title: Targeting the mRNA-binding protein HuR impairs malignant characteristics of pancreatic ductal adenocarcinoma cells.
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.
authors: Department of Surgery and The Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Masaya
authors: M
authors: Jimbo
authors: Department of Surgery and The Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.|Department of Pharmacology & Experimental Therapeutics, Division of Clinical Pharmacology, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Fernando F
authors: FF
authors: Blanco
authors: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA.
authors: Yu-Hung
authors: YH
authors: Huang
authors: Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Aristeidis G
authors: AG
authors: Telonis
authors: Department of Surgery and The Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Brad A
authors: BA
authors: Screnci
authors: Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Gabriela L
authors: GL
authors: Cosma
authors: Department of Dermatology, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Vitali
authors: V
authors: Alexeev
authors: NanoString Technologies, Seattle, WA, USA.
authors: Gregory E
authors: GE
authors: Gonye
authors: Department of Surgery and The Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Charles J
authors: CJ
authors: Yeo
authors: Lankenau Institute for Medical Research, Wynnewood, PA, USA.
authors: Janet A
authors: JA
authors: Sawicki
authors: Department of Surgery and The Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Jordan M
authors: JM
authors: Winter
authors: Department of Surgery and The Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Jonathan R
authors: JR
authors: Brody
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism*; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000378:metabolism*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D003593:Cytoplasm / Q000378:metabolism; D004318:Doxycycline / Q000737:chemistry; D000067780:ELAV-Like Protein 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010641:Phenotype; D025341:Principal Component Analysis; D012313:RNA / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D015398:Signal Transduction
chemical_list: D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; C000593997:Elavl1 protein, mouse; D012313:RNA; D004318:Doxycycline
keywords: ELAVL1; HuR; pancreatic cancer; pancreatic ductal adenocarcinoma; post-transcriptional regulation