KrasG12D-induced IKK2/?/NF-?B activation by IL-1? and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma.

ABSTRACT: Constitutive Kras and NF-?B activation is identified as signature alterations in pancreatic ductal adenocarcinoma (PDAC). However, how NF-?B is activated in PDAC is not yet understood. Here, we report that pancreas-targeted IKK2/? inactivation inhibited NF-?B activation and PDAC development in Kras(G12D) and Kras(G12D);Ink4a/Arf(F/F) mice, demonstrating a mechanistic link between IKK2/? and Kras(G12D) in PDAC inception. Our findings reveal that Kras(G12D)-activated AP-1 induces IL-1?, which, in turn, activates NF-?B and its target genes IL-1? and p62, to initiate IL-1?/p62 feedforward loops for inducing and sustaining NF-?B activity. Furthermore, IL-1? overexpression correlates with Kras mutation, NF-?B activity, and poor survival in PDAC patients. Therefore, our findings demonstrate the mechanism by which IKK2/?/NF-?B is activated by Kras(G12D) through dual feedforward loops of IL-1?/p62.

SUBMITTER: Ling J 

PROVIDER: S-EPMC3360958 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature