miR-301a as an NF-κB activator in pancreatic cancer cells

NF-kappa B is constitutively activated in most human pancreatic adenocarcinoma, which is a deadly malignancy with a 5-year survival rate of about 5%. In this work, we investigate whether microRNAs (miRNAs) contribute to NF-kappa B activation in pancreatic cancer. We demonstrate that miR-301a down-regulates NF-kappa B-repressing factor (Nkrf) and elevates NF-kappa B activation. As NF-kappa B promotes the transcription of miR-301a, our results support a positive feedback loop as a mechanism for persistent NF-kappa B activation, in which miR-301a represses Nkrf to elevate NF-kappa B activity, which in turn promotes miR-301a transcription. Nkrf was found down-regulated and miR-301a up-regulated in human pancreatic adenocarcinoma tissues. Moreover, miR-301a inhibition or Nkrf up-regulation in pancreatic cancer cells led to reduced NF-kappa B target gene expression and attenuated xenograft tumour growth, indicating that miR-301a overexpression contributes to NF-kappa B activation. Revealing this novel mechanism of NF-kappa B activation by an miRNA offers new avenues for therapeutic interventions against pancreatic cancer. The EMBO Journal (2011) 30, 57-67. doi:10.1038/emboj.2010.296; Published online 26 November 2010