GNASR201Hand KrasG12Dcooperate to promote murine pancreatic tumorigenesis recapitulating human intraductal papillary mucinous neoplasm
In: Oncogene, Jg. 35 (2016-05-05), Heft 18, S. 2407-2412
Online
serialPeriodical
Zugriff:
Intraductal papillary mucinous neoplasm (IPMN), the most common pancreatic cystic neoplasm, is known to progress to invasive ductal adenocarcinoma. IPMNs commonly harbor activating somatic mutations in GNASand KRAS, primarily GNASR201Hand KRASG12D. GNASencodes the stimulatory G-protein α subunit (Gsα) that mediates a stimulatory signal to adenylyl cyclase to produce cyclic adenosine monophosphate (cAMP), subsequently activating cAMP-dependent protein kinase A. The GNASR201Hmutation results in constitutive activation of Gsα. To study the potential role of GNASin pancreatic tumorigenesis in vivo, we generated lines of transgenic mice in which the transgene consisted of Lox-STOP-Lox (LSL)-GNASR201Hunder the control of the CAG promoter (Tg(CAG-LSL-GNAS)). These mice were crossed with pancreatic transcription factor 1a (Ptf1a)-Cre mice (Ptf1aCre/+), generating Tg(CAG-LSL-GNAS);Ptf1aCre/+mice. This mouse line showed elevated cAMP levels, small dilated tubular complex formation, loss of acinar cells and fibrosis in the pancreas; however, no macroscopic tumorigenesis was apparent by 2 months of age. We then crossed Tg(CAG-LSL-GNAS);Ptf1aCre/+mice with LSL-KrasG12Dmice, generating Tg(CAG-LSL-GNAS);LSL-KrasG12D;Ptf1aCre/+mice. We used these mice to investigate a possible cooperative effect of GNASR201Hand KrasG12Din pancreatic tumorigenesis. Within 5 weeks, Tg(CAG-LSL-GNAS);LSL-KrasG12D;Ptf1aCre/+mice developed a cystic tumor consisting of marked dilated ducts lined with papillary dysplastic epithelia in the pancreas, which closely mimicked the human IPMN. Our data strongly suggest that activating mutations in GNASand Krascooperatively promote murine pancreatic tumorigenesis, which recapitulates IPMN. Our mouse model may serve as a unique in vivoplatform to find biomarkers and effective drugs for diseases associated with GNASmutations.
Titel: |
GNASR201Hand KrasG12Dcooperate to promote murine pancreatic tumorigenesis recapitulating human intraductal papillary mucinous neoplasm
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Autor/in / Beteiligte Person: | Taki, K ; Ohmuraya, M ; Tanji, E ; Komatsu, H ; Hashimoto, D ; Semba, K ; Araki, K ; Kawaguchi, Y ; Baba, H ; Furukawa, T |
Link: | |
Zeitschrift: | Oncogene, Jg. 35 (2016-05-05), Heft 18, S. 2407-2412 |
Veröffentlichung: | 2016 |
Medientyp: | serialPeriodical |
ISSN: | 0950-9232 (print) ; 1476-5594 (print) |
DOI: | 10.1038/onc.2015.294 |
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