Author Information
1Cancer Science Institute of Singapore, National University of Singapore, Singapore.
2Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
3Department of Medicine, National University of Singapore, Singapore.
4Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore.
5Singapore Immunology Network, Agency for Science, Technology and Research, Singapore.
6Graduate School of Medicine, Kyoto University, Kyoto, Japan.
7Department of Pharmacology, School of Medicine, Teikyo University, Tokyo, Japan.
8Strategic Innovation and Research Center, Teikyo University, Tokyo, Japan.
9Laboratory of Barriology and Cell Biology, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
10Department of Pathology, National University of Singapore, Singapore.
11Department of Surgery, National University Health System, National University of Singapore, Singapore.
12Department of Hematology-Oncology, National University Cancer Institute, Singapore.
13Genome Institute of Singapore, Singapore.
14Department of Gastroenterology and Hepatology, National University Hospital, Singapore.
15Cancer Science Institute of Singapore, National University of Singapore, Singapore csiitoy@nus.edu.sg atsukita@biosci.med.osaka-u.ac.jp csicshl@nus.edu.sg.
16Strategic Innovation and Research Center, Teikyo University, Tokyo, Japan csiitoy@nus.edu.sg atsukita@biosci.med.osaka-u.ac.jp csicshl@nus.edu.sg.
Abstract:
Objective: Tissue stem cells are central regulators of organ homoeostasis. We looked for a protein that is exclusively expressed and functionally involved in stem cell activity in rapidly proliferating isthmus stem cells in the stomach corpus.
Design: We uncovered the specific expression of Iqgap3 in proliferating isthmus stem cells through immunofluorescence and in situ hybridisation. We performed lineage tracing and transcriptomic analysis of Iqgap3 +isthmus stem cells with the Iqgap3-2A-tdTomato mouse model. Depletion of Iqgap3 revealed its functional importance in maintenance and proliferation of stem cells. We further studied Iqgap3 expression and the associated gene expression changes during tissue repair after tamoxifen-induced damage. Immunohistochemistry revealed elevated expression of Iqgap3 in proliferating regions of gastric tumours from patient samples.
Results: Iqgap3 is a highly specific marker of proliferating isthmus stem cells during homoeostasis. Iqgap3+isthmus stem cells give rise to major cell types of the corpus unit. Iqgap3 expression is essential for the maintenance of stem potential. The Ras pathway is a critical partner of Iqgap3 in promoting strong proliferation in isthmus stem cells. The robust induction of Iqgap3 expression following tissue damage indicates an active role for Iqgap3 in tissue regeneration.
Conclusion: IQGAP3 is a major regulator of stomach epithelial tissue homoeostasis and repair. The upregulation of IQGAP3 in gastric cancer suggests that IQGAP3 plays an important role in cancer cell proliferation.
Keywords: cell proliferation; gastric cancer; gastric pre-cancer; gastric wound repair; stem cells.
PMID: 33293280 DOI: 10.1136/gutjnl-2020-322779