Please use this identifier to cite or link to this item: https://doi.org/10.1016/j.jcmgh.2022.01.010
Title: A Point Mutation R122C in RUNX3 Promotes the Expansion of Isthmus Stem Cells and Inhibits Their Differentiation in the Stomach
Authors: Douchi, Daisuke
Yamamura, Akihiro 
Matsuo, Junichi 
Lee, Jung-Won
Nuttonmanit, Napat 
Lim, Yi Hui Melissa 
Suda, Kazuto 
Shimura, Mitsuhiro 
Chen, Sabirah 
Pang, ShuChin
Kohu, Kazuyoshi
Kaneko, Mari
Kiyonari, Hiroshi
Kaneda, Atsushi
Yoshida, Hideyuki
Taniuchi, Ichiro
Osato, Motomi 
Yang, Henry
Unno, Michiaki
So, Jimmy Bok-Yan 
Yeoh, Khay Guan 
Chuang, Linda Shyue Huey 
Bae, Suk-Chul
Ito, Yoshiaki 
Keywords: Science & Technology
Life Sciences & Biomedicine
Gastroenterology & Hepatology
Isthmus
<p>Stem/Progenitor Cell</p>
Enhanced Stem Cell Activity
Preneoplastic State
Gastric Carcinogenesis
POLYPEPTIDE-EXPRESSING METAPLASIA
HELICOBACTER-PYLORI INFECTION
RESTRICTION-POINT
TUMOR-SUPPRESSOR
EPITHELIAL-CELLS
METHYLATION
CARCINOGENESIS
IDENTIFICATION
CORPUS
GROWTH
Issue Date: 17-Mar-2022
Publisher: ELSEVIER INC
Citation: Douchi, Daisuke, Yamamura, Akihiro, Matsuo, Junichi, Lee, Jung-Won, Nuttonmanit, Napat, Lim, Yi Hui Melissa, Suda, Kazuto, Shimura, Mitsuhiro, Chen, Sabirah, Pang, ShuChin, Kohu, Kazuyoshi, Kaneko, Mari, Kiyonari, Hiroshi, Kaneda, Atsushi, Yoshida, Hideyuki, Taniuchi, Ichiro, Osato, Motomi, Yang, Henry, Unno, Michiaki, So, Jimmy Bok-Yan, Yeoh, Khay Guan, Chuang, Linda Shyue Huey, Bae, Suk-Chul, Ito, Yoshiaki (2022-03-17). A Point Mutation R122C in RUNX3 Promotes the Expansion of Isthmus Stem Cells and Inhibits Their Differentiation in the Stomach. CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY 13 (5) : 1317-1345. ScholarBank@NUS Repository. https://doi.org/10.1016/j.jcmgh.2022.01.010
Abstract: Background & Aims: RUNX transcription factors play pivotal roles in embryonic development and neoplasia. We previously identified the single missense mutation R122C in RUNX3 from human gastric cancer. However, how RUNX3R122C mutation disrupts stem cell homeostasis and promotes gastric carcinogenesis remained unclear. Methods: To understand the oncogenic nature of this mutation in vivo, we generated the RUNX3R122C knock-in mice. Stomach tissues were harvested, followed by histologic and immunofluorescence staining, organoid culture, flow cytometry to isolate gastric corpus isthmus and nonisthmus epithelial cells, and RNA extraction for transcriptomic analysis. Results: The corpus tissue of RUNX3R122C/R122C homozygous mice showed a precancerous phenotype such as spasmolytic polypeptide-expressing metaplasia. We observed mucous neck cell hyperplasia; massive reduction of pit, parietal, and chief cell populations; as well as a dramatic increase in the number of rapidly proliferating isthmus stem/progenitor cells in the corpus of RUNX3R122C/R122C mice. Transcriptomic analyses of the isolated epithelial cells showed that the cell-cycle–related MYC target gene signature was enriched in the corpus epithelial cells of RUNX3R122C/R122C mice compared with the wild-type corpus. Mechanistically, RUNX3R122C mutant protein disrupted the regulation of the restriction point where cells decide to enter either a proliferative or quiescent state, thereby driving stem cell expansion and limiting the ability of cells to terminally differentiate. Conclusions: RUNX3R122C missense mutation is associated with the continuous cycling of isthmus stem/progenitor cells, maturation arrest, and development of a precancerous state. This work highlights the importance of RUNX3 in the prevention of metaplasia and gastric cancer.
Source Title: CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
URI: https://scholarbank.nus.edu.sg/handle/10635/239101
ISSN: 2352-345X
DOI: 10.1016/j.jcmgh.2022.01.010
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