Journal
ONCOTARGET
Volume 8, Issue 1, Pages 705-721Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.13525
Keywords
miRNA-206; ulcerative colitis; adenosine A3 receptor; NF-kappa B
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Funding
- National Natural Science Foundation of China for young scientists [81400605]
- Natural Science Foundation of Guangdong Province of China [S2012010008136]
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Increasing evidence suggests that miRNAs are widely dysregulated in ulcerative colitis (UC), potentially affecting UC pathogenesis, diagnosis, and therapy. microRNA (miR) -206 has been reported to be upregulated in UC; however, its function and role in UC remain unknown. Here, we elucidate the function of miR-206 in the pathogenesis of UC. In patients with active-UC, miR-206 and adenosine A3 receptor (A3AR) levels were significantly upregulated and downregulated, respectively, and were inversely correlated. A3AR was expressed in the colon mucosa (particularly in colon epithelial-cell membranes). In HT-29 cells, miR-206 downregulated A3AR mRNA/protein expression by directly targeting the A3AR 3'-UTR; miR-206 overexpression and knockdown respectively increased and decreased TNF-alpha-induced nuclear NF-kappa B/p65, p-I kappa B-alpha, IKK alpha, p-IKK alpha and IL-8/IL-1 beta secretion. However, A3AR-siRNA reversed the miR-206 inhibitory effect. Furthermore, miR-206 increased dextran sodium sulphate-induced colitis severity (i.e., increased bodyweight loss, DAI score, colon shrinkage, and MPO activity), which was partially ameliorated by miR-206-antagomir treatment. miR-206-agomir treatment potently suppressed A3AR expression and increased NF-kappa B signalling and downstream cytokine (TNF-alpha/IL-8/IL-1 beta) expression in the mouse colon, in contrast to miR-206-antagomir administration. Taken together, our results demonstrated that miR-206 has a proinflammatory role in UC by downregulating A3AR expression and activating NF-kappa B signalling.
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