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Aberrant Gata-3 Expression in Human Pancreatic Cancer

Antanas Gulbinas¹, Pascal O. Berberat¹, Zilvinas Dambrauskas, Thomas Giese, Nathalia Giese, Frank Autschbach, Joerg Kleeff, Stefan Meuer, Markus W. Büchler and Helmut Friess

Department of General Surgery (AG,POB,ZD,NG,JK,MWB,HF), Institute of Immunology (POB,TG,SM), and Department of Pathology (FA), University of Heidelberg, Heidelberg, Germany

Correspondence to: Helmut Friess, MD, Department of General Surgery, University of Heidelberg, Im Neuenheimer Feld 110 69120, Heidelberg, Germany. E-mail: helmut_friess{at}med.uni-heidelberg.de

Gata-3 has been shown to specifically alter its expression patterns in different types of cancers. Recent evidence suggests that an interference of Gata-3 exists in the TGF-ß signaling pathway. To determine the role of Gata-3 in pancreatic cancer, pancreatic cancer samples were analyzed in comparison to normal pancreatic tissues. Furthermore, four different pancreatic cancer cell lines with different alterations of the TGF-ß pathway were studied. To evaluate if a potential relationship with TGF-ß signaling pathway exists, we correlated mRNA expression levels with the expression of TGF-ßs, TGF-ß receptors, and Smad-3. Finally, we analyzed the influence of TGF-ß on Gata-3 expression in vitro. All pancreatic cancer samples demonstrated a marked overexpression of Gata-3 mRNA and protein. Immunohistochemical staining revealed strong and persistent cytoplasmic Gata-3 immunoreactivity in cancer cells. In an electrophoretic mobility shift assay, a disturbed nuclear translocation was confirmed. The expression of Gata-3 showed a significant correlation with the expression of TGF-ßs, TGF-ß receptors, and Smad-3. TGF-ß responsive cell lines showed a downregulation of Gata-3 mRNA upon TGF-ß exposure, whereas in TGF-ß-unresponsive cell lines, Gata-3 mRNA expression persisted at high levels. Furthermore, strong specific upregulation of Gata-3 impaired nuclear translocation and its cooperative action with the TGF-ß pathway, suggesting that Gata-3 plays a central role in human pancreatic cancer. (J Histochem Cytochem 54:161–169, 2006)

Key Words: Gata-3 • TGF-ß • pancreas • pancreatic cancer

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