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Cell. 2014 May 22;157(5):1104-16. doi: 10.1016/j.cell.2014.03.055.

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

Author information

1
Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
2
Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
3
Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA.
4
Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
5
Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Harold C. Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: joshua.mendell@utsouthwestern.edu.

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.

PMID:
24855947
PMCID:
PMC4175516
DOI:
10.1016/j.cell.2014.03.055
[Indexed for MEDLINE]
Free PMC Article
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