Aberrant gata-3 expression in human pancreatic cancer.
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-beta 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-beta pathway were studied. To evaluate if a potential relationship with TGF-beta signaling pathway exists, we correlated mRNA expression levels with the expression of TGF-betas, TGF-beta receptors, and Smad-3. Finally, we analyzed the influence of TGF-beta 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-betas, TGF-beta receptors, and Smad-3. TGF-beta responsive cell lines showed a downregulation of Gata-3 mRNA upon TGF-beta exposure, whereas in TGF-beta-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-beta pathway, suggesting that Gata-3 plays a central role in human pancreatic cancer.
Gulbinas
Antanas
A
Department of General Surgery, University of Heidelberg, Im Neuenheimer Feld 110 69120, Heidelberg, Germany.
Berberat
Pascal O
PO
Dambrauskas
Zilvinas
Z
Giese
Thomas
T
Giese
Nathalia
N
Autschbach
Frank
F
Kleeff
Joerg
J
Meuer
Stefan
S
Büchler
Markus W
MW
Friess
Helmut
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D050990:GATA3 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D009367:Neoplasm Staging; D010179:Pancreas / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D021381:Protein Transport; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology; D015854:Up-Regulation
D050990:GATA3 Transcription Factor; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta