MicroRNA214 Is Associated With Progression of Ulcerative Colitis, and Inhibition Reduces Development of Colitis and Colitis-Associated Cancer in Mice
| Autor: | Hein W. Verspaget, Daniel W. Hommes, Dimitrios Iliopoulos, Tiziana Palumbo, Eleni Birli, Charalabos Pothoulakis, Peter A. Anton, Philip N. Tsichlis, Christina Vorvis, Georgios Koukos, Lin Chang, Welmoed K. van Deen, Maria Hatziapostolou, Angelos Oikonomopoulos, Jennifer M. Choi, Oksana B. Serebrennikova, Andrea E. van der Meulen-de Jong, Marina Koutsioumpa, Christos Polytarchou |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Transcription
Genetic Colorectal cancer Ulcerative medicine.disease_cause Oral and gastrointestinal Mice chemistry.chemical_compound Tumor Cells Cultured 2.1 Biological and endogenous factors Medicine Phosphorylation Irritable bowel syndrome Cancer Crohn's disease Cultured Tumor biology Dextran Sulfate NF-kappa B Gastroenterology Adaptor Proteins LIM Domain Proteins Colitis Ulcerative colitis Tumor Cells Colo-Rectal Cancer Gene Expression Regulation Neoplastic Colonic Neoplasms Disease Progression RNA Interference Inflammation Mediators Transcription Signal Transduction STAT3 Transcription Factor Colon Clinical Sciences Azoxymethane Transfection Autoimmune Disease Article Cell Line IBD Progression Paediatrics and Reproductive Medicine Genetic Chronic Inflammation Genetics Biomarkers Tumor Animals Humans PTEN Adaptor Proteins Signal Transducing Nutrition Neoplastic Mouse Model Gastroenterology & Hepatology Hepatology Animal Interleukin-6 business.industry Inflammatory Bowel Disease Signal Transducing PTEN Phosphohydrolase Neurosciences medicine.disease IL6 Disease Models Animal MicroRNAs RNAi Therapeutics Gene Expression Regulation chemistry Case-Control Studies Disease Models biology.protein Cancer research Colitis Ulcerative Digestive Diseases business Carcinogenesis Proto-Oncogene Proteins c-akt Biomarkers |
| Zdroj: | Polytarchou, C; Hommes, DW; Palumbo, T; Hatziapostolou, M; Koutsioumpa, M; Koukos, G; et al.(2015). MicroRNA214 Is Associated With Progression of Ulcerative Colitis, and Inhibition Reduces Development of Colitis and Colitis-Associated Cancer in Mice. Gastroenterology, 149(4), 981-992. doi: 10.1053/j.gastro.2015.05.057. UCLA: Retrieved from: http://www.escholarship.org/uc/item/10q2q0wj Gastroenterology, vol 149, iss 4 |
| DOI: | 10.1053/j.gastro.2015.05.057. |
| Popis: | © 2015 AGA Institute. Background & Aims 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. |
| Databáze: | OpenAIRE |
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