THE FHIT GENE-PRODUCT IS HIGHLY EXPRESSED IN THE CYTOPLASM OF RENAL TUBULAR EPITHELIUM AND IS DOWN-REGULATED IN KIDNEY CANCERS

Loss of heterozygosity and homozygous deletion of the 3p14.2 region in human cancers implies the existence of a tumor suppressor gene. One s uch candidate is the fragile histidine triad (FHIT) gene. To investiga te the role of FHIT gene product in tumorigenesis, we generated specif ic polyclonal antibodies to the human protein and studied its expressi on in normal and tumor tissues. Immunoblot analysis revealed highly va riable expression of pFhit in normal adult human tissues. The highest steady-state level of pFhit was found in kidney and brain, whereas bre ast, intestine, and skeletal muscle expressed only trace amounts, With in the kidney, the pattern of pFhit immunoreactivity was confined to t he tubular epithelium and absent in the glomeruli, Immunofluorescence analysis and biochemical fractionation have sublocalized pFhit to the cytosolic compartment, Compared with normal kidney, pFhit was found to be down-regulated in a subset of primary renal cell carcinoma. Two of 12 renal cell carcinoma cell lines that are known not to contain VHL mutations showed complete loss of pFhit expression. This is supported by the appearance of aberrant reverse transcription-polymerase chain r eaction products and loss of the normal-size fragment. Our results are consistent with a potential role of pFhit loss or dysfunction in huma n renal cell carcinoma independent of VHL involvement.