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

Zhiwei Wang, Sanjeev Banerjee, Aamir Ahmad, Yiwei Li, Asfar S. Azmi, Jason R. Gunn, Dejuan Kong, Bin Bao, Shadan Ali, Jiankun Gao, Ramzi M. Mohammad, Lucio Miele, Murray Korc, Fazlul H. Sarkar

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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-rasG12D 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-rasG12D 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-rasG12D and Ink4a/Arf deficient transgenic mice.

Original languageEnglish (US)
Article numbere20537
JournalPloS one
Volume6
Issue number6
DOIs
StatePublished - Jan 1 2011

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Wang, Z., Banerjee, S., Ahmad, A., Li, Y., Azmi, A. S., Gunn, J. R., Kong, D., Bao, B., Ali, S., Gao, J., Mohammad, R. M., Miele, L., Korc, M., & Sarkar, F. H. (2011). 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, 6(6), [e20537]. https://doi.org/10.1371/journal.pone.0020537