Please use this identifier to cite or link to this item: https://doi.org/10.1016/j.jcmgh.2022.01.010
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dc.titleA Point Mutation R122C in RUNX3 Promotes the Expansion of Isthmus Stem Cells and Inhibits Their Differentiation in the Stomach
dc.contributor.authorDouchi, Daisuke
dc.contributor.authorYamamura, Akihiro
dc.contributor.authorMatsuo, Junichi
dc.contributor.authorLee, Jung-Won
dc.contributor.authorNuttonmanit, Napat
dc.contributor.authorLim, Yi Hui Melissa
dc.contributor.authorSuda, Kazuto
dc.contributor.authorShimura, Mitsuhiro
dc.contributor.authorChen, Sabirah
dc.contributor.authorPang, ShuChin
dc.contributor.authorKohu, Kazuyoshi
dc.contributor.authorKaneko, Mari
dc.contributor.authorKiyonari, Hiroshi
dc.contributor.authorKaneda, Atsushi
dc.contributor.authorYoshida, Hideyuki
dc.contributor.authorTaniuchi, Ichiro
dc.contributor.authorOsato, Motomi
dc.contributor.authorYang, Henry
dc.contributor.authorUnno, Michiaki
dc.contributor.authorSo, Jimmy Bok-Yan
dc.contributor.authorYeoh, Khay Guan
dc.contributor.authorChuang, Linda Shyue Huey
dc.contributor.authorBae, Suk-Chul
dc.contributor.authorIto, Yoshiaki
dc.date.accessioned2023-05-02T06:25:56Z
dc.date.available2023-05-02T06:25:56Z
dc.date.issued2022-03-17
dc.identifier.citationDouchi, 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
dc.identifier.issn2352-345X
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/239101
dc.description.abstractBackground & 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.
dc.language.isoen
dc.publisherELSEVIER INC
dc.sourceElements
dc.subjectScience & Technology
dc.subjectLife Sciences & Biomedicine
dc.subjectGastroenterology & Hepatology
dc.subjectIsthmus
dc.subject<p>Stem/Progenitor Cell</p>
dc.subjectEnhanced Stem Cell Activity
dc.subjectPreneoplastic State
dc.subjectGastric Carcinogenesis
dc.subjectPOLYPEPTIDE-EXPRESSING METAPLASIA
dc.subjectHELICOBACTER-PYLORI INFECTION
dc.subjectRESTRICTION-POINT
dc.subjectTUMOR-SUPPRESSOR
dc.subjectEPITHELIAL-CELLS
dc.subjectMETHYLATION
dc.subjectCARCINOGENESIS
dc.subjectIDENTIFICATION
dc.subjectCORPUS
dc.subjectGROWTH
dc.typeArticle
dc.date.updated2023-05-02T01:38:48Z
dc.contributor.departmentCANCER SCIENCE INSTITUTE OF SINGAPORE
dc.contributor.departmentSURGERY
dc.contributor.departmentMEDICINE
dc.description.doi10.1016/j.jcmgh.2022.01.010
dc.description.sourcetitleCELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
dc.description.volume13
dc.description.issue5
dc.description.page1317-1345
dc.published.statePublished
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