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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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Neoplasia Press
2016
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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. |
format | Online Article Text |
id | pubmed-5071541 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Neoplasia Press |
record_format | MEDLINE/PubMed |
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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