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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 7

Inhibition of Notch/NF-κB signaling attenuates the inflammatory profile of malignant cells.

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Inhibition of Notch/NF-κB signaling attenuates the inflammatory profile ...
(A) KrasG12DTnfaΔPdx cells were stimulated with 1 ng/ml rTnf-α for 6 hours in the presence or absence of L685458 or Bay11-7082. Hes1 mRNA expression was quantified by real-time PCR. Results were normalized to unstimulated KrasG12D cells. Data are shown as mean + SD of triplicate determinants and are representative of 3 independent experiments. (B) Hes1 mRNA expression in pancreases of 5-month-old untreated KrasG12D and KrasG12DIkk2ΔPdx mice and of KrasG12D mice treated with anti–Tnf-α, control IgG, DAPT, Bay11-7082, or the vehicle control. Results were normalized to Kras pancreases. Data are shown as mean + SD; n = 6. **P < 0.01. The experiment was done in duplicate. (C) KrasG12D PanIN cells were treated with DAPT or Bay11-7082. Tnfa mRNA expression and cytokine secretion are indicated. Data are shown as mean + SD of triplicate experiments and are representative of 3 independent experiments. (D) Cytokine and chemokine array on whole pancreases of DAPT or vehicle-treated 5-month-old KrasG12D mice. The data are represented graphically as normalized signal intensity. (E) Tnfa, Il6, Il1b, and Mmp7 expression in FACS-sorted EYFP-positive KrasG12D cells treated for 1 week with DAPT or vehicle. Data are shown as mean + SD; n = 12. *P < 0.05, **P < 0.01, ***P < 0.001. Analysis of Mmp7 expression did not reveal statistical significance.

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