{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T12:23:23Z","timestamp":1788870203880,"version":"build-2803163510"},"reference-count":48,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2014,8,4]],"date-time":"2014-08-04T00:00:00Z","timestamp":1407110400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001863","name":"New Energy and Industrial Technology Development Organisation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001863","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Grants-in-Aid for Scientific Research on Priority Area from the Ministry of Education, Culture, Sports, Science and Technology of Japan","award":["24590498"],"award-info":[{"award-number":["24590498"]}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2014,10]]},"abstract":"Abstract<\/jats:title>\n \n The premalignant lesions of pancreatic cancer, pancreatic intraepithelial neoplasia (\n PanIN<\/jats:styled-content>\n ), have a high frequency of mutations in\n Kirsten rat sarcoma viral oncogene homologue<\/jats:italic>\n (\n \n KRAS<\/jats:styled-content>\n <\/jats:italic>\n ), and genetic alterations in the retinoblastoma (Rb)\u2013\n E2<\/jats:styled-content>\n factor (\n E2F<\/jats:styled-content>\n ) and transformed\n 3T3<\/jats:styled-content>\n cell double minute 2 (\n MDM2<\/jats:styled-content>\n )\u2013p53 pathways accelerate development of pancreatic ductal adenocarcinoma. The viral oncoprotein\n SV40<\/jats:styled-content>\n large T antigen (\n TAg<\/jats:styled-content>\n ) can inhibit the effects of the Rb family of molecules and of p53 on these pathways, and targeted expression of\n TAg<\/jats:styled-content>\n in mouse pancreas is associated with the development of endocrine or acinar cell tumours. In this study, to determine whether the viral oncoprotein promotes pancreatic duct carcinogenesis initiated by oncogenic\n KRAS<\/jats:styled-content>\n , we generated mice expressing temperature\u2010sensitive\n SV40<\/jats:styled-content>\n large T antigen (\n tsTAg<\/jats:styled-content>\n ) on pancreatic epithelial cells in the presence or absence of\n \n Kras\n G12D<\/jats:sup>\n <\/jats:styled-content>\n . Mice with pancreas\u2010specific\n tsTAg<\/jats:styled-content>\n expression developed acinar cell dysplasia by 22 weeks without\n PanIN<\/jats:styled-content>\n formation, while mice expressing both\n tsTAg<\/jats:styled-content>\n and\n \n Kras\n G12D<\/jats:sup>\n <\/jats:styled-content>\n developed highly aggressive adenocarcinoma with a ductal cell phenotype within a short period, and died within 3 weeks. The tumours resembled human pancreatic ductal adenocarcinoma (\n PDAC<\/jats:styled-content>\n ) at the histological level, and oncogenic Kras and\n tsTAg<\/jats:styled-content>\n synergistically activated\n E2f<\/jats:italic>\n and\n Sre<\/jats:italic>\n transcription in established\n PDAC<\/jats:styled-content>\n cell lines. These results suggest that\n tsTAg<\/jats:styled-content>\n synergistically promotes\n \n Kras\n G12D<\/jats:sup>\n <\/jats:styled-content>\n \u2010associated\n PDAC<\/jats:styled-content>\n formation, and our study identifies a new mouse model of\n PDAC<\/jats:styled-content>\n that may allow a better understanding of the mechanism of carcinogenesis in pancreatic carcinoma, which shows a catastrophic clinical course. Copyright \u00a9 2014 Pathological Society of Great Britain and Ireland. 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