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Crosstalk between the canonical NF-κB and Notch signaling pathways inhibits Pparγ expression and promotes pancreatic cancer progression in mice
Eleni Maniati, … , David A. Tuveson, Thorsten Hagemann
Eleni Maniati, … , David A. Tuveson, Thorsten Hagemann
Published November 7, 2011
Citation Information: J Clin Invest. 2011;121(12):4685-4699. https://doi.org/10.1172/JCI45797.
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Research Article Oncology

Crosstalk between the canonical NF-κB and Notch signaling pathways inhibits Pparγ expression and promotes pancreatic cancer progression in mice

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Abstract

The majority of human pancreatic cancers have activating mutations in the KRAS proto-oncogene. These mutations result in increased activity of the NF-κB pathway and the subsequent constitutive production of proinflammatory cytokines. Here, we show that inhibitor of κB kinase 2 (Ikk2), a component of the canonical NF-κB signaling pathway, synergizes with basal Notch signaling to upregulate transcription of primary Notch target genes, resulting in suppression of antiinflammatory protein expression and promotion of pancreatic carcinogenesis in mice. We found that in the KrasG12DPdx1-cre mouse model of pancreatic cancer, genetic deletion of Ikk2 in initiated pre-malignant epithelial cells substantially delayed pancreatic oncogenesis and resulted in downregulation of the classical Notch target genes Hes1 and Hey1. Tnf-α stimulated canonical NF-κB signaling and, in collaboration with basal Notch signals, induced optimal expression of Notch targets. Mechanistically, Tnf-α stimulation resulted in phosphorylation of histone H3 at the Hes1 promoter, and this signal was lost with Ikk2 deletion. Hes1 suppresses expression of Pparg, which encodes the antiinflammatory nuclear receptor Pparγ. Thus, crosstalk between Tnf-α/Ikk2 and Notch sustains the intrinsic inflammatory profile of transformed cells. These findings reveal what we believe to be a novel interaction between oncogenic inflammation and a major cell fate pathway and show how these pathways can cooperate to promote cancer progression.

Authors

Eleni Maniati, Maud Bossard, Natalie Cook, Juliana B. Candido, Nia Emami-Shahri, Sergei A. Nedospasov, Frances R. Balkwill, David A. Tuveson, Thorsten Hagemann

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Figure 6

Tnf-α/NF-κB and Notch crosstalk leads to Hes1-mediated Pparg inhibition.

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Tnf-α/NF-κB and Notch crosstalk leads to Hes1-mediated Pparg inhibition....
(A) Pparg mRNA expression in 2- and 5-month-old KrasG12DTnfaΔPdx and KrasG12DIkk2ΔPdx pancreases. Data were normalized to KrasG12D pancreases. Data are shown as mean + SD; n = 6. ***P < 0.001. The experiment was performed in duplicate. (B) Tnf-α stimulation (1 ng/ml) induced downregulation of Pparg in KrasG12DTnfaΔPdx PanIN cell lines. (C) ChIP was performed on KrasG12D cells using anti-Hes1 or a control IgG. Precipitated DNA was amplified by real-time PCR using primers specific for Pparg. (D) siRNA knockdown of Hes1 upregulated Pparg and Cebpa expression in KrasG12D PanIN cells. (E) KrasG12D and KrasG12DTnfaΔPdx PanIN cells were cotransfected in duplicate with a Pparg reporter construct containing 1,500 bases of the proximal Pparg promoter (full length) and a Hes1 expression plasmid or empty vector control. Twenty-four hours after transfection, cells were analyzed for luciferase activity. (F) Transfection of KrasG12DTnfaΔPdx PanIN cells as described in E with a full-length Pparg reporter construct or a construct with a truncated Hes1-binding sequence. All data are shown as mean + SD from duplicate transfections and are representative of 3 independent experiments.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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