Early epigenetic downregulation of microRNA-192 expression promotes pancreatic cancer progression
Pancreatic ductal adenocarcinoma (PDAC) is characterized by very early metastasis, suggesting the hypothesis that metastasis-associated changes may occur prior to actual tumor formation. In this study, we identified miR-192 as an epigenetically regulated suppressor gene with predictive value in this...
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| Main Authors: | , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
23 May 2016
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| In: |
Cancer research
Year: 2016, Volume: 76, Issue: 14, Pages: 4149-4159 |
| ISSN: | 1538-7445 |
| DOI: | 10.1158/0008-5472.CAN-15-0390 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1158/0008-5472.CAN-15-0390 Verlag, Volltext: https://core.ac.uk/display/80779130 
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| Author Notes: | Sandeep K. Botla, Soniya Savant, Pouria Jandaghi, Andrea S. Bauer, Oliver Mücke, Evgeny A. Moskalev, John P. Neoptolemos, Eithne Costello, William Greenhalf, Aldo Scarpa, Matthias M. Gaida, Markus W. Büchler, Oliver Strobel, Thilo Hackert, Nathalia A. Giese, Hellmut G. Augustin, and Jörg D. Hoheisel |
| Summary: | Pancreatic ductal adenocarcinoma (PDAC) is characterized by very early metastasis, suggesting the hypothesis that metastasis-associated changes may occur prior to actual tumor formation. In this study, we identified miR-192 as an epigenetically regulated suppressor gene with predictive value in this disease. miR-192 was downregulated by promoter methylation in both PDAC and chronic pancreatitis, the latter of which is a major risk factor for the development of PDAC. Functional studies in vitro and in vivo in mouse models of PDAC showed that overexpression of miR-192 was sufficient to reduce cell proliferation and invasion. Mechanistic analyses correlated changes in miR-192 promoter methylation and expression with epithelial-mesenchymal transition. Cell proliferation and invasion were linked to altered expression of the miR-192 target gene SERPINE1 that is encoding the protein plasminogen activator inhibitor-1 (PAI-1), an established regulator of these properties in PDAC cells. Notably, our data suggested that invasive capacity was altered even before neoplastic transformation occurred, as triggered by miR-192 downregulation. Overall, our results highlighted a role for miR-192 in explaining the early metastatic behavior of PDAC and suggested its relevance as a target to develop for early diagnostics and therapy. Cancer Res; 76(14); 4149-59. ©2016 AACR. |
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| Item Description: | Gesehen am 09.01.2019 |
| Physical Description: | Online Resource |
| ISSN: | 1538-7445 |
| DOI: | 10.1158/0008-5472.CAN-15-0390 |