A Promising Novel Target in Pancreatic Cancer: HuR Modulates Multiple Core Signaling Pathways Required for Pancreatic Tumorigenesis
Vanessa a. Talbott*1, Koree Ahn2, David W. Rittenhouse1, Nathan G. Richards1, Agnes Witkiewicz3, Eugene P. Kennedy1, Myriam Gorospe4, Charles J. Yeo1, Jonathan R. Brody1
1Surgery, Thomas Jefferson University, Philadelphia, PA; 2Biochemistry & Molecular Biology, Jefferson College of Graduate Studies, Philadelphia, PA; 3Pathology, Thomas Jefferson University, Philadelphia, PA; 4National Institutes of Health, Baltimore, MD
Introduction: Twelve core signaling pathways with 540 overexpressed individual genes have recently been identified as critical for the development of pancreatic ductal adenocarcinoma (PDA) (Science 2008, 321:1801-1806). The mechanism of overexpression for nearly all (99%) of the identified up-regulated genes in pancreatic tumorigenesis is unknown. We explored the hypothesis that post-transcriptional gene regulation may be a powerful alternative process in which these up-regulated genes were being disrupted. A key component of this regulatory process is Human antigen R (HuR), which can modulate gene expression by binding to mRNAs that encode for tumor-promoting proteins in cancer cells. Previously, we discovered that HuR is a key marker for poor pathologic features in PDA and is a predictive marker for gemcitabine-based chemotherapy. Methods: Using a bioinformatic approach, we identified putative HuR targets from the 540 overexpressed genes in PDA (Nucl. Acids Res. 2001, 29:246-254, PNAS 2004, 101:2987-92). HuR binding to mRNA-targets was validated by PCR-based analysis in ribonucleoprotein immunoprecipitated HuR:RNA complexes. Further validation of expression of HuR target genes was performed by quantitative PCR analysis and immunoblotting.Results: We identified 60 putative targets (11.1%) for HuR regulation among the overexpressed genes in PDA. In comparison, genetic and epigenetic alterations contribute only 1% and 1.8% respectively to the proposed mechanisms by which these 540 genes are disrupted in PDA. Ten of the 60 putative target genes which are a part of 5 of the 12 core signaling pathways in PDA, including K-Ras, were experimentally validated as specific HuR targets.Conclusion: HuR is an unprecedented regulatory protein of at least 5 critical signaling pathways in PDA. Targeting multiple core pathways in PDA through silencing HuR expression may be a potent therapeutic strategy to treat this disease.
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