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

• Published in: PloS one 2021-08, Vol.16 (8), p.e0256774-e0256774
• Main Authors: Kotani, Takenori, Ihara, Noriko, Okamoto, Saki, Setiawan, Jajar, Konno, Tasuku, Saito, Yasuyuki, Murata, Yoji, Matozaki, Takashi
• Format: Article
• Language: English
• Subjects: Ablation; Analysis; Animals; Antibodies; Biochemistry; Biology and Life Sciences; Carcinogenesis - genetics; Cell proliferation; Cell Proliferation - genetics; Colon; Colon - growth & development; Colon - pathology; Crosstalk; Crypts; Epidermal growth factor; Epithelial cells; Epithelium; Ethylenediaminetetraacetic acid; Gene expression; Gene Expression Regulation, Neoplastic - genetics; Goblet cells; Goblet Cells - metabolism; Homeostasis; Homeostasis - genetics; Humans; Hyperplasia; Intestinal Mucosa - growth & development; Intestinal Mucosa - pathology; Intestine; Intestine, Small - metabolism; K-Ras protein; Kinases; Ligands; Medicine; Medicine and Health Sciences; Mice; Molecular biology; Mutation; Organoids; Organoids - metabolism; Paneth cells; Peptides; Proto-Oncogene Proteins p21(ras) - genetics; Regulation; Research and Analysis Methods; Signaling; Small intestine; Tumorigenesis; University graduates; Wnt protein; Wnt Signaling Pathway - genetics
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0256774

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.