miRNA-26b Overexpression in Ulcerative Colitis-associated Carcinogenesis.

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.

Association of survivin promoter polymorphisms with inflammatory bowel disease and response to antitumor necrosis factor therapy.

BACKGROUND/AIM: Recent evidence suggests that survivin, a member of the inhibitors of apoptosis family that prevents cell death and regulates cell division is implicated in the pathogenesis of inflammatory bowel disease (IBD). The aim of the study was to identify a possible association between individual genetic variation, IBD susceptibility, and response to infliximab (IFX). MATERIAL AND METHODS: The expression levels of survivin were detected in pathologic areas of fresh tissues and blood samples by real-time reverse transcriptase - polymerase chain reaction (RT-PCR) from IBD patients. Polymorphisms were identified using the polymerase chain reaction - Restriction Fragment Length Polymorphism (PCR-RFLP) technique. Clinical and endoscopic response to IFX was evaluated by ileocolonoscopy performed at baseline and after 12-20 weeks of therapy with patients classified as either responders or nonresponders. RESULTS: No significant differences were found between survivin mRNA levels between patients and controls. Significant differences in both allele and genotype frequencies between Crohn's disease (CD) and ulcerative colitis (UC) patients and controls were found in -31C/G polymorphism. No association with IBD development was found for the -625G/C and -241T/C polymorphisms, since those polymorphisms were overrepresented in a healthy population. Additionally no significant association was found between -31C/G polymorphism and the clinical response of CD patients to IFX. CONCLUSIONS: Survivin promoter polymorphism -31C/G might influence the susceptibility to IBD in the Greek population, but not the CD patient's response to anti-TNF drugs.