title: Early Epigenetic Downregulation of microRNA-192 Expression Promotes Pancreatic Cancer Progression.
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. ©2016 AACR.
authors.affiliation: Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Sandeep K
authors.initials: SK
authors.lastname: Botla
authors.affiliation: 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.
authors.forename: Soniya
authors.initials: S
authors.lastname: Savant
authors.affiliation: Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Pouria
authors.initials: P
authors.lastname: Jandaghi
authors.affiliation: Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Andrea S
authors.initials: AS
authors.lastname: Bauer
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Mücke
authors.affiliation: Diagnostic Molecular Pathology, Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Evgeny A
authors.initials: EA
authors.lastname: Moskalev
authors.affiliation: National Institute for Health Research, Liverpool Pancreas Biomedical Research Unit, Liverpool, UK.
authors.forename: John P
authors.initials: JP
authors.lastname: Neoptolemos
authors.affiliation: National Institute for Health Research, Liverpool Pancreas Biomedical Research Unit, Liverpool, UK.
authors.forename: Eithne
authors.initials: E
authors.lastname: Costello
authors.affiliation: National Institute for Health Research, Liverpool Pancreas Biomedical Research Unit, Liverpool, UK.
authors.forename: William
authors.initials: W
authors.lastname: Greenhalf
authors.affiliation: Department of Pathology and Diagnostics, Università di Verona, Verona, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.affiliation: Department of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Matthias M
authors.initials: MM
authors.lastname: Gaida
authors.affiliation: Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Markus W
authors.initials: MW
authors.lastname: Büchler
authors.affiliation: Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Strobel
authors.affiliation: Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Thilo
authors.initials: T
authors.lastname: Hackert
authors.affiliation: Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Nathalia A
authors.initials: NA
authors.lastname: Giese
authors.affiliation: 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.
authors.forename: Hellmut G
authors.initials: HG
authors.lastname: Augustin
authors.affiliation: Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany. j.hoheisel@dkfz.de.
authors.forename: Jörg D
authors.initials: JD
authors.lastname: Hoheisel
mesh_terms: D000818:Animals; D015820:Cadherins / Q000032:analysis; D021441:Carcinoma, Pancreatic Ductal / Q000209:etiology* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D019175:DNA Methylation; D018450:Disease Progression; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000209:etiology* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D014746:Vimentin / Q000032:analysis
chemical_list: D015820:Cadherins; C546783:MIRN192 microRNA, human; D035683:MicroRNAs; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D014746:Vimentin