title: 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.
authors.affiliation: Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Raghu R
authors.initials: RR
authors.lastname: Chivukula
authors.affiliation: Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Guanglu
authors.initials: G
authors.lastname: Shi
authors.affiliation: Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Asha
authors.initials: A
authors.lastname: Acharya
authors.affiliation: Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Mills
authors.affiliation: Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Lauren R
authors.initials: LR
authors.lastname: Zeitels
authors.affiliation: Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Joselin L
authors.initials: JL
authors.lastname: Anandam
authors.affiliation: Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Abier A
authors.initials: AA
authors.lastname: Abdelnaby
authors.affiliation: Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Glen C
authors.initials: GC
authors.lastname: Balch
authors.affiliation: Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Mansour
authors.affiliation: Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Yopp
authors.affiliation: Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.affiliation: 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.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Mendell
mesh_terms: D000818:Animals; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate; D006801:Humans; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000235:genetics; D007413:Intestinal Mucosa / Q000166:cytology / Q000502:physiology*; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D058628:Myofibroblasts / Q000378:metabolism; D019899:Paracrine Communication; D012038:Regeneration; D013002:Somatomedins / Q000378:metabolism
chemical_list: D018975:Insulin-Like Growth Factor Binding Protein 5; C543499:MIRN145a microRNA, mouse; D035683:MicroRNAs; C532884:MIRN143 microRNA, mouse; D013002:Somatomedins; D016264:Dextran Sulfate