miR-301a as an NF-κB activator in pancreatic cancer cells
Supplementary Material
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.
Acknowledgments
This project is supported by Clinical & Translational Science Pilot Grant Program Innovative Award and the Diabetes and Obesity Center at University of Louisville funded by NCRR/NIH (P20 RR024489). YL is also supported by the Center for Environmental Genomics and Integrated Biology at University of Louisville funded by NIEHS/NIH (P30 ES014443) and a Scientist Development Grant from American Heart Association. We are indebted to the critical reviews of Drs Nancy Martin and Robert Mitchell and Ms Juanita R Barker and to Cox2 promoter constructs from Drs Shozo Yamamoto and Tomoko Takano. YL is extremely grateful to Drs Aruni Bhatnagar and Kenneth S Ramos for their mentoring and support.
Footnotes
The authors declare that they have no conflict of interest.