Role of Ras in regulation of intestinal epithelial cell homeostasis and crosstalk with Wnt signaling

PLoS One. 2021 Aug 26;16(8):e0256774. doi: 10.1371/journal.pone.0256774. eCollection 2021.

Abstract

Cross talk between different signaling pathways is thought to be important for regulation of homeostasis of, as well as oncogenesis of, the intestinal epithelium. Expression of an active form of K-Ras specifically in intestinal epithelial cells (IECs) of mice (IEC-RasDA mice) resulted in the development of hyperplasia in the small intestine and colon of mice. IEC-RasDA mice also manifested the increased proliferation of IECs. In addition, the number of goblet cells markedly increased, while that of Paneth cells decreased in IEC-RasDA mice. Development of intestinal organoids was markedly enhanced for IEC-RasDA mice compared with control mice. Whereas, the expression of Wnt target genes was significantly reduced in the in intestinal crypts from IEC-RasDA mice compared with that apparent for the control. Our results thus suggest that K-Ras promotes the proliferation of IECs as well as generation of goblet cells. By contrast, Ras counter-regulates the Wnt signaling and thereby contribute to the proper regulation of intestinal epithelial cell homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / genetics
  • Cell Proliferation / genetics*
  • Colon / growth & development
  • Colon / pathology
  • Gene Expression Regulation, Neoplastic / genetics
  • Goblet Cells / metabolism
  • Homeostasis / genetics*
  • Humans
  • Intestinal Mucosa / growth & development*
  • Intestinal Mucosa / pathology
  • Intestine, Small / metabolism
  • Mice
  • Organoids / metabolism*
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Wnt Signaling Pathway / genetics

Substances

  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)

Grants and funding

This work was supported by a Grant-in-Aid for Scientific Research (C) (20K07358 to Takenori K.) and a Grant-in-Aid for Challenging Exploratory Research (16K15219 to T.M.) from the Japan Society for the Promotion of Science, as well as by the Uehara Memorial Foundation (to Takenori K.) and Takeda Science Foundation (to Takenori K.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.