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



Botla, SK, Savant, S, Jandaghi, P, Bauer, AS, Mucke, O, Moskalev, EA, Neoptolemos, JP, Costello, E, Greenhalf, W, Scarpa, A
et al (show 7 more authors) (2016) Early epigenetic downregulation of microRNA-192 expression promotes pancreatic cancer progression. Cancer Research, 76 (14). 4149 - 4159.

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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.

Item Type: Article
Depositing User: Symplectic Admin
Date Deposited: 06 Apr 2017 15:41
Last Modified: 09 Jan 2021 08:04
DOI: 10.1158/0008-5472.CAN-15-0390
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3004337