CDKN2B deletion is essential for pancreatic cancer development instead of unmeaningful co-deletion due to juxtaposition to CDKN2A

Pancreatic cancer is among the deadliest malignancies; however, the genetic events that lead to pancreatic carcinogenesis in adults remain unclear. In vivo models in which these genetic alterations occur in adult animals may more accurately reflect the features of human cancer. In this study, we dem...

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Autores principales: Tu, Q, Hao, J, Zhou, X, Yan, L, Dai, H, Sun, B, Yang, D, An, S, Lv, L, Jiao, B, Chen, C, Lai, R, Shi, P, Zhao, X
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2018
Materias:
Original Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5759028/
https://www.ncbi.nlm.nih.gov/pubmed/28892048
http://dx.doi.org/10.1038/onc.2017.316
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author Tu, Q
Hao, J
Zhou, X
Yan, L
Dai, H
Sun, B
Yang, D
An, S
Lv, L
Jiao, B
Chen, C
Lai, R
Shi, P
Zhao, X
author_facet Tu, Q
Hao, J
Zhou, X
Yan, L
Dai, H
Sun, B
Yang, D
An, S
Lv, L
Jiao, B
Chen, C
Lai, R
Shi, P
Zhao, X
author_sort Tu, Q
collection PubMed
description Pancreatic cancer is among the deadliest malignancies; however, the genetic events that lead to pancreatic carcinogenesis in adults remain unclear. In vivo models in which these genetic alterations occur in adult animals may more accurately reflect the features of human cancer. In this study, we demonstrate that inactivation of Cdkn2b (p15ink4b) is necessary for induction of pancreatic cancer by oncogenic KRAS(G12D) expression and inactivation of Tp53 and Cdkn2a in adult mouse pancreatic ductal cells (P60 or older). KRAS(G12D) overexpression in these cells activated transforming growth factor-β signaling and expression of CDKN2B, which, along with CDKN2A, led to cellular senescence and protected cells from KRAS-mediated transformation via inhibition of retinoblastoma phosphorylation. These results show a critical role of CDKN2B inactivation in pancreatic carcinogenesis, and provide a useful adult animal model by genetic engineering via lentiviral delivery.
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spelling pubmed-57590282018-01-12 CDKN2B deletion is essential for pancreatic cancer development instead of unmeaningful co-deletion due to juxtaposition to CDKN2A Tu, Q Hao, J Zhou, X Yan, L Dai, H Sun, B Yang, D An, S Lv, L Jiao, B Chen, C Lai, R Shi, P Zhao, X Oncogene Original Article Pancreatic cancer is among the deadliest malignancies; however, the genetic events that lead to pancreatic carcinogenesis in adults remain unclear. In vivo models in which these genetic alterations occur in adult animals may more accurately reflect the features of human cancer. In this study, we demonstrate that inactivation of Cdkn2b (p15ink4b) is necessary for induction of pancreatic cancer by oncogenic KRAS(G12D) expression and inactivation of Tp53 and Cdkn2a in adult mouse pancreatic ductal cells (P60 or older). KRAS(G12D) overexpression in these cells activated transforming growth factor-β signaling and expression of CDKN2B, which, along with CDKN2A, led to cellular senescence and protected cells from KRAS-mediated transformation via inhibition of retinoblastoma phosphorylation. These results show a critical role of CDKN2B inactivation in pancreatic carcinogenesis, and provide a useful adult animal model by genetic engineering via lentiviral delivery. Nature Publishing Group 2018-01-04 2017-09-11 /pmc/articles/PMC5759028/ /pubmed/28892048 http://dx.doi.org/10.1038/onc.2017.316 Text en Copyright © 2018 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
spellingShingle Original Article
Tu, Q
Hao, J
Zhou, X
Yan, L
Dai, H
Sun, B
Yang, D
An, S
Lv, L
Jiao, B
Chen, C
Lai, R
Shi, P
Zhao, X
CDKN2B deletion is essential for pancreatic cancer development instead of unmeaningful co-deletion due to juxtaposition to CDKN2A
title CDKN2B deletion is essential for pancreatic cancer development instead of unmeaningful co-deletion due to juxtaposition to CDKN2A
title_full CDKN2B deletion is essential for pancreatic cancer development instead of unmeaningful co-deletion due to juxtaposition to CDKN2A
title_fullStr CDKN2B deletion is essential for pancreatic cancer development instead of unmeaningful co-deletion due to juxtaposition to CDKN2A
title_full_unstemmed CDKN2B deletion is essential for pancreatic cancer development instead of unmeaningful co-deletion due to juxtaposition to CDKN2A
title_short CDKN2B deletion is essential for pancreatic cancer development instead of unmeaningful co-deletion due to juxtaposition to CDKN2A
title_sort cdkn2b deletion is essential for pancreatic cancer development instead of unmeaningful co-deletion due to juxtaposition to cdkn2a
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5759028/
https://www.ncbi.nlm.nih.gov/pubmed/28892048
http://dx.doi.org/10.1038/onc.2017.316
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