Details der Publikation - Early epigenetic downregulation of microRNA-192 expression promotes pancreatic cancer progression

Early epigenetic downregulation of microRNA-192 expression promotes pancreatic cancer progression / 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

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..

Medienart:	E-Artikel

Erscheinungsjahr:	23 May 2016 2016
Erschienen:	23 May 2016

Enthalten in:	Zur Gesamtaufnahme - volume:76
Enthalten in:	Cancer research - 76(2016), 14, Seite 4149-4159

Sprache:	Englisch

Beteiligte Personen:	Botla, Sandeep Kumar [VerfasserIn] Savant, Soniya [VerfasserIn] Gaida, Matthias, 1982- [VerfasserIn] Büchler, Markus W., 1955- [VerfasserIn] Strobel, Oliver, 1974- [VerfasserIn] Hackert, Thilo, 1971- [VerfasserIn] Giese, Nathalia [VerfasserIn] Augustin, Hellmut, 1959- [VerfasserIn]

Links:	Volltext Volltext

Themen:	Animals Cadherins Carcinoma, Pancreatic Ductal Cell Line, Tumor DNA Methylation Disease Progression Down-Regulation Epigenesis, Genetic Epithelial-Mesenchymal Transition Humans Mice MicroRNAs Neoplasm Invasiveness Pancreatic Neoplasms Plasminogen Activator Inhibitor 1 Vimentin

Anmerkungen:	Gesehen am 09.01.2019

Umfang:	11

doi:	10.1158/0008-5472.CAN-15-0390

funding:
Förderinstitution / Projekttitel:

PPN (Katalog-ID):	1586048287

Internformat


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245	1	0	\|a Early epigenetic downregulation of microRNA-192 expression promotes pancreatic cancer progression \|c 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
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520			\|a 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.
650		4	\|a Animals
650		4	\|a Cadherins
650		4	\|a Carcinoma, Pancreatic Ductal
650		4	\|a Cell Line, Tumor
650		4	\|a Disease Progression
650		4	\|a DNA Methylation
650		4	\|a Down-Regulation
650		4	\|a Epigenesis, Genetic
650		4	\|a Epithelial-Mesenchymal Transition
650		4	\|a Humans
650		4	\|a Mice
650		4	\|a MicroRNAs
650		4	\|a Neoplasm Invasiveness
650		4	\|a Pancreatic Neoplasms
650		4	\|a Plasminogen Activator Inhibitor 1
650		4	\|a Vimentin
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