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Inflamm Bowel Dis. 2017 Aug;23(8):1328-1337. doi: 10.1097/MIB.0000000000001104.

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

Author information

1
*Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago, Chicago, Illinois; †Department of Chemistry, University of Chicago, Chicago, Illinois; ‡Section of Gastroenterology, Northwestern University, Chicago, Illinois; §Department of Surgery, University of Chicago, Chicago, Illinois; ‖Department of Surgery, University of Washington, Seattle, Washington; and ¶Department of Pathology, University of Chicago, Chicago, Illinois.

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.

PMID:
28594651
PMCID:
PMC5535754
DOI:
10.1097/MIB.0000000000001104
[Indexed for MEDLINE]
Free PMC Article

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