Oncotarget

Research Papers:

Targeting the mRNA-binding protein HuR impairs malignant characteristics of pancreatic ductal adenocarcinoma cells

Masaya Jimbo _, Fernando F. Blanco, Yu-Hung Huang, Aristeidis G. Telonis, Brad A. Screnci, Gabriela L. Cosma, Vitali Alexeev, Gregory E. Gonye, Charles J. Yeo, Janet A. Sawicki, Jordan M. Winter and Jonathan R. Brody

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Oncotarget. 2015; 6:27312-27331. https://doi.org/10.18632/oncotarget.4743

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Abstract

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

Correspondence to:

Jonathan R. Brody, e-mail: jonathan.brody@jefferson.edu

Keywords: pancreatic ductal adenocarcinoma, pancreatic cancer, post-transcriptional regulation, HuR, ELAVL1

Received: May 25, 2015     Accepted: July 13, 2015     Published: July 25, 2015

ABSTRACT

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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