Abstract | BACKGROUND & AIMS: METHODS: 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 | Christos Polytarchou, Daniel W Hommes, Tiziana Palumbo, Maria Hatziapostolou, Marina Koutsioumpa, Georgios Koukos, Andrea E van der Meulen-de Jong, Angelos Oikonomopoulos, Welmoed K van Deen, Christina Vorvis, Oksana B Serebrennikova, Eleni Birli, Jennifer Choi, Lin Chang, Peter A Anton, Philip N Tsichlis, Charalabos Pothoulakis, Hein W Verspaget, Dimitrios Iliopoulos |
Journal | Gastroenterology
(Gastroenterology)
Vol. 149
Issue 4
Pg. 981-92.e11
(Oct 2015)
ISSN: 1528-0012 [Electronic] United States |
PMID | 26055138
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
|
Copyright | Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- Adaptor Proteins, Signal Transducing
- Biomarkers, Tumor
- Inflammation Mediators
- Interleukin-6
- LIM Domain Proteins
- MIRN214 microRNA, human
- MicroRNAs
- Mirn214 microRNA, mouse
- NF-kappa B
- Pdlim2 protein, mouse
- STAT3 Transcription Factor
- Stat3 protein, mouse
- interleukin-6, mouse
- Dextran Sulfate
- Proto-Oncogene Proteins c-akt
- PTEN Phosphohydrolase
- Pten protein, mouse
- Azoxymethane
|
Topics |
- Adaptor Proteins, Signal Transducing
(metabolism)
- Animals
- Azoxymethane
- Biomarkers, Tumor
(genetics, metabolism)
- Case-Control Studies
- Cell Line
- Colitis, Ulcerative
(chemically induced, genetics, metabolism, pathology, prevention & control)
- Colon
(metabolism, pathology)
- Colonic Neoplasms
(chemically induced, genetics, metabolism, pathology, prevention & control)
- Dextran Sulfate
- Disease Models, Animal
- Disease Progression
- Gene Expression Regulation, Neoplastic
- Humans
- Inflammation Mediators
(metabolism)
- Interleukin-6
(metabolism)
- LIM Domain Proteins
(metabolism)
- Mice
- MicroRNAs
(genetics, metabolism)
- NF-kappa B
(metabolism)
- PTEN Phosphohydrolase
(metabolism)
- Phosphorylation
- Proto-Oncogene Proteins c-akt
(metabolism)
- RNA Interference
- RNAi Therapeutics
- STAT3 Transcription Factor
(metabolism)
- Signal Transduction
- Transcription, Genetic
- Transfection
- Tumor Cells, Cultured
|
|
Join CureHunter, for free Research Interface BASIC access!
Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease.
Find out why thousands of doctors, pharma researchers and patient activists
around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!
|