Growth inhibition by keratinocyte growth factor receptor of human salivary adenocarcinoma cells through induction of differentiation and apoptosis.
We have reported that normal human salivary gland-derived epithelial cells exclusively express keratinocyte growth factor receptor (KGFR). In the process of malignant transformation of human salivary gland tumors, KGFR gene expression disappeared concomitantly with the de novo expression of the fibroblast growth factor receptor 1 (FGFR1) and FGFR4 genes. In the present study, we introduced wild-type KGFR cDNA or chimeric KGFR/FGFR1 cDNA, which encoded the extracellular domain of KGFR and the intracellular domain of FGFR1, into the HSY human salivary adenocarcinoma cell line. The KGFR tyrosine kinase suppressed the activity of FGF receptor substrate 2 (FRS2) and inhibited the growth of HSY by inducing differentiation and apoptosis in vitro and in vivo. Our results provided significant insight into the mechanism of KGFR tumor suppression and suggest that KGFR gene therapy might be a viable method of inhibiting human salivary adenocarcinoma growth.
Zhang
Y
Y
Department of Molecular Oral Medicine and Maxillofacial Surgery 1, Hiroshima University Faculty of Dentistry, 1-2-3 Kasumi, Minami-Ku, Hiroshima 734-8553, Japan.
Wang
H
H
Toratani
S
S
Sato
J D
JD
Kan
M
M
McKeehan
W L
WL
Okamoto
T
T
D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology*; D005260:Female; D006801:Humans; D007700:Kinetics; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051499:Receptor, Fibroblast Growth Factor, Type 4; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D012468:Salivary Gland Neoplasms / Q000473:pathology*; D013363:Submandibular Gland / Q000166:cytology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; C106534:FRS2 protein, human; D008565:Membrane Proteins; D010750:Phosphoproteins; D017468:Receptors, Fibroblast Growth Factor; D011994:Recombinant Proteins; C496348:FGFR1 protein, human; C496371:FGFR4 protein, human; C496349:Fgfr1 protein, mouse; C496372:Fgfr4 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051499:Receptor, Fibroblast Growth Factor, Type 4; C065104:keratinocyte growth factor receptor