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, Jonathan R. Brody

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)27312-27331
Number of pages20
JournalOncotarget
Volume6
Issue number29
DOIs
StatePublished - 2015
Externally publishedYes

Keywords

  • ELAVL1
  • HuR
  • Pancreatic cancer
  • Pancreatic ductal adenocarcinoma
  • Post-transcriptional regulation

ASJC Scopus subject areas

  • Oncology

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