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Cited by 513NF-κB Signaling PathwaysPancreatic and Hepatic Oncology ResearchSignaling Pathways in Disease

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

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Ling, Jianhua, Kang, Ya'an, Zhao, Ruiying, Xia, Qianghua, Lee, Dung-Fang, Chang, Zhe, Li, Jin, Peng, Bailu +6 more·2012·Cancer Cell
DOI 10.1016/j.ccr.2011.12.006PMC PMC3360958
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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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  • A signature derived from IMR90 cells undergoing paracrine senescence is found enriched in mouse PANIN and human serrated sessile adenomas (SSA).

    “A signature derived from IMR90 cells undergoing paracrine senescence is found enriched in mouse PANIN 44 and human serrated sessile adenomas (SSA) 36 .”

    From A complex secretory program orchestrated by the inflammasome controls paracrine senescence (2013) · cites this paper as [44]

    The Results section, “Inhibition of Key Proinflammatory Cytokines,” reports gene-expression profiles from mouse PanIN, so this paper provides the mouse PanIN data cited as reference 44. It does not report testing or finding enrichment of an IMR90 paracrine-senescence signature in those profiles. The SSA finding is attached to a different citation (36), not this source. (LLM, conf=0.79)

    Experimental — accuracy not yet measured

  • K-RAS-induced activation of NF-κB is required for pancreatic cancer development, which depends on IL-6 trans-signaling-mediated STAT3 activation.

    “Mutated K-RAS activates NF-κB in a mouse model of lung cancer (315), and the K-RAS-induced activation of NF-κB is required for pancreatic cancer development (316), which depends on IL-6 trans-signaling-mediated STAT3 activation (317).”

    From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [316]

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Cited by

Sorted by citations

Authors
Ling, J., Kang, Y., Zhao, R., Xia, Q., Lee, D.-F., Chang, Z., Li, J., Peng, B., Fleming, J. B., Wang, H., Liu, J., Lemischka, I. R., Hung, M.-C., & Chiao, P. J.
Affiliations
  • The University of Texas MD Anderson Cancer Center (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • Children's Hospital of Philadelphia (US)
Corresponding author
Chiao, Paul J.
ORCID
Venue
Cancer Cell
Publisher
Elsevier BV
Published
2012-01
Volume
21
Issue
1
Pages
105-120
ISSN
1535-6108 (ISSN-L)
DOI
10.1016/j.ccr.2011.12.006
PMC
PMC3360958
OpenAlex
W2063382154
Cited by
513
References
4
Citations by year
2026: 20 · 2025: 18 · 2024: 24 · 2023: 24 · 2022: 32 · 2021: 44 · 2020: 54 · 2019: 36 · 2018: 42 · 2017: 45 · 2016: 41 · 2015: 35 · 2014: 40 · 2013: 41 · 2012: 16
FWCI
14.12
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Public Health Agency of Canada
  • National Cancer Institute (CA-16672, R01CA109405, CA142674, R01CA142674, CA109405, R01CA097159, P30CA016672)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords
pancreatic ductal adenocarcinoma, KRAS G12D, NF-κB activation, IL-1α, p62, feed-forward loop, AP-1, Ink4a/Arf, tumor initiation
MeSH terms
Sequestosome-1 Protein, Animals, Humans, Mutation, Pancreatic Neoplasms, Proto-Oncogene Proteins, Signal Transduction, Gene Expression Regulation, Neoplastic, Cytokines, Proto-Oncogene Proteins p21(ras), NF-kappa B, ras Proteins, Transcription Factor AP-1, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Cell Proliferation, Mice, I-kappa B Kinase, Interleukin-1alpha

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