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.
Highlights
Pancreatic ductal adenocarcinoma (PDA) is currently the fourth most common cause of cancer-related death in the United States, yet will likely become the second leading cause of cancer-related death by 2020, behind only non-small cell lung cancer [1]
Two cell lines generated by lentiviral transduction express distinct short hairpin RNAs that target HuR messenger RNA (mRNA), in response to DOX treatment
Despite the discovery of multiple genomic alterations that give rise to pancreatic ductal adenocarcinoma (PDA), attempts to exploit these lesions for either early detection or treatment have so far been unsuccessful in the clinical setting [2,3,4,5, 7, 61]
Summary
Pancreatic ductal adenocarcinoma (PDA) is currently the fourth most common cause of cancer-related death in the United States, yet will likely become the second leading cause of cancer-related death by 2020, behind only non-small cell lung cancer [1]. The development of effective therapies achieved for other common cancers (e.g. breast, prostate, colorectal) has so far eluded PDA, despite the vastly improved understanding of underlying www.impactjournals.com/oncotarget genetic alterations (e.g. KRAS, p16/CDKN2A, TP53) and dysregulated signaling pathways involved in pancreatic tumorigenesis [2,3,4,5]. Genetic mutations and copy number changes can dramatically influence gene expression, but they emerge in cancer cells over many years of biologic selection [8]. RNA expression changes are rapid, efficient, and reversible [9,10,11]. Speaking, these changes may be classified as transcriptional and impact the quantity of RNA made by a cancer cell, or posttranscriptional and affect other aspects of RNA regulation (e.g. stability, translation). RBPs are more stable and require a greater investment of cell energy for synthesis; roughly 5% of all genes are believed to encode RBPs [19]
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