KrasG12D-Induced IKK2/β/NF-κB Activation by IL-1α and p62 Feedforward Loops Is Required for Development of Pancreatic Ductal Adenocarcinoma

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