Tumor suppressor APC protein is essential in mucosal repair from colonic inflammation through angiogenesis.

Abstract

Mucosal repair after acute colonic inflammation is central to maintaining mucosal homeostasis. Failure of mucosal repair often leads to chronic inflammation, sometimes associated with inflammatory bowel disease (IBD). The adenomatous polyposis coli (APC) tumor suppressor gene regulates the Wnt signaling pathway, which is essential for epithelial development, and inactivation of APC facilitates colorectal cancer. Our previous study suggested that APC is involved in pathogenesis of colonic inflammation; however, its role in mucosal repair remains unknown. In this article, we report that colitis induced by dextran sodium sulfate persisted with delayed mucosal repair in Kyoto Apc Delta (KAD) rats lacking the APC C terminus. Defects in the repair process were accompanied by an absence of a fibrin layer covering damaged mucosa and reduced microvessel angiogenesis. APC was up-regulated in vascular endothelial cells (VECs) in inflamed mucosa in KAD and F344 (control) rats. The VECs of KAD rats revealed elevated cell adhesion and low-branched and short-length tube formation. We also found that DLG5, which is associated with IBD pathogenesis, was up-regulated in VECs in inflamed mucosa and interacted with the C terminus of APC. This finding suggests that loss of interaction between the APC C terminus and DLG5 affects VEC morphology and function and leads to persistence of colitis. Therefore, APC is essential for maintenance of intestinal mucosal homeostasis and can consequently contribute to IBD pathogenesis.

• Authors: Kazuto Yoshimi, Takuji Tanaka, Tadao Serikawa, Takashi Kuramoto
• Journal: The American journal of pathology (Am J Pathol) Vol. 182 Issue 4 Pg. 1263-74 (Apr 2013) ISSN: 1525-2191 [Electronic] United States
• PMID: 23395091 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Adenomatous Polyposis Coli Protein
• Cytokines
• Inflammation Mediators
• Mapre1 protein, rat
• Membrane Proteins
• Microtubule-Associated Proteins
• Fibrin
• Dextran Sulfate

Topics

• Adenomatous Polyposis Coli Protein (chemistry, metabolism)
• Animals
• Cell Adhesion
• Colitis (chemically induced, metabolism, pathology)
• Colon (blood supply, pathology)
• Cytokines (metabolism)
• Dextran Sulfate
• Endothelial Cells (metabolism, pathology)
• Epithelium (metabolism, pathology)
• Fibrin (metabolism)
• Inflammation (pathology)
• Inflammation Mediators (metabolism)
• Intestinal Mucosa (metabolism, pathology)
• Male
• Membrane Proteins (metabolism)
• Microtubule-Associated Proteins (metabolism)
• Neovascularization, Physiologic
• Protein Binding
• Protein Transport
• Rats
• Rats, Inbred F344
• Time Factors
• Wnt Signaling Pathway
• Wound Healing