Contribution of IQGAP3 in the Repair of Damaged Stomach Epithelium and Potential Role in Gastric Cancer Initiation

Authors:
Junichi MATSUO¹, Daisuke DOCHI^1,2, Linda Shyue Huey CHUANG¹, Yoshiaki ITO¹


Affliations:
¹Cancer Science Institute of Singapore, National University of Singapore, Singapore
²Department of Surgery, Tohoku University Graduate School of Medicine, Japan


Corresponding email address:
Yoshiaki ITO (csiitoy@nus.edu.sg)

Publication:
A part of this work was published in the following paper.
Matsuo J^*, Douchi D^*, Myint K, Mon NN, Yamamura A, Kohu K, Heng DL, Chen S, Mawan NA, Nuttonmanit N, Li Y, Srivastava S, Ho SWT, Lee, NYS, Lee, HK, Adachi M, Tamura A, Chen J, Yang H, Teh M, So JB, Yong WP, Tan P, Yeoh KG, Chuang LSH, Tsukita S, Ito Y. Iqgap3-Ras axis drives stem cell proliferation in the stomach corpus during homoeostasis and repair. GUT 2021;70:1833-1846.
^*Co-first author. ^**This paper was highlighted and recommended as an exceptional paper in Faculty Opinions (08 Feb 2021).

Abstract

Adult tissue stem cells play significant roles in the homeostasis of the stomach. We previously identified stomach stem cell marker IQGAP3, which is co-expressed in Ki67+ rapidly proliferating isthmus stem cells of normal human and mouse stomach. IQGAP3 is also co-expressed with Ki67+ cells in gastric cancer. Yet, the molecular function of IQGAP3 in gastric cancer development has not been fully understood.

To induce tissue damage in the stomach epithelium, we treated mice with high-dose tamoxifen (HDT). Pepsinogen-inducing chief cells are terminally differentiated cells and do not express IQGAP3 in homeostasis. After HDT treatment, however, robust expression of IQGAP3 was induced in the chief cells. Single-cell RNA-sequencing analysis for normal- and HDT-damaged-stomach epithelial cells revealed upregulation of Myc- and Wnt-pathways in chief cells, suggesting that chief cells might be undergoing a carcinogenic process. These observations are reminiscent of earlier suggestion that “Tumors: Wounds that do not heal (Dvorak, 1986)”. We next generated a stomach epithelial-specific Iqgap3-cKO mouse to find out the role of IQGAP3 in tissue repair and cancer-related signalling pathways. At 1-month post-HDT-damage induction, we observed decreasing numbers of isthmus cells and shrinkage of chief cell populations. Depletion of IQGAP3 expression appears to have attenuated the stem cell activity in both isthmus and chief cells. We are currently analysing the role of IQGAP3 in cancer-related signalling pathways.