Activated K-ras and INK4a/Arf deficiency cooperate during the development of pancreatic cancer by activation of Notch and NF-κB signaling pathways

PLoS One. 2011;6(6):e20537. doi: 10.1371/journal.pone.0020537. Epub 2011 Jun 3.

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the United States, suggesting that novel strategies for the prevention and treatment of PDAC are urgently needed. K-ras mutations are observed in >90% of pancreatic cancer, suggesting its role in the initiation and early developmental stages of PDAC. In order to gain mechanistic insight as to the role of mutated K-ras, several mouse models have been developed by targeting a conditionally mutated K-ras(G12D) for recapitulating PDAC. A significant co-operativity has been shown in tumor development and metastasis in a compound mouse model with activated K-ras and Ink4a/Arf deficiency. However, the molecular mechanism(s) by which K-ras and Ink4a/Arf deficiency contribute to PDAC has not been fully elucidated.

Methodology/principal findings: To assess the molecular mechanism(s) that are involved in the development of PDAC in the compound transgenic mice with activated K-ras and Ink4a/Arf deficiency, we used multiple methods, such as Real-time RT-PCR, western blotting assay, immunohistochemistry, MTT assay, invasion, EMSA and ELISA. We found that the deletion of Ink4a/Arf in K-ras(G12D) expressing mice leads to PDAC, which is in part mediated through the activation of Notch and NF-κB signaling pathways. Moreover, we found down-regulation of miR-200 family, which could also play important roles in tumor development and progression of PDAC in the compound transgenic mice.

Conclusions/significance: Our results suggest that the activation of Notch and NF-κB together with the loss of miR-200 family is mechanistically linked with the development and progression of PDAC in the compound K-ras(G12D) and Ink4a/Arf deficient transgenic mice.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Calcium-Binding Proteins / metabolism
  • Carcinoma, Ductal / genetics
  • Carcinoma, Ductal / pathology*
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p16 / deficiency*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • DNA / metabolism
  • Down-Regulation / genetics
  • Epithelial-Mesenchymal Transition / genetics
  • Genes, ras / genetics*
  • Homeodomain Proteins / genetics
  • Integrases / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Ligands
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • MicroRNAs / genetics
  • NF-kappa B / metabolism*
  • Neoplasm Invasiveness
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / pathology*
  • Receptors, Notch / metabolism*
  • Serrate-Jagged Proteins
  • Signal Transduction* / genetics
  • Trans-Activators / genetics

Substances

  • Calcium-Binding Proteins
  • Cyclin-Dependent Kinase Inhibitor p16
  • Homeodomain Proteins
  • Intercellular Signaling Peptides and Proteins
  • Ligands
  • Membrane Proteins
  • MicroRNAs
  • Mirn200 microRNA, mouse
  • NF-kappa B
  • Receptors, Notch
  • Serrate-Jagged Proteins
  • Trans-Activators
  • pancreatic and duodenal homeobox 1 protein
  • DNA
  • Cre recombinase
  • Integrases