title: miRNA-26b Overexpression in Ulcerative Colitis-associated Carcinogenesis.
abstract: 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.
authors.affiliation: *Department of Experimental Tumor Pathology, Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany; †Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany; ‡First Department of Medicine, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany; Departments of §Urology and ‖Pediatrics and Adolescent Medicine, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany; ¶Stratifyer Molecular Pathology GmbH, Cologne, Germany; **Faculty of School of Chemical and Biotechnology, SASTRA University, Thanjavur, India; ††Institute of Pathology, University Regensburg, Regensburg, Germany; and ‡‡Department of Basic Biomedical Sciences, Laboratory of Biology, School of Medicine, University of Athens, Athens, Greece.
authors.forename: Natalya
authors.initials: N
authors.lastname: Benderska
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Dittrich
authors.forename: Sabine
authors.initials: S
authors.lastname: Knaup
authors.forename: Tilman T
authors.initials: TT
authors.lastname: Rau
authors.forename: Clemens
authors.initials: C
authors.lastname: Neufert
authors.forename: Sven
authors.initials: S
authors.lastname: Wach
authors.forename: Fabian B
authors.initials: FB
authors.lastname: Fahlbusch
authors.forename: Manfred
authors.initials: M
authors.lastname: Rauh
authors.forename: Ralph M
authors.initials: RM
authors.lastname: Wirtz
authors.forename: Abbas
authors.initials: A
authors.lastname: Agaimy
authors.forename: Swetha
authors.initials: S
authors.lastname: Srinivasan
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Mahadevan
authors.forename: Petra
authors.initials: P
authors.lastname: Rümmele
authors.forename: Emmanouela
authors.initials: E
authors.lastname: Rapti
authors.forename: Maria
authors.initials: M
authors.lastname: Gazouli
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.forename: Regine
authors.initials: R
authors.lastname: Schneider-Stock
mesh_terms: D000328:Adult; D060565:Argonaute Proteins / Q000235:genetics / Q000378:metabolism; D019313:BRCA1 Protein / Q000235:genetics; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics*; D050882:CREB-Binding Protein / Q000235:genetics; D063646:Carcinogenesis / Q000378:metabolism*; D002446:Celiac Disease / Q000097:blood / Q000150:complications; D002648:Child; D003093:Colitis, Ulcerative / Q000097:blood / Q000150:complications*; D003106:Colon / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000097:blood / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017403:In Situ Hybridization; D019394:Ki-67 Antigen / Q000378:metabolism; D008156:Luciferases; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D011446:Prospective Studies; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D012313:RNA / Q000378:metabolism; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics
chemical_list: D060565:Argonaute Proteins; D019313:BRCA1 Protein; D014408:Biomarkers, Tumor; D050882:CREB-Binding Protein; D019394:Ki-67 Antigen; D008156:Luciferases; D035683:MicroRNAs; D051736:Proto-Oncogene Proteins c-mdm2; D012313:RNA; D014157:Transcription Factors; C466422:AGO2 protein, human; C485815:CCNDBP1 protein, human; C528163:MIRN26 microRNA, human; C494363:CREBBP protein, human; C497206:MDM2 protein, human