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

Abstract

NF‐κB 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‐κB activation in pancreatic cancer. We demonstrate that miR‐301a down‐regulates NF‐κB‐repressing factor (Nkrf) and elevates NF‐κB activation. As NF‐κB promotes the transcription of miR‐301a, our results support a positive feedback loop as a mechanism for persistent NF‐κB activation, in which miR‐301a represses Nkrf to elevate NF‐κB 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‐κB target gene expression and attenuated xenograft tumour growth, indicating that miR‐301a overexpression contributes to NF‐κB activation. Revealing this novel mechanism of NF‐κB activation by an miRNA offers new avenues for therapeutic interventions against pancreatic cancer.

MicroRNA-520/373 family functions as a tumor suppressor in estrogen receptor negative breast cancer by targeting NF-κB and TGF-β signaling pathways

“…Several studies have demonstrated the regulation of the NF-kB pathway by miRNAs, such as miR-301a in pancreatic cancer (Lu et al, 2011), miR-146a in human monocytes (Taganov et al, 2006) and miR-199b in ovarian cancer (Chen et al, 2008). However, little is known about the regulation of NF-kB signaling in the context of breast cancer.…”

Epigenetic markers for chemosensitivity and chemoresistance in pancreatic cancer—A review

“…MiRNA-301a activates NFjB by downregulating the expression of the NFjB-repressing factor gene. 87 Multiple signaling pathways, including NFjB-and miRNA-mediated ones, contribute to the genesis and maintenance of EMT phenotypic cells and cancer stem cells (CSCs). These cell type configurations are linked to drug resistance.…”

Augmentation of Ras-induced cell transformation : a new role for miR-200a in malignancy.

“…The method involves a published lentiviral-based miRNA genetic library that contains a large number of human miRNA minigenes [142]. To screen miRNAs that specifically target TFs of interest, we utilized luciferase constructs plus the miRNA library.…”

“…c-Myc activity was measured using an E2F2-Luc reporter vector consisting of the E2F2 promotor with four distinct E-boxes, CACGTG [143]. The parental vector, pSIF [142], substituted for the miRNA construct, serves as a normalization control for miRNA expression. Rluc from pRL-TK (Promega) is used to normalize transfection efficiency and total protein synthesis.…”

“…While it is clear that miRNA clusters are frequently predicted to target specific cell signaling pathways, no experimental evidence based on systematic screening has been provided. In this study, we intend to address these deficiencies by analyzing the role of 366 human miRNAs as clusters in these four major signaling pathways using an existing genetic library [142].…”