Abstract
Constitutive Kras and NF-κB activation is identified as signature alterations in pancreatic ductal adenocarcinoma (PDAC). However, how NF-κB is activated in PDAC is not yet understood. Here, we report that pancreas-targeted IKK2/β inactivation inhibited NF-κB activation and PDAC development in Kras(G12D) and Kras(G12D);Ink4a/Arf(F/F) mice, demonstrating a mechanistic link between IKK2/β and Kras(G12D) in PDAC inception. Our findings reveal that Kras(G12D)-activated AP-1 induces IL-1α, which, in turn, activates NF-κB and its target genes IL-1α and p62, to initiate IL-1α/p62 feedforward loops for inducing and sustaining NF-κB activity. Furthermore, IL-1α overexpression correlates with Kras mutation, NF-κB activity, and poor survival in PDAC patients. Therefore, our findings demonstrate the mechanism by which IKK2/β/NF-κB is activated by Kras(G12D) through dual feedforward loops of IL-1α/p62.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
MeSH terms
- Adaptor Proteins, Signal Transducing / metabolism*
- Animals
- Carcinoma, Pancreatic Ductal / genetics
- Carcinoma, Pancreatic Ductal / metabolism*
- Carcinoma, Pancreatic Ductal / pathology
- Cell Line, Tumor
- Cell Proliferation
- Cytokines / antagonists & inhibitors
- Cytokines / metabolism
- Gene Expression Regulation, Neoplastic
- Humans
- I-kappa B Kinase / metabolism*
- Interleukin-1alpha / genetics
- Interleukin-1alpha / metabolism*
- Mice
- Mutation
- NF-kappa B / genetics
- NF-kappa B / metabolism*
- Pancreatic Neoplasms / genetics
- Pancreatic Neoplasms / metabolism*
- Pancreatic Neoplasms / pathology
- Proto-Oncogene Proteins / genetics
- Proto-Oncogene Proteins / metabolism
- Proto-Oncogene Proteins / physiology*
- Proto-Oncogene Proteins p21(ras) / genetics
- Proto-Oncogene Proteins p21(ras) / metabolism
- Proto-Oncogene Proteins p21(ras) / physiology
- Sequestosome-1 Protein
- Signal Transduction
- Transcription Factor AP-1 / metabolism
- ras Proteins / genetics
- ras Proteins / metabolism
- ras Proteins / physiology*
Substances
- Adaptor Proteins, Signal Transducing
- Cytokines
- Interleukin-1alpha
- KRAS protein, human
- NF-kappa B
- Proto-Oncogene Proteins
- SQSTM1 protein, human
- Sequestosome-1 Protein
- Transcription Factor AP-1
- I-kappa B Kinase
- Ikbkb protein, mouse
- Hras protein, mouse
- Proto-Oncogene Proteins p21(ras)
- ras Proteins