title: MicroRNA214 Is Associated With Progression of Ulcerative Colitis, and Inhibition Reduces Development of Colitis and Colitis-Associated Cancer in Mice.
abstract: OBJECTIVE
  Persistent activation of the inflammatory response contributes to the development of inflammatory bowel diseases, which increase the risk of colorectal cancer. We aimed to identify microRNAs that regulate inflammation during the development of ulcerative colitis (UC) and progression to colitis-associated colon cancer (CAC).
  
  
  METHODS
  We performed a quantitative polymerase chain reaction analysis to measure microRNAs in 401 colon specimens from patients with UC, Crohn's disease, irritable bowel syndrome, sporadic colorectal cancer, or CAC, as well as subjects without these disorders (controls); levels were correlated with clinical features and disease activity of patients. Colitis was induced in mice by administration of dextran sodium sulfate (DSS), and carcinogenesis was induced by addition of azoxymethane; some mice also were given an inhibitor of microRNA214 (miR214).
  
  
  RESULTS
  A high-throughput functional screen of the human microRNAome found that miR214 regulated the activity of nuclear factor-κB. Higher levels of miR214 were detected in colon tissues from patients with active UC or CAC than from patients with other disorders or controls and correlated with disease progression. Bioinformatic and genome-wide profile analyses showed that miR214 activates an inflammatory response and is amplified through a feedback loop circuit mediated by phosphatase and tensin homolog (PTEN) and PDZ and LIM domain 2 (PDLIM2). Interleukin-6 induced signal transducer and activator of transcription 3 (STAT3)-mediated transcription of miR214. A miR214 chemical inhibitor blocked this circuit and reduced the severity of DSS-induced colitis in mice, as well as the number and size of tumors that formed in mice given azoxymethane and DSS. In fresh colonic biopsy specimens from patients with active UC, the miR214 inhibitor reduced inflammation by increasing levels of PDLIM2 and PTEN.
  
  
  CONCLUSIONS
  Interleukin-6 up-regulates STAT3-mediated transcription of miR214 in colon tissues, which reduces levels of PDLIM2 and PTEN, increases phosphorylation of AKT, and activates nuclear factor-κB. The activity of this circuit correlates with disease activity in patients with UC and progression to colorectal cancer.
authors.affiliation: Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
authors.forename: Christos
authors.initials: C
authors.lastname: Polytarchou
authors.affiliation: Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands; Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Hommes
authors.affiliation: Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Palumbo
authors.affiliation: Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
authors.forename: Maria
authors.initials: M
authors.lastname: Hatziapostolou
authors.affiliation: Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
authors.forename: Marina
authors.initials: M
authors.lastname: Koutsioumpa
authors.affiliation: Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
authors.forename: Georgios
authors.initials: G
authors.lastname: Koukos
authors.affiliation: Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: van der Meulen-de Jong
authors.affiliation: Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
authors.forename: Angelos
authors.initials: A
authors.lastname: Oikonomopoulos
authors.affiliation: Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands; Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
authors.forename: Welmoed K
authors.initials: WK
authors.lastname: van Deen
authors.affiliation: Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
authors.forename: Christina
authors.initials: C
authors.lastname: Vorvis
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.
authors.forename: Oksana B
authors.initials: OB
authors.lastname: Serebrennikova
authors.affiliation: Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
authors.forename: Eleni
authors.initials: E
authors.lastname: Birli
authors.affiliation: Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Choi
authors.affiliation: Gail and Gerard Oppenheimer Family Center of Neurobiology of Stress, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
authors.forename: Lin
authors.initials: L
authors.lastname: Chang
authors.affiliation: Center for HIV Prevention Research, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Anton
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.
authors.forename: Philip N
authors.initials: PN
authors.lastname: Tsichlis
authors.affiliation: Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
authors.forename: Charalabos
authors.initials: C
authors.lastname: Pothoulakis
authors.affiliation: Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Hein W
authors.initials: HW
authors.lastname: Verspaget
authors.affiliation: Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California. Electronic address: diliopoulos@mednet.ucla.edu.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Iliopoulos
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001397:Azoxymethane; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D002460:Cell Line; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D060588:LIM Domain Proteins / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D000067492:RNAi Therapeutics; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D018836:Inflammation Mediators; D015850:Interleukin-6; D060588:LIM Domain Proteins; C547397:MIRN214 microRNA, human; D035683:MicroRNAs; C534781:Mirn214 microRNA, mouse; D016328:NF-kappa B; C508508:Pdlim2 protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C577686:interleukin-6, mouse; D016264:Dextran Sulfate; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D001397:Azoxymethane
keywords: Chronic Inflammation; IBD Progression; IL6; Mouse Model