MicroRNAs of the mir-17~92 cluster regulate multiple aspects of pancreatic tumor development and progression
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Brian Quattrochi1, Anushree Gulvady2, David R. Driscoll1, Makoto Sano3, David S. Klimstra4, Christopher E. Turner2, Brian C. Lewis1,5,6
1Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA
2Department of Cell and Developmental Biology, State University of New York Upstate Medical Center, Syracuse, NY 13210, USA
3Division of Pathology, Department of Pathology and Microbiology, Nihon University School of Medicine, Itabashi-ku, Tokyo, 173-8610, Japan
4Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
5Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
6Department of Radiation Oncology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Brian C. Lewis, email: Brian.Lewis@umassmed.edu
Keywords: pancreatic cancer, mir-17~92, PanIN, regression, invasion
Received: May 30, 2016 Accepted: March 08, 2017 Published: March 16, 2017
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy characterized by resistance to currently employed chemotherapeutic approaches. Members of the mir-17~92 cluster of microRNAs (miRNAs) are upregulated in PDAC, but the precise roles of these miRNAs in PDAC are unknown. Using genetically engineered mouse models, we show that loss of mir-17~92 reduces ERK pathway activation downstream of mutant KRAS and promotes the regression of KRASG12D-driven precursor pancreatic intraepithelial neoplasias (PanINs) and their replacement by normal exocrine tissue. In a PDAC model driven by concomitant KRASG12D expression and Trp53 heterozygosity, mir-17~92 deficiency extended the survival of mice that lacked distant metastasis. Moreover, mir-17~92-deficient PDAC cell lines display reduced invasion activity in transwell assays, form fewer invadopodia rosettes than mir-17~92-competent cell lines and are less able to degrade extracellular matrix. Specific inhibition of miR-19 family miRNAs with antagomirs recapitulates these phenotypes, suggesting that miR-19 family miRNAs are important mediators of PDAC cell invasion. Together these data demonstrate an oncogenic role for mir-17~92 at multiple stages of pancreatic tumorigenesis and progression; specifically, they link this miRNA cluster to ERK pathway activation and precursor lesion maintenance in vivo and identify a novel role for miR-19 family miRNAs in promoting cancer cell invasion.
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