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

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 - PLoS ONE (2011)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, Michigan, United States of America.

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.

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The schematic representation of our proposed molecular mechanism involved in the development and progression of tumors in the compound KCI transgenic mice.
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pone-0020537-g007: The schematic representation of our proposed molecular mechanism involved in the development and progression of tumors in the compound KCI transgenic mice.

Mentions: Based on our results, we conclude that one possible mechanism by which the tumors developed in the compound KCI transgenic mice with activated K-ras and Ink4a/Arf deficiency is in part due to the loss of miR-200 family, which leads to the activation of Jagged/Notch and NF-κB signaling pathway, resulting in the up-regulation of NF-κB target genes, such as MMP-9, c-myc, survivin, Bcl-2, cyclin D1, and COX-2 as summarized in the cartoon diagram (Fig. 7) and contributes to tumor aggressiveness. Although we have demonstrated the loss of miR-200, and the activation of Notch and NF-κB signaling pathway in the current animal model; however, there maybe other genetic alterations causing tumor aggressiveness in this compound mice with activated K-ras and Ink4a/Arf deficiency, suggesting that further in-depth studies are needed to investigate the precise molecular mechanism of tumor progression in this mouse model. Moreover, novel strategies for the re-expression of miR-200 and its consequence could be tested in this animal model, which would help in the rational drug design in addition to Notch and NF-κB targeted drugs for the treatment of human PDAC for improving the overall survival of patients diagnosed with this devastating disease.


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

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 - PLoS ONE (2011)

The schematic representation of our proposed molecular mechanism involved in the development and progression of tumors in the compound KCI transgenic mice.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3108612&req=5

pone-0020537-g007: The schematic representation of our proposed molecular mechanism involved in the development and progression of tumors in the compound KCI transgenic mice.
Mentions: Based on our results, we conclude that one possible mechanism by which the tumors developed in the compound KCI transgenic mice with activated K-ras and Ink4a/Arf deficiency is in part due to the loss of miR-200 family, which leads to the activation of Jagged/Notch and NF-κB signaling pathway, resulting in the up-regulation of NF-κB target genes, such as MMP-9, c-myc, survivin, Bcl-2, cyclin D1, and COX-2 as summarized in the cartoon diagram (Fig. 7) and contributes to tumor aggressiveness. Although we have demonstrated the loss of miR-200, and the activation of Notch and NF-κB signaling pathway in the current animal model; however, there maybe other genetic alterations causing tumor aggressiveness in this compound mice with activated K-ras and Ink4a/Arf deficiency, suggesting that further in-depth studies are needed to investigate the precise molecular mechanism of tumor progression in this mouse model. Moreover, novel strategies for the re-expression of miR-200 and its consequence could be tested in this animal model, which would help in the rational drug design in addition to Notch and NF-κB targeted drugs for the treatment of human PDAC for improving the overall survival of patients diagnosed with this devastating disease.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, Michigan, United States of America.

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.

Show MeSH
Related in: MedlinePlus