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 ch romosome band 3p14.2 and down-regulation of its gene product are found in t he majority of renal cell carcinomas (RCCs). Functional tumor suppressive a ctivity of Fhit in renal cancer cells previously was observed in RCC cell l ine RC48, which lacks endogenous Fhit expression. To further investigate th e potential role of FHIT as a tumor suppressor gene in RCC, rye 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 Hipp el-Lindau (VHL) gene. Stable transfectants of both cell lines showed no alt erations of cell morphology, proliferation kinetics, or cell cycle paramete rs in vitro. The FHIT gene transfer rate, however, was significantly lower in RCC-1 cells compared with SN12C cells, suggesting a selection against ex ogenous Fhit expression. In addition, in nude mouse assays, a significant d elay of tumor formation was observed for FHIT-transfected RCC-1 cell lines, with outgrowing tumors demonstrating loss of Fhit expression in the majori ty of cells. In contrast, tumorigenicity of FHIT-transfected SN12C cell clo nes 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.