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Hypoxia Signature of Splice Forms of Tryptophanyl-tRNA Synthetase Marks Pancreatic Cancer Cells With Distinct Metastatic Abilities

Paley, Elena L. PhD*†; Paley, Deana E. DO; Merkulova-Rainon, Tatyana PhD§; Subbarayan, Pochi R. PhD

doi: 10.1097/MPA.0b013e318222e635
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Objectives: Pancreatic cancer is one of most deadly because of its aggressive growth and high metastatic ability that correlates with intratumoral hypoxia. Earlier diagnosis and prognosis marker of pancreatic cancer is not yet available. In colorectal cancer, protein biosynthesis enzyme, tryptophanyl-tRNA synthetase (TrpRS), is up-regulated in good-prognosis tumors and down-regulated in metastatic poor-prognosis tumors. Tryptophanyl-tRNA synthetase status in pancreatic cancer is unknown. To correlate metastatic ability with hypoxia and TrpRS as a possible prognostic marker, we examined mRNA and protein expression in 2 human pancreatic cancer cell lines with different metastatic abilities and TrpRS levels using our site-specific monoclonal antibodies directed to conformation-dependent epitopes on pancreatic TrpRS.

Methods: Pancreatic MIAPaCa-2, Panc-1, cervical HeLa, and prostate cancer PC-3 cells were cultivated under normoxia or in hypoxic chamber. Expression of full-length TrpRS, antiangiogenic TrpRS, cyclin B1, hypoxia-inducible factor 1α, and Glut-1 was determined with reverse transcriptase-polymerase chain reaction, immunoblotting, and immunocytochemistry.

Results: We demonstrate that hypoxia regulates differentially TrpRS splice forms. Pronounced down-regulation of full-length TrpRS by hypoxia is concomitant with higher metastatic ability.

Conclusions: Tryptophanyl-tRNA synthetase down-regulation by hypoxia may be a factor responsible for low TrpRS in tumors with high metastatic ability. Tryptophanyl-tRNA synthetase recognizability is important for pancreatic cancer prognosis and as a new target for metastasis treatment.

Supplemental Digital Content is available in the text.

From the *Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale; †Expert BioMed, Inc, Miami, FL; ‡Department of Surgery, Saint Barnabas Hospital, New York, NY; §Institut des Vaisseaux et du Sang, Université Paris 7, Hôpital Lariboisiére, Paris, France; and ∥Department of Medicine, Division of Hematology and Oncology, University of Miami School of Medicine, Miami, FL.

Received for publication August 6, 2010; accepted January 27, 2011.

Reprints: Elena L. Paley, PhD, 1301 NE Miami Gardens Dr #302, Miami, FL 33179 (e-mail: ep180@nova.edu).

The authors declare no conflict of interest.

Supplemental digital contents are available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the Journal's Web site (www.pancreasjournal.com).

© 2011 Lippincott Williams & Wilkins, Inc.