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 - 2011
Externally publishedYes

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pancreatic neoplasms
adenocarcinoma
Pancreatic Neoplasms
Tumors
Assays
Adenocarcinoma
Chemical activation
Transgenic Mice
mice
genetically modified organisms
neoplasms
animal models
Neoplasms
assays
metastasis
immunohistochemistry
Real-Time Polymerase Chain Reaction
Western blotting
Down-Regulation
Western Blotting

ASJC Scopus subject areas

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

Cite this

Activated K-ras and INK4a/Arf deficiency cooperate during the development of pancreatic cancer by activation of notch and NF-κB signaling pathways. / Wang, Zhiwei; Banerjee, Sanjeev; Ahmad, Aamir; Li, Yiwei; Azmi, Asfar S.; Gunn, Jason R.; Kong, Dejuan; Bao, Bin; Ali, Shadan; Gao, Jiankun; Mohammad, Ramzi M.; Miele, Lucio; Korc, Murray; Sarkar, Fazlul H.

In: PLoS One, Vol. 6, No. 6, e20537, 2011.

Research output: Contribution to journalArticle

Wang, Z, Banerjee, S, Ahmad, A, Li, Y, Azmi, AS, Gunn, JR, Kong, D, Bao, B, Ali, S, Gao, J, Mohammad, RM, Miele, L, Korc, M & Sarkar, FH 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, vol. 6, no. 6, e20537. https://doi.org/10.1371/journal.pone.0020537
Wang, Zhiwei ; Banerjee, Sanjeev ; Ahmad, Aamir ; Li, Yiwei ; Azmi, Asfar S. ; Gunn, Jason R. ; Kong, Dejuan ; Bao, Bin ; Ali, Shadan ; Gao, Jiankun ; Mohammad, Ramzi M. ; Miele, Lucio ; Korc, Murray ; Sarkar, Fazlul H. / Activated K-ras and INK4a/Arf deficiency cooperate during the development of pancreatic cancer by activation of notch and NF-κB signaling pathways. In: PLoS One. 2011 ; Vol. 6, No. 6.
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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-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.",
author = "Zhiwei Wang and Sanjeev Banerjee and Aamir Ahmad and Yiwei Li and Azmi, {Asfar S.} and Gunn, {Jason R.} and Dejuan Kong and Bin Bao and Shadan Ali and Jiankun Gao and Mohammad, {Ramzi M.} and Lucio Miele and Murray Korc and Sarkar, {Fazlul H.}",
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T1 - Activated K-ras and INK4a/Arf deficiency cooperate during the development of pancreatic cancer by activation of notch and NF-κB signaling pathways

AU - Wang, Zhiwei

AU - Banerjee, Sanjeev

AU - Ahmad, Aamir

AU - Li, Yiwei

AU - Azmi, Asfar S.

AU - Gunn, Jason R.

AU - Kong, Dejuan

AU - Bao, Bin

AU - Ali, Shadan

AU - Gao, Jiankun

AU - Mohammad, Ramzi M.

AU - Miele, Lucio

AU - Korc, Murray

AU - Sarkar, Fazlul H.

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

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