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Fbxw7 Deletion Accelerates Kras(G12D)-Driven Pancreatic Tumorigenesis via Yap Accumulation()()()

Pancreatic cancers driven by KRAS mutations require additional mutations for tumor progression. The tumor suppressor FBXW7 is altered in pancreatic cancers, but its contribution to pancreatic tumorigenesis is unknown. To determine potential cooperation between Kras mutation and Fbxw7 inactivation in...

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Autores principales: Zhang, Qiang, Zhang, Yaqing, Parsels, Joshua D., Lohse, Ines, Lawrence, Theodore S., Pasca di Magliano, Marina, Sun, Yi, Morgan, Meredith A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Neoplasia Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5071541/
https://www.ncbi.nlm.nih.gov/pubmed/27764699
http://dx.doi.org/10.1016/j.neo.2016.08.009
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author Zhang, Qiang
Zhang, Yaqing
Parsels, Joshua D.
Lohse, Ines
Lawrence, Theodore S.
Pasca di Magliano, Marina
Sun, Yi
Morgan, Meredith A.
author_facet Zhang, Qiang
Zhang, Yaqing
Parsels, Joshua D.
Lohse, Ines
Lawrence, Theodore S.
Pasca di Magliano, Marina
Sun, Yi
Morgan, Meredith A.
author_sort Zhang, Qiang
collection PubMed
description Pancreatic cancers driven by KRAS mutations require additional mutations for tumor progression. The tumor suppressor FBXW7 is altered in pancreatic cancers, but its contribution to pancreatic tumorigenesis is unknown. To determine potential cooperation between Kras mutation and Fbxw7 inactivation in pancreatic tumorigenesis, we generated P48-Cre;LSL-Kras(G12D);Fbxw7(fl/fl) (KFC(fl/fl)) compound mice. We found that KFC(fl/fl) mice displayed accelerated tumorigenesis: all mice succumbed to pancreatic ductal adenocarcinoma (PDA) by 40 days of age, with PDA onset occurring by 2 weeks of age. PDA in KFC(fl/fl) mice was preceded by earlier onset of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) lesions, and associated with chromosomal instability and the accumulation of Fbxw7 substrates Yes-associated protein (Yap), c-Myc, and Notch. Using KFC(fl/fl) and FBXW7-deficient human pancreatic cancer cells, we found that Yap silencing attenuated growth promotion by Fbxw7 deletion. Our data demonstrate that Fbxw7 is a potent suppressor of Kras(G12D)-induced pancreatic tumorigenesis due, at least in part, to negative regulation of Yap.
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spelling pubmed-50715412016-10-28 Fbxw7 Deletion Accelerates Kras(G12D)-Driven Pancreatic Tumorigenesis via Yap Accumulation()()() Zhang, Qiang Zhang, Yaqing Parsels, Joshua D. Lohse, Ines Lawrence, Theodore S. Pasca di Magliano, Marina Sun, Yi Morgan, Meredith A. Neoplasia Short communication Pancreatic cancers driven by KRAS mutations require additional mutations for tumor progression. The tumor suppressor FBXW7 is altered in pancreatic cancers, but its contribution to pancreatic tumorigenesis is unknown. To determine potential cooperation between Kras mutation and Fbxw7 inactivation in pancreatic tumorigenesis, we generated P48-Cre;LSL-Kras(G12D);Fbxw7(fl/fl) (KFC(fl/fl)) compound mice. We found that KFC(fl/fl) mice displayed accelerated tumorigenesis: all mice succumbed to pancreatic ductal adenocarcinoma (PDA) by 40 days of age, with PDA onset occurring by 2 weeks of age. PDA in KFC(fl/fl) mice was preceded by earlier onset of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) lesions, and associated with chromosomal instability and the accumulation of Fbxw7 substrates Yes-associated protein (Yap), c-Myc, and Notch. Using KFC(fl/fl) and FBXW7-deficient human pancreatic cancer cells, we found that Yap silencing attenuated growth promotion by Fbxw7 deletion. Our data demonstrate that Fbxw7 is a potent suppressor of Kras(G12D)-induced pancreatic tumorigenesis due, at least in part, to negative regulation of Yap. Neoplasia Press 2016-10-18 /pmc/articles/PMC5071541/ /pubmed/27764699 http://dx.doi.org/10.1016/j.neo.2016.08.009 Text en © 2016 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Short communication
Zhang, Qiang
Zhang, Yaqing
Parsels, Joshua D.
Lohse, Ines
Lawrence, Theodore S.
Pasca di Magliano, Marina
Sun, Yi
Morgan, Meredith A.
Fbxw7 Deletion Accelerates Kras(G12D)-Driven Pancreatic Tumorigenesis via Yap Accumulation()()()
title Fbxw7 Deletion Accelerates Kras(G12D)-Driven Pancreatic Tumorigenesis via Yap Accumulation()()()
title_full Fbxw7 Deletion Accelerates Kras(G12D)-Driven Pancreatic Tumorigenesis via Yap Accumulation()()()
title_fullStr Fbxw7 Deletion Accelerates Kras(G12D)-Driven Pancreatic Tumorigenesis via Yap Accumulation()()()
title_full_unstemmed Fbxw7 Deletion Accelerates Kras(G12D)-Driven Pancreatic Tumorigenesis via Yap Accumulation()()()
title_short Fbxw7 Deletion Accelerates Kras(G12D)-Driven Pancreatic Tumorigenesis via Yap Accumulation()()()
title_sort fbxw7 deletion accelerates kras(g12d)-driven pancreatic tumorigenesis via yap accumulation()()()
topic Short communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5071541/
https://www.ncbi.nlm.nih.gov/pubmed/27764699
http://dx.doi.org/10.1016/j.neo.2016.08.009
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