Kras G12D-Induced IKK2/β/NF-κB Activation by IL-1α and p62 Feedforward Loops Is Required for Development of Pancreatic Ductal Adenocarcinoma

Jianhua Ling, Ya'an Kang, Ruiying Zhao, Qianghua Xia, Dung Fang Lee, Zhe Chang, Jin Li, Bailu Peng, Jason B. Fleming, Huamin Wang, Jinsong Liu, Ihor R. Lemischka, Mien Chie Hung, PaulJ Chiao

    Research output: Contribution to journalArticlepeer-review

    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. © 2012 Elsevier Inc.
    Original languageEnglish
    Pages (from-to)105-120
    Number of pages15
    JournalCancer Cell
    Volume21
    Issue number1
    DOIs
    Publication statusPublished - 17 Jan 2012

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