Dataset Information

MicroRNA214 Is Associated With Progression of Ulcerative Colitis, and Inhibition Reduces Development of Colitis and Colitis-Associated Cancer in Mice.

ABSTRACT: 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).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).A high-throughput functional screen of the human microRNAome found that miR214 regulated the activity of nuclear factor-?B. 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.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-?B. The activity of this circuit correlates with disease activity in patients with UC and progression to colorectal cancer.

SUBMITTER: Polytarchou C

PROVIDER: S-EPMC4584179 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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MicroRNA214 Is Associated With Progression of Ulcerative Colitis, and Inhibition Reduces Development of Colitis and Colitis-Associated Cancer in Mice.

Polytarchou Christos C Hommes Daniel W DW Palumbo Tiziana T Hatziapostolou Maria M Koutsioumpa Marina M Koukos Georgios G van der Meulen-de Jong Andrea E AE Oikonomopoulos Angelos A van Deen Welmoed K WK Vorvis Christina C Serebrennikova Oksana B OB Birli Eleni E Choi Jennifer J Chang Lin L Anton Peter A PA Tsichlis Philip N PN Pothoulakis Charalabos C Verspaget Hein W HW Iliopoulos Dimitrios D

Gastroenterology 20150606 4

<h4>Background & aims</h4>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).<h4>Methods</h4>We performed a quantitative polymerase chain reaction analysis to measure microRNAs in 401 colon specimens from patients with UC, Cro ...[more]

PMID: 26055138

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Project description:BackgroundUlcerative colitis (UC) is a chronic inflammatory disease of the intestinal mucosa, the incidence of which has increased worldwide. There is still a lack of clear understanding of the pathogenesis of ulcerative colitis that ultimately leads to colitis-associated colorectal cancer.MethodWe download UC transcriptome data from the GEO database and pass the limma package in order to identify differentially expressed genes. Gene Set Enrichment Analysis (GSEA) was used to identify potential biological pathways. We identified immune cells associated with UC by CIBERSORT and Weighted co-expression network analysis (WGCNA). We used validation cohorts and mouse models to verify the expression of the hub genes and the role of neutrophils.ResultWe identified 65 differentially expressed genes in UC samples and healthy controls. GSEA, KEGG, and GO analyses displayed that DEGs were enriched in immune-related pathways. CIBERSORT analysis revealed increased infiltration of neutrophils in UC tissues. The red module, obtained by WGCNA analysis, was considered to be the most relevant module for neutrophils.Based on neutrophil-associated differentially expressed genes, UC patients were classified into two subtypes of neutrophil infiltration. We discovered that the highly neutrophil-infiltrated subtype B of UC patients had a higher risk of developing CAC. Five genes were identified as biomarkers by searching for DEGs between distinct subtypes. Finally, using the mouse model, we determined the expression of these five genes in the control, DSS, and AOM/DSS groups. The degree of neutrophil infiltration in mice and the percentage of MPO and pSTAT3 expression in neutrophils were analyzed by flow cytometry. In the AOM/DSS model, MPO and pSTAT3 expressions were significantly increased.ConclusionsThese findings suggested neutrophils might promote the conversion of UC into CAC. These findings improve our understanding of the pathogenesis of CAC and provide new and more effective insights into the prevention and treatment of CAC.

Dataset Information

MicroRNA214 Is Associated With Progression of Ulcerative Colitis, and Inhibition Reduces Development of Colitis and Colitis-Associated Cancer in Mice.

Publications

MicroRNA214 Is Associated With Progression of Ulcerative Colitis, and Inhibition Reduces Development of Colitis and Colitis-Associated Cancer in Mice.

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