Differential susceptibility of renal carcinoma cell lines to tumor suppression by exogenous Fhit expression.
Hemizygous deletions of the fragile histidine triad (FHIT) gene at human chromosome band 3p14.2 and down-regulation of its gene product are found in the majority of renal cell carcinomas (RCCs). Functional tumor suppressive activity of Fhit in renal cancer cells previously was observed in RCC cell line RC48, which lacks endogenous Fhit expression. To further investigate the potential role of FHIT as a tumor suppressor gene in RCC, we transfected FHIT cDNA expression constructs into RCC cell lines RCC-1 and SN12C, which show low-level expression of endogenous Fhit and reveal an intact von Hippel-Lindau (VHL) gene. Stable transfectants of both cell lines showed no alterations of cell morphology, proliferation kinetics, or cell cycle parameters in vitro. The FHIT gene transfer rate, however, was significantly lower in RCC-1 cells compared with SN12C cells, suggesting a selection against exogenous Fhit expression. In addition, in nude mouse assays, a significant delay of tumor formation was observed for FHIT-transfected RCC-1 cell lines, with outgrowing tumors demonstrating loss of Fhit expression in the majority of cells. In contrast, tumorigenicity of FHIT-transfected SN12C cell clones was not suppressed, despite stable transgene expression. In conclusion, our results demonstrate a selective tumor suppressive activity of Fhit in RCC cells in vivo and suggest that the susceptibility to suppression is not restricted to cancer cells with complete loss of Fhit expression.
Werner
N S
NS
Innere Klinik und Poliklinik (Tumorforschung), Universitätsklinikum Essen, Germany.
Siprashvili
Z
Z
Fong
L Y
LY
Marquitan
G
G
Schröder
J K
JK
Bardenheuer
W
W
Seeber
S
S
Huebner
K
K
Schütte
J
J
Opalka
B
B
D017766:Acid Anhydride Hydrolases; D000818:Animals; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics; D002893:Chromosomes, Human, Pair 3; D018076:DNA, Complementary / Q000378:metabolism; D015536:Down-Regulation; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins; D009368:Neoplasm Transplantation; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D013489:Suppression, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D018076:DNA, Complementary; D009363:Neoplasm Proteins; D011506:Proteins; D000099170:Bis(5'-adenosyl)triphosphatase