activity necessary for tissue regeneration and the formation of metaplasia.