miR-301A downregulates NKRF expression, which in turn relieves the suppression of NF-κB activity
MicroRNAs (miRNAs) have been shown to be effectors that function downstream of NF-κB activation, so Lu, Li and colleagues screened a library of miRNAs for those that modulate NF-κB activation. The most potent activator of NF-κB signalling was miR-301A, which upregulated NF-κB activity by fivefold. miR-301A was not predicted to bind any transcripts encoding subunits of the NF-κB transcription factor complex, but NF-κB repressing factor(NKRF), which encodes an inhibitor of NF-κB, was shown to be a target of miR-301A. NKRF protein and mRNA expression was reduced by ∼threefold when miR-301A was exogenously overexpressed in 293T cells, and this upregulated NF-κB activity by ∼2.5-fold. Knock down of miR-301A by antisense oligonucleotides in pancreatic cancer cell lines upregulated NKRF expression and downregulated the expression of five NF-κB target genes. One of these five genes, spindle and kinetochore associated complex subunit 2 (SKA2), encodes miR-301A in its first intron. The authors identified a functional NF-κB (specifically NFKB1–RELA) binding site upstream of SKA2, suggesting that miR-301A is also a target of activated NF-κB. Indeed, knock down of RELA and NFKB1 downregulated miR-301A expression. These data identify a feedforward loop in which miR-301A downregulates NKRF expression, which in turn relieves the suppression of NF-κB activity and activates target genes, which includes miR-301A. Moreover, they found that NKRF expression was reduced in pancreatic adenocarcinoma tissues compared with normal pancreas and tumour-adjacent tissue, and this correlated with miR-301A overexpression and NF-κB activation.
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