A Point Mutation R122C in RUNX3 Promotes the Expansion of Isthmus Stem Cells and Inhibits Their Differentiation in the Stomach

Daisuke Douchi, Akihiro Yamamura, Junichi Matsuo, Jung Won Lee, Napat Nuttonmanit, Yi Hui Melissa Lim, Kazuto Suda, Mitsuhiro Shimura, Sabirah Chen, Shu Chin Pang, Kazuyoshi Kohu, Mari Kaneko, Hiroshi Kiyonari, Atsushi Kaneda, Hideyuki Yoshida, Ichiro Taniuchi, Motomi Osato, Henry Yang, Michiaki Unno, Jimmy Bok-Yan SoKhay Guan Yeoh, Linda Shyue Huey Chuang, Suk Chul Bae, Yoshiaki Ito

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1317-1345
Number of pages29
Issue number5
Publication statusPublished - 2022 Jan
Externally publishedYes


  • Enhanced Stem Cell Activity
  • Gastric Carcinogenesis
  • Isthmus
  • Preneoplastic State
  • Stem/Progenitor Cell

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology


Dive into the research topics of 'A Point Mutation R122C in RUNX3 Promotes the Expansion of Isthmus Stem Cells and Inhibits Their Differentiation in the Stomach'. Together they form a unique fingerprint.

Cite this