MIR-4728-3p Functions as a Tumor Suppressor in Ulcerative Colitis-associated Colorectal Neoplasia Through Regulation of Focal Adhesion Signaling

Joel Pekow*, Alan L. Hutchison, Katherine Meckel, Kymberly Harrington, Zifeng Deng, Nitya Talasila, David T. Rubin, Stephen B. Hanauer, Roger Hurst, Konstantin Umanskiy, Alessandro Fichera, John Hart, Aaron R. Dinner, Marc Bissonnette

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Background: As mechanisms of neoplasia in patients with ulcerative colitis (UC) remain poorly understood, we sought to identify pathways of carcinogenesis in this high-risk population. Methods: MicroRNA (miRNA) and mRNA expression was examined in nondysplastic rectosigmoid mucosa from UC patients with (n = 19) or without remote colon neoplasia (n = 23). We developed a method to identify miRNA-regulated pathways based on differentially expressed miRNAs and their putative mRNAs targets in the same samples. One key pathway identified in the analysis, miR-4728-3p regulation of focal adhesion signaling was further evaluated in vitro and through examination of expression in UC-cancers. Results: There were 101 significantly up-regulated and 98 down-regulated miRNAs (adjusted P < 0.05) in the rectal mucosa of UC patients harboring proximal neoplasia. Bioinformatic analysis identified miR-4728-3p as a regulator of 3 proteins involved in focal adhesion signaling, CAV1, THBS2, and COL1A2. Real-time PCR validated down-regulation of miR-4728-3p in nondysplastic tissue remote from UC-neoplasia and in UC-associated colon cancers. miR-4728-3p transfection into colon cancer cells down-regulated expression levels and decreased luciferase activities in cells expressing a wild type 3′ untranslated region compared with a mutant 3′ untranslated region for all 3 genes. Exogenous transfected miR-4728-3p also delayed wound healing and decreased formation of focal adhesion complexes. Conclusions: Patients with long-standing UC who harbor neoplasia can be identified based on miRNA and mRNA profiles in nondysplastic tissue. Using a method to analyze miRNA and mRNA expression from the same tissues, we identified that miR-4728-3p is likely an important tumor suppressor in UC-associated colon carcinogenesis.

Original languageEnglish (US)
Pages (from-to)1328-1337
Number of pages10
JournalInflammatory bowel diseases
Volume23
Issue number8
DOIs
StatePublished - Aug 1 2017

Keywords

  • colon cancer
  • dysplasia
  • focal adhesion
  • inflammatory bowel disease
  • miRNA
  • ulcerative colitis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Gastroenterology

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