Journal
NUCLEIC ACIDS RESEARCH
Volume 44, Issue 8, Pages 3772-3787Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkw205
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Funding
- National Institutes of Health [RO1AI077679, RO1GM046454]
- Houston Endowment, Inc.
- NIH [RO1]
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MiR-26 has emerged as a key tumour suppressor in various cancers. Accumulating evidence supports that miR-26 regulates inflammation and tumourigenicity largely through down-regulating IL-6 production, but the underlying mechanism remains obscure. Here, combining a transcriptome-wide approach with manipulation of cellular miR-26 levels, we showed that instead of directly targeting IL-6 mRNA for gene silencing, miR-26 diminishes IL-6 transcription activated by TNF-alpha through silencing NF-kappa B signalling related factors HMGA1 and MALT1. We demonstrated that miR-26 extensively dampens the induction of many inflammation-related cytokine, chemokine and tissue-remodelling genes that are activated via NF-kappa B signalling pathway. Knocking down both HMGA1 and MALT1 by RNAi had a silencing effect on NF-kappa B-responsive genes similar to that caused by miR-26. Moreover, we discovered that poor patient prognosis in human lung adenocarcinoma is associated with low miR-26 and high HMGA1 or MALT1 levels and not with levels of any of them individually. These new findings not only unravel a novel mechanism by which miR-26 dampens IL-6 production transcriptionally but also demonstrate a direct role of miR-26 in down-regulating NF-kappa B signalling pathway, thereby revealing a more critical and broader role of miR-26 in inflammation and cancer than previously realized.
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