miRNA-26b Overexpression in Ulcerative Colitis-associated Carcinogenesis

Benderska, Natalya; Dittrich, Anna-Lena; Knaup, Sabine; Rau, Tilman; Neufert, Clemens; Wach, Sven; Fahlbusch, Fabian B; Rauh, Manfred; Wirtz, Ralph M; Agaimy, Abbas; Srinivasan, Swetha; Mahadevan, Vijayalakshmi; Rümmele, Petra; Rapti, Emmanouela; Gazouli, Maria; Hartmann, Arndt; Schneider-Stock, Regine (2015). miRNA-26b Overexpression in Ulcerative Colitis-associated Carcinogenesis. Inflammatory bowel diseases, 21(9), pp. 2039-2051. Lippincott Williams & Wilkins 10.1097/MIB.0000000000000453

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BACKGROUND

Longstanding ulcerative colitis (UC) bears a high risk for development of UC-associated colorectal carcinoma (UCC). The inflammatory microenvironment influences microRNA expression, which in turn deregulates target gene expression. microRNA-26b (miR-26b) was shown to be instrumental in normal tissue growth and differentiation. Thus, we aimed to investigate the impact of miR-26b in inflammation-associated colorectal carcinogenesis.

METHODS

Two different cohorts of patients were investigated. In the retrospective group, a tissue microarray with 38 samples from 17 UC/UCC patients was used for miR-26b in situ hybridization and quantitative reverse transcription polymerase chain reaction analyses. In the prospective group, we investigated miR-26b expression in 25 fresh-frozen colon biopsies and corresponding serum samples of 6 UC and 15 non-UC patients, respectively. In silico analysis, Ago2-RNA immunoprecipitation, luciferase reporter assay, quantitative reverse transcription polymerase chain reaction examination, and miR-26b mimic overexpression were employed for target validation.

RESULTS

miR-26b expression was shown to be upregulated with disease progression in tissues and serum of UC and UCC patients. Using miR-26b and Ki-67 expression levels, an UCC was predicted with high accuracy. We identified 4 novel miR-26b targets (DIP1, MDM2, CREBBP, BRCA1). Among them, the downregulation of the E3 ubiquitin ligase DIP1 was closely related to death-associated protein kinase stabilization along the normal mucosa-UC-UCC sequence. In silico functional pathway analysis revealed that the common cellular pathways affected by miR-26b are highly related to cancerogenesis and the development of gastrointestinal diseases.

CONCLUSIONS

We suggest that miR-26b could serve as a biomarker for inflammation-associated processes in the gastrointestinal system. Because miR-26b expression is downregulated in sporadic colon cancer, it could discriminate between UCC and the sporadic cancer type.

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