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Cancer Res. 2016 Jul 15;76(14):4149-59. doi: 10.1158/0008-5472.CAN-15-0390. Epub 2016 May 23.

Early Epigenetic Downregulation of microRNA-192 Expression Promotes Pancreatic Cancer Progression.

Author information

1
Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
2
Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faulty Mannheim, Heidelberg University, Mannheim, Germany.
3
Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
4
Diagnostic Molecular Pathology, Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.
5
National Institute for Health Research, Liverpool Pancreas Biomedical Research Unit, Liverpool, UK.
6
Department of Pathology and Diagnostics, Università di Verona, Verona, Italy.
7
Department of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
8
Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany.
9
Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faulty Mannheim, Heidelberg University, Mannheim, Germany. German Cancer Consortium, Heidelberg, Germany.
10
Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany. j.hoheisel@dkfz.de.

Abstract

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.

PMID:
27216198
DOI:
10.1158/0008-5472.CAN-15-0390
[Indexed for MEDLINE]
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