miRNA-26b Overexpression in Ulcerative Colitis-associated Carcinogenesis

• Published in: Inflammatory bowel diseases Vol. 21; no. 9; pp. 2039 - 2051
• Main Authors: Benderska, Natalya, Dittrich, Anna-Lena, Knaup, Sabine, Rau, Tilman T, 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
• Format: Journal Article
• Language: English
• Published: England Lippincott Williams & Wilkins 01-09-2015
• Subjects: Adult; Argonaute Proteins - genetics; Argonaute Proteins - metabolism; Biomarkers, Tumor - blood; Biomarkers, Tumor - genetics; BRCA1 Protein - genetics; Carcinogenesis - metabolism; Celiac Disease - blood; Celiac Disease - complications; Child; Colitis, Ulcerative - blood; Colitis, Ulcerative - complications; Colon - metabolism; Colon - pathology; Colorectal Neoplasms - blood; Colorectal Neoplasms - genetics; CREB-Binding Protein - genetics; Disease Progression; Female; Gene Expression Regulation, Neoplastic; Humans; In Situ Hybridization; Ki-67 Antigen - metabolism; Luciferases; Male; MicroRNAs - metabolism; Middle Aged; Original Basic Science; Prospective Studies; Proto-Oncogene Proteins c-mdm2 - genetics; Retrospective Studies; Reverse Transcriptase Polymerase Chain Reaction; RNA - metabolism; Transcription Factors - genetics
• ISSN: 1078-0998; 1536-4844
• DOI: 10.1097/MIB.0000000000000453

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.
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.
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.
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.