2. Academic Validation
  3. KrasG12D-induced IKK2/β/NF-κB activation by IL-1α and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma

KrasG12D-induced IKK2/β/NF-κB activation by IL-1α and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma

  • Cancer Cell. 2012 Jan 17;21(1):105-20. doi: 10.1016/j.ccr.2011.12.006.
Jianhua Ling 1,  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,  Paul J Chiao
Affiliations

Affiliation

  • 1 Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Centre, Houston, 77030, USA.
PMID: 22264792 DOI: 10.1016/j.ccr.2011.12.006
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.

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