Targeting the mRNA-binding protein HuR impairs malignant characteristics of pancreatic ductal adenocarcinoma cells
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Masaya Jimbo1, Fernando F. Blanco1,2, Yu-Hung Huang3,*, Aristeidis G. Telonis4,*, Brad A. Screnci1, Gabriela L. Cosma5, Vitali Alexeev6, Gregory E. Gonye7, Charles J. Yeo1, Janet A. Sawicki8, Jordan M. Winter1, Jonathan R. Brody1
1Department of Surgery and The Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
2Department of Pharmacology & Experimental Therapeutics, Division of Clinical Pharmacology, Thomas Jefferson University, Philadelphia, PA, USA
3Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA
4Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
5Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
6Department of Dermatology, Thomas Jefferson University, Philadelphia, PA, USA
7NanoString Technologies, Seattle, WA, USA
8Lankenau Institute for Medical Research, Wynnewood, PA, USA
*These authors have contributed equally to this work
Jonathan R. Brody, e-mail: firstname.lastname@example.org
Keywords: pancreatic ductal adenocarcinoma, pancreatic cancer, post-transcriptional regulation, HuR, ELAVL1
Received: May 25, 2015 Accepted: July 13, 2015 Published: July 25, 2015
Post-transcriptional regulation is a powerful mediator of gene expression, and can rapidly alter the expression of numerous transcripts involved in tumorigenesis. We have previously shown that the mRNA-binding protein HuR (ELAVL1) is elevated in human pancreatic ductal adenocarcinoma (PDA) specimens compared to normal pancreatic tissues, and its cytoplasmic localization is associated with increased tumor stage. To gain a better insight into HuR's role in PDA biology and to assess it as a candidate therapeutic target, we altered HuR expression in PDA cell lines and characterized the resulting phenotype in preclinical models. HuR silencing by short hairpin and small interfering RNAs significantly decreased cell proliferation and anchorage-independent growth, as well as impaired migration and invasion. In comparison, HuR overexpression increased migration and invasion, but had no significant effects on cell proliferation and anchorage-independent growth. Importantly, two distinct targeted approaches to HuR silencing showed marked impairment in tumor growth in mouse xenografts. NanoString nCounter® analyses demonstrated that HuR regulates core biological processes, highlighting that HuR inhibition likely thwarts PDA viability through post-transcriptional regulation of diverse signaling pathways (e.g. cell cycle, apoptosis, DNA repair). Taken together, our study suggests that targeted inhibition of HuR may be a novel, promising approach to the treatment of PDA.
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