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

Authors

Masaya Jimbo, Department of Surgery and The Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson UniversityFollow
Fernando F Blanco, Department of Pharmacology and oExperimental Therapeutics, Division of Clinical Pharmacology; Department of Surgery and The Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University;Follow
Yu-Hung Huang, Department of Biochemistry and Molecular Biology, Drexel University College of MedicineFollow
Aristeidis G Telonis, Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson UniversityFollow
Brad A Screnci, Department of Surgery and The Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University
Gabriela L Cosma, Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson UniversityFollow
Vitali Alexeev, Department of Dermatology, Thomas Jefferson UniversityFollow
Gregory E Gonye, NanoString TechnologiesFollow
Charles Yeo, Department of Surgery and The Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson UniversityFollow
Janet A Sawicki, Lankenau Institute for Medical ResearchFollow
Jordan M Winter, Department of Surgery and The Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson UniversityFollow
Jonathan Brody, MD, Department of Surgery and The Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

9-29-2015

Comments

This article has been peer reviewed. It was published in: Oncotarget.

Volume 6, Issue 29, 2015, Pages 27312-27331.

The published version is available at DOI: 10.18632/oncotarget.4743

Copyright © 2015 The Authors

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.

Recommended Citation

Jimbo, Masaya; Blanco, Fernando F; Huang, Yu-Hung; Telonis, Aristeidis G; Screnci, Brad A; Cosma, Gabriela L; Alexeev, Vitali; Gonye, Gregory E; Yeo, Charles; Sawicki, Janet A; Winter, Jordan M; and Brody, MD, Jonathan, "Targeting the mRNA-binding protein HuR impairs malignant characteristics of pancreatic ductal adenocarcinoma cells." (2015). Computational Medicine Center Faculty Papers. Paper 9.
https://jdc.jefferson.edu/tjucompmedctrfp/9

PubMed ID

26314962