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Fbxw7 Deletion Accelerates KrasG12D-Driven Pancreatic Tumorigenesis via Yap Accumulation.


ABSTRACT: 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-KrasG12D;Fbxw7fl/fl (KFCfl/fl) compound mice. We found that KFCfl/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 KFCfl/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 KFCfl/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 KrasG12D-induced pancreatic tumorigenesis due, at least in part, to negative regulation of Yap.

SUBMITTER: Zhang Q 

PROVIDER: S-EPMC5071541 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Fbxw7 Deletion Accelerates Kras<sup>G12D</sup>-Driven Pancreatic Tumorigenesis via Yap Accumulation.

Zhang Qiang Q   Zhang Yaqing Y   Parsels Joshua D JD   Lohse Ines I   Lawrence Theodore S TS   Pasca di Magliano Marina M   Sun Yi Y   Morgan Meredith A MA  

Neoplasia (New York, N.Y.) 20161018 11


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<sup>G12D</sup>;Fbxw7<sup>fl/fl</sup> (KFC<sup>fl/fl</sup>) compound mice. We found that KFC<sup>fl/fl</sup> mice displayed accelerated tumorige  ...[more]

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