Enhancing miR-132 expression by aryl hydrocarbon receptor attenuates tumorigenesis associated with chronic colitis

Publication date: November 2017
Source:International Immunopharmacology, Volume 52
Author(s): Abdullah M. Alzahrani, Hamza Hanieh, Hairul-islam Mohamed Ibrahim, Omar Mohafez, Tamer Shehata, Mohammad Bani Ismail, Manal Alfwuaires
BackgroundChronic inflammation in ulcerative colitis (UC) patients is the major risk factor for colitis-associated colon cancer (CAC). Recent evidences have shown that microRNAs (miRNAs) are implicated in CAC pathogenesis. However, the interaction of miRNAs with the transcription factors that alleviate CAC has not been reported.Methods2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 3,3′-diindolylmethane (DIM) were used to activate aryl hydrocarbon receptor (Ahr) in azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CAC in mice. Real-time PCR was used to quantify the mRNAs of miRNA and coding genes while western blot and ELISA were used to quantify protein levels. Silencing miRNA was carried out by means of electroporation and locked nucleic acid (LNA)-miRNA.ResultsInducing CAC in mice upregulated miR-132 expression in the colon, spleen and lymph nodes at all stages of disease development. Activation of Ahr by TCDD or DIM boosted miR-132 expression and alleviated CAC severity by suppression of macrophage infiltration and pro-inflammatory cytokines. Interestingly, TCDD, but not DIM, augmented a cholinergic anti-inflammation by inducing acetylcholinesterase (AChE)-targeting miR-132. This anti-inflammation was manifested by suppressed production of TNF-α, IL-1β and IL-6. Silencing miR-132 in vivo in TCDD-treated mice abrogated the cholinergic anti-inflammation and exacerbated CAC. In addition, inhibition of miR-132 in vitro in CD4⁺ cells and macrophages mitigated the inhibitory effect of TCDD on AChE catalytic activity.ConclusionOur findings identify miR-132 as a new molecule implicated in CAC pathogenesis, and reveal that miR-132 mediates the ameliorating effects of TCDD on CAC, suggesting miR-132 as a promising therapeutic candidate to control autoimmune inflammation and tumorigenesis in CAC patients.



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