MiR-143 and miR-145 are downregulated in ulcerative colitis: Putative regulators of inflammation and protooncogenes

Joel R. Pekow*, Urszula Dougherty, Reba Mustafi, Hongyan Zhu, Masha Kocherginsky, David T. Rubin, Stephen B. Hanauer, John Hart, Eugene B. Chang, Alessandro Fichera, Loren J. Joseph, Marc Bissonnette

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

Background: miR-143 and miR-145 are believed to function as colon cancer tumor suppressors, as they inhibit colon cancer cell growth and are downregulated in sporadic colonic tumors. We speculated that miR-143 and miR-145 might also be downregulated and contribute to malignant transformation of colonic epithelium in longstanding ulcerative colitis (UC). Methods: Biopsies were obtained 20 cm proximal to the anus from individuals with quiescent UC and from normal controls. RNA and proteins were extracted and measured. miR-143 and miR-145 were quantified by real-time polymerase chain reaction (PCR) and miR-145 was also assessed by in situ hybridization. Putative targets of these miRNAs, K-RAS, API5, MEK-2 (miR-143), and IRS-1 (miR-145) were determined by western blotting. To assess the effects of miR-143 and miR-145 on these predicted targets, HCT116 and HCA-7 colorectal cancer cells were transfected with miR-143 and miR-145 and expression levels of these proteins were measured. Results: In UC, miR-143 and miR-145 were significantly downregulated 8.3-fold (3.4-20.1) (P < 0.0001) and 4.3-fold (2.3-7.8) (P < 0.0001), respectively, compared to normal colon. In contrast, IRS-1, K-RAS, API5, and MEK-2 were upregulated in UC, consistent with their assignments as targets of these miRNAs. Furthermore, transfected miR-143 and miR-145 significantly downregulated these proteins in HCT116 or HCA-7 cells. Conclusions: Compared to normal colonic mucosa, in chronic UC miR-143 and miR-145 were significantly downregulated and their predicted targets, IRS-1, K-RAS, API5, and MEK-2 were upregulated. We postulate that loss of these tumor suppressor miRNAs predispose to chronic inflammation and neoplastic progression in IBD.

Original languageEnglish (US)
Pages (from-to)94-100
Number of pages7
JournalInflammatory bowel diseases
Volume18
Issue number1
DOIs
StatePublished - Jan 2012

Keywords

  • colorectal cancer
  • microRNA
  • ulcerative colitis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Gastroenterology

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