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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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