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.
Highlights
Intestinal stem cells (ISCs), which reside at the base of intestinal crypts, maintain renewal of intestinal epithelial cells (IECs) by generating proliferating progeny, known as transient amplifying (TA) cells [1, 2]
Histological examination revealed that epithelial hyperplasia was pronounced in the ileum and colon of IEC-RasDA mice compared with control mice (Fig 1C)
Given that ablation of Shp2, a protein tyrosine phosphatase which is essential for activation by growth factors of Ras, up-regulates the expression of stem-cell–associated genes and Wnt target genes in the small intestine [13], we focused on the Wnt–β-catenin signaling in IECs from IEC-RasDA mice
Summary
Intestinal stem cells (ISCs), which reside at the base of intestinal crypts, maintain renewal of intestinal epithelial cells (IECs) by generating proliferating progeny, known as transient amplifying (TA) cells [1, 2]. The best characterized signaling as a positive regulator for maintaining ISCs is the Wnt–β-catenin signaling [3, 4]. Wnt ligands, such as Wnt, are predominantly secreted by Paneth cells and activates the Wnt–β-catenin signaling in IECs [3]. The Wnt–β-catenin signaling normally promotes the proliferation of ISCs or TA cells and the maturation of Paneth cells [4, 5].
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