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An essential mesenchymal function for miR-143/145 in intestinal epithelial regeneration.

Abstract
Downregulation of the miR-143/145 microRNA (miRNA) cluster has been repeatedly reported in colon cancer and other epithelial tumors. In addition, overexpression of these miRNAs inhibits tumorigenesis, leading to broad consensus that they function as cell-autonomous epithelial tumor suppressors. We generated mice with deletion of miR-143/145 to investigate the functions of these miRNAs in intestinal physiology and disease in vivo. Although intestinal development proceeded normally in the absence of these miRNAs, epithelial regeneration after injury was dramatically impaired. Surprisingly, we found that miR-143/145 are expressed and function exclusively within the mesenchymal compartment of intestine. Defective epithelial regeneration in miR-143/145-deficient mice resulted from the dysfunction of smooth muscle and myofibroblasts and was associated with derepression of the miR-143 target Igfbp5, which impaired IGF signaling after epithelial injury. These results provide important insights into the regulation of epithelial wound healing and argue against a cell-autonomous tumor suppressor role for miR-143/145 in colon cancer.
AuthorsRaghu R Chivukula, Guanglu Shi, Asha Acharya, Eric W Mills, Lauren R Zeitels, Joselin L Anandam, Abier A Abdelnaby, Glen C Balch, John C Mansour, Adam C Yopp, Anirban Maitra, Joshua T Mendell
JournalCell (Cell) Vol. 157 Issue 5 Pg. 1104-16 (May 22 2014) ISSN: 1097-4172 [Electronic] United States
PMID24855947 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 Elsevier Inc. All rights reserved.
Chemical References
  • Insulin-Like Growth Factor Binding Protein 5
  • MIRN145a microRNA, mouse
  • MicroRNAs
  • MIRN143 microRNA, mouse
  • Somatomedins
  • Dextran Sulfate
Topics
  • Animals
  • Colonic Neoplasms (metabolism, pathology)
  • Dextran Sulfate
  • Humans
  • Insulin-Like Growth Factor Binding Protein 5 (genetics)
  • Intestinal Mucosa (cytology, physiology)
  • Mesoderm (metabolism)
  • Mice
  • MicroRNAs (genetics, metabolism)
  • Myofibroblasts (metabolism)
  • Paracrine Communication
  • Regeneration
  • Somatomedins (metabolism)

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