Crosstalk between the canonical NF-κB and Notch signaling pathways inhibits Pparγ expression and promotes pancreatic cancer progression in mice
| Autor: | Thorsten Hagemann, Maud Bossard, Frances R. Balkwill, Sergei A. Nedospasov, Juliana Candido, Natalie Cook, Nia Emami-Shahri, David A. Tuveson, Eleni Maniati |
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| Rok vydání: | 2011 |
| Předmět: |
Cell signaling
Notch signaling pathway Down-Regulation Biology medicine.disease_cause Proto-Oncogene Mas Proinflammatory cytokine Histones Rosiglitazone Mice Basic Helix-Loop-Helix Transcription Factors medicine Animals Phosphorylation RNA Small Interfering HES1 Homeodomain Proteins Inflammation Receptors Notch Tumor Necrosis Factor-alpha NF-kappa B Pancreatic Diseases General Medicine I-kappa B Kinase Neoplasm Proteins Gene Expression Regulation Neoplastic Mice Inbred C57BL PPAR gamma Pancreatic Neoplasms Crosstalk (biology) Genes ras Hes3 signaling axis Disease Progression Cancer research Transcription Factor HES-1 Thiazolidinediones Signal transduction Carcinogenesis Precancerous Conditions Protein Processing Post-Translational Research Article Carcinoma Pancreatic Ductal Signal Transduction |
| Zdroj: | Journal of Clinical Investigation. 121:4685-4699 |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/jci45797 |
| Popis: | 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 Kras(G12D)Pdx1-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. |
| Databáze: | OpenAIRE |
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