HuR status is a powerful marker for prognosis and response to gemcitabine-based chemotherapy for resected pancreatic ductal adenocarcinoma patients.
BACKGROUND
Pancreatic ductal adenocarcinoma (PDA) is a devastating disease that killed nearly 38,000 people in the United States this past year.


OBJECTIVE
Treatment of PDA typically includes surgery and/or chemotherapy with gemcitabine. No reliable biomarker exists for prognosis or response to chemotherapy. Two previously proposed prognostic markers, cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF), are regulated by Hu protein antigen R (HuR), an mRNA binding protein that we have previously demonstrated to be a promising predictive marker of gemcitabine response. This study was designed to evaluate the clinical utility of HuR, COX-2, and VEGF as potential prognostic and predictive biomarkers for PDA.


METHODS
A tissue microarray of 53 PDA specimens from patients who underwent potentially curative pancreatic resection was analyzed. HuR, COX-2, and VEGF status were correlated with clinicopathologic and survival data. We also performed ribonucleoprotein immunoprecipitation assays using an HuR antibody to assess VEGF and COX-2 mRNA binding to HuR in pancreatic cancer cells.


RESULTS
Roughly 50% (27/53) of patients had high cytoplasmic HuR expression. These patients had worse pathologic features as assessed by T staging (P = 0.005). Only cytoplasmic HuR status correlated with tumor T staging, whereas VEGF (P = 1.0) and COX-2 (P = 0.39) expression did not correlate with T staging. Additionally, HuR status was an unprecedented positive predictive marker for overall survival in patients treated with gemcitabine, pushing median survival over 45 months in the high cytoplasmic HuR expressing patient population compared with less than 23 months in the low cytoplasmic HuR expressing patient group (P = 0.033 for log-rank test and P = 0.04 in a Cox regression model) for the low versus high cytoplasmic HuR expressing group. We also validated that mRNA transcripts for both VEGF and the gemcitabine metabolizing enzyme, deoxycytidine kinase, are specifically bound by HuR in pancreatic cancer cells.


CONCLUSIONS
HuR is a useful prognostic biomarker for PDA patients as indicated by its association with higher tumor T stage. Additionally, HuR status is a robust predictor of outcome for patients with resected PDA in the setting of adjuvant gemcitabine therapy. Finally, HuR binds to VEGF mRNA implying that HuR, in part, regulates VEGF expression in PDA. This study supports the notion that HuR status should be used by clinicians for the individualized treatment of PDA in the future.
Richards
Nathan G
NG
Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Rittenhouse
David W
DW
Freydin
Boris
B
Cozzitorto
Joseph A
JA
Grenda
Dane
D
Rui
Hallgeir
H
Gonye
Greg
G
Kennedy
Eugene P
EP
Yeo
Charles J
CJ
Brody
Jonathan R
JR
Witkiewicz
Agnieszka K
AK
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D014408:Biomarkers, Tumor / Q000378:metabolism; D003131:Combined Modality Therapy; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051959:ELAV Proteins / Q000378:metabolism*; D000067777:ELAV-Like Protein 2; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D046228:Microarray Analysis; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D011379:Prognosis; D016016:Proportional Hazards Models; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000093542:Gemcitabine
D014408:Biomarkers, Tumor; D051959:ELAV Proteins; D000067777:ELAV-Like Protein 2; C086811:ELAVL2 protein, human; D042461:Vascular Endothelial Growth Factor A; D003841:Deoxycytidine; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000093542:Gemcitabine