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

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.

• Authors: 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
• Journal: Inflammatory bowel diseases (Inflamm Bowel Dis) Vol. 23 Issue 8 Pg. 1328-1337 (08 2017) ISSN: 1536-4844 [Electronic] England
• PMID: 28594651 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)

Chemical References

• Biomarkers, Tumor
• CAV1 protein, human
• COL1A2 protein, human
• Caveolin 1
• Collagen Type I
• MIRN4728 microRNA, human
• MicroRNAs
• Thrombospondins
• thrombospondin 2

Topics

• Adult
• Biomarkers, Tumor (genetics, metabolism)
• Caveolin 1 (genetics, metabolism)
• Colitis, Ulcerative (complications)
• Collagen Type I (genetics, metabolism)
• Colorectal Neoplasms (etiology, metabolism, pathology)
• Female
• Focal Adhesions (genetics)
• Follow-Up Studies
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• MicroRNAs (genetics)
• Middle Aged
• Prognosis
• Signal Transduction
• Thrombospondins (genetics, metabolism)