title: Activated K-ras and INK4a/Arf deficiency cooperate during the development of pancreatic cancer by activation of Notch and NF-κB signaling pathways.
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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Department of Pathology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Wang
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Banerjee
authors.forename: Aamir
authors.initials: A
authors.lastname: Ahmad
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Li
authors.forename: Asfar S
authors.initials: AS
authors.lastname: Azmi
authors.forename: Jason R
authors.initials: JR
authors.lastname: Gunn
authors.forename: Dejuan
authors.initials: D
authors.lastname: Kong
authors.forename: Bin
authors.initials: B
authors.lastname: Bao
authors.forename: Shadan
authors.initials: S
authors.lastname: Ali
authors.forename: Jiankun
authors.initials: J
authors.lastname: Gao
authors.forename: Ramzi M
authors.initials: RM
authors.lastname: Mohammad
authors.forename: Lucio
authors.initials: L
authors.lastname: Miele
authors.forename: Murray
authors.initials: M
authors.lastname: Korc
authors.forename: Fazlul H
authors.initials: FH
authors.lastname: Sarkar
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000378:metabolism; D044584:Carcinoma, Ductal / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency* / Q000235:genetics; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D011905:Genes, ras / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics; D019426:Integrases / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology*; D051880:Receptors, Notch / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics
chemical_list: D002135:Calcium-Binding Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D035683:MicroRNAs; C543719:Mirn200 microRNA, mouse; D016328:NF-kappa B; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D004247:DNA; C045073:Cre recombinase; D019426:Integrases