PRDM3 attenuates pancreatitis and pancreatic tumorigenesis by regulating inflammatory response
| Autor: | Mineo Kurokawa, Chu-Xia Deng, Anni M.Y. Zhang, Wen Li, Anpei Huang, Tomohiko Sato, David F. Schaeffer, Susumu Goyama, Janel L. Kopp, Ruiyu Xie, Qingping Lan, Jie Ye, Xiaojun Huang, Haitao Wang, Maike Sander |
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| Rok vydání: | 2020 |
| Předmět: |
Cancer Research
Tumor initiation medicine.disease_cause Oral and gastrointestinal Transcriptome Mice 0302 clinical medicine 2.1 Biological and endogenous factors Aetiology Cancer 0303 health sciences lcsh:Cytology Middle Aged medicine.anatomical_structure Pancreatic Ductal 030220 oncology & carcinogenesis KRAS medicine.symptom Pancreas Carcinoma Pancreatic Ductal Immunology Oncology and Carcinogenesis Inflammation Biology Adenocarcinoma Article 03 medical and health sciences Cellular and Molecular Neuroscience Pancreatic Cancer Rare Diseases medicine Acinar cell Animals Humans lcsh:QH573-671 030304 developmental biology Animal Carcinoma Pancreatic cancer Cell Biology medicine.disease MDS1 and EVI1 Complex Locus Protein Disease Models Animal Pancreatitis Cardiovascular and Metabolic Diseases Disease Models Cancer research Biochemistry and Cell Biology Carcinogenesis Digestive Diseases |
| Zdroj: | Cell death & disease, vol 11, iss 3 Cell Death and Disease, Vol 11, Iss 3, Pp 1-14 (2020) Cell Death & Disease |
| Popis: | Pancreatic 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 (Ptf1aCreER;Prdm3flox/flox mice) in the context of oncogenic Kras expression and supraphysiological cerulein injections, respectively. In Prdm3-deficient mice, KrasG12D-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. |
| Databáze: | OpenAIRE |
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