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PRDM3 attenuates pancreatitis and pancreatic tumorigenesis by regulating inflammatory response
Ye,Jie1,2; Huang,Anpei3; Wang,Haitao1,4; Zhang,Anni M.Y.5; Huang,Xiaojun1,2; Lan,Qingping1,2; Sato,Tomohiko6; Goyama,Susumu6; Kurokawa,Mineo6; Deng,Chuxia1,2; Sander,Maike7; Schaeffer,David F.8; Li,Wen3; Kopp,Janel L.5; Xie,Ruiyu1,2
2020-03-01
Source PublicationCell Death and Disease
Volume11Issue:3
AbstractPancreatic ductal adenocarcinoma (PDAC) is associated with metaplastic changes in the pancreas but the transcriptional program underlying these changes is incompletely understood. The zinc finger transcription factor, PRDM3, is lowly expressed in normal pancreatic acini and its expression increases during tumorigenesis. Although PRDM3 promotes proliferation and migration of PDAC cell lines, the role of PRDM3 during tumor initiation from pancreatic acinar cells in vivo is unclear. In this study, we showed that high levels of PRDM3 expression in human pancreas was associated with pancreatitis, and well-differentiated but not poorly differentiated carcinoma. We examined PRDM3 function in pancreatic acinar cells during tumor formation and pancreatitis by inactivating Prdm3 using a conditional allele (Ptf1a;Prdm3 mice) in the context of oncogenic Kras expression and supraphysiological cerulein injections, respectively. In Prdm3-deficient mice, Kras-driven preneoplastic lesions were more abundant and progressed to high-grade precancerous lesions more rapidly. This is consistent with our observations that low levels of PRDM3 in human PDAC was correlated significantly with poorer survival in patient. Moreover, loss of Prdm3 in acinar cells elevated exocrine injury, enhanced immune cell activation and infiltration, and greatly increased acinar-to-ductal cell reprogramming upon cerulein-induced pancreatitis. Whole transcriptome analyses of Prdm3 knockout acini revealed that pathways involved in inflammatory response and Hif-1 signaling were significantly upregulated in Prdm3-depleted acinar cells. Taken together, our results suggest that Prdm3 favors the maintenance of acinar cell homeostasis through modulation of their response to inflammation and oncogenic Kras activation, and thus plays a previously unexpected suppressive role during PDAC initiation.
DOI10.1038/s41419-020-2371-x
URLView the original
Language英语
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Document TypeJournal article
CollectionFaculty of Health Sciences
Corresponding AuthorXie,Ruiyu
Affiliation1.Cancer Centre,Faculty of Health Sciences,University of Macau,999078,Macao
2.Institute of Translational Medicine,Faculty of Health of Sciences,University of Macau,999078,Macao
3.Laboratory of General Surgery,The First Affiliated Hospital,Sun Yat-sen University,Guangzhou,510275,China
4.Division of Medical Sciences,National Cancer Centre Singapore,Duke-NUS Medical School,Singapore,169857,Singapore
5.Department of Cellular and Physiological Sciences,University of British Columbia,Vancouver,V6T 1Z4,Canada
6.Department of Hematology and Oncology,University of Tokyo,Tokyo,113-8654,Japan
7.Department of Pediatrics and Cellular and Molecular Medicine,University of California-San Diego,La Jolla,92093,United States
8.Department of Pathology and Laboratory Medicine,University of British Columbia,Vancouver,V6T 1Z4,Canada
First Author AffilicationFaculty of Health Sciences;  University of Macau
Corresponding Author AffilicationFaculty of Health Sciences;  University of Macau
Recommended Citation
GB/T 7714
Ye,Jie,Huang,Anpei,Wang,Haitao,et al. PRDM3 attenuates pancreatitis and pancreatic tumorigenesis by regulating inflammatory response[J]. Cell Death and Disease,2020,11(3).
APA Ye,Jie.,Huang,Anpei.,Wang,Haitao.,Zhang,Anni M.Y..,Huang,Xiaojun.,...&Xie,Ruiyu.(2020).PRDM3 attenuates pancreatitis and pancreatic tumorigenesis by regulating inflammatory response.Cell Death and Disease,11(3).
MLA Ye,Jie,et al."PRDM3 attenuates pancreatitis and pancreatic tumorigenesis by regulating inflammatory response".Cell Death and Disease 11.3(2020).
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