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

Q Tu; J Hao; X Zhou; L Yan; H Dai; B Sun; D Yang; S An; L Lv; B Jiao; C Chen; R Lai; P Shi; X Zhao

doi:10.1038/onc.2017.316

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

Oncogene. 2018 Jan 4;37(1):128-138. doi: 10.1038/onc.2017.316. Epub 2017 Sep 11.

Authors

Q Tu^{1

2}, J Hao³, X Zhou^{1

2}, L Yan^{1

4}, H Dai¹, B Sun^{1

2}, D Yang^{1

2}, S An^{1

2}, L Lv⁴, B Jiao³, C Chen¹, R Lai¹, P Shi³, X Zhao^{1

4

5}

Affiliations

¹ Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Kunming, China.
² Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, China.
³ State Key Laboratory of Genetic Resources and Evolution, Laboratory of Evolutionary and Functional Genomics, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
⁴ Kunming Primate Research Center, Chinese Academy of Sciences, Kunming, China.
⁵ KIZ-SU Joint Laboratory of Animal Model and Drug Development, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinogenesis / genetics
Cell Line, Tumor
Cell Proliferation / genetics
Cellular Senescence / genetics
Cyclin-Dependent Kinase Inhibitor p15 / genetics*
Cyclin-Dependent Kinase Inhibitor p15 / metabolism
Cyclin-Dependent Kinase Inhibitor p16 / genetics*
Cyclin-Dependent Kinase Inhibitor p16 / metabolism
Cyclin-Dependent Kinase Inhibitor p18 / genetics
Cyclin-Dependent Kinase Inhibitor p18 / metabolism
Gene Expression Regulation, Neoplastic*
Genetic Engineering / methods
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neoplasms, Experimental / genetics
Neoplasms, Experimental / pathology
Pancreatic Neoplasms / genetics*
Pancreatic Neoplasms / pathology
Proto-Oncogene Proteins p21(ras) / genetics
Proto-Oncogene Proteins p21(ras) / metabolism
RNA, Small Interfering / administration & dosage
Retinoblastoma Protein / metabolism
Sequence Deletion
Tumor Suppressor Protein p53 / genetics

Substances

CDKN2A protein, human
CDKN2B protein, human
Cdkn2a protein, mouse
Cdkn2b protein, mouse
Cyclin-Dependent Kinase Inhibitor p15
Cyclin-Dependent Kinase Inhibitor p16
Cyclin-Dependent Kinase Inhibitor p18
KRAS protein, human
RNA, Small Interfering
Retinoblastoma Protein
Tumor Suppressor Protein p53
Proto-Oncogene Proteins p21(ras)