EXPRESSION OF ALPHA-FETOPROTEIN AND ALBUMIN GENES IN HUMAN HEPATOCELLULAR CARCINOMAS - LIMITATIONS IN THE APPLICATION OF THE GENES FOR TARGETING HUMAN HEPATOCELLULAR-CARCINOMA IN GENE-THERAPY

For an approach of gene therapy for hepatocellular carcinoma (HCC), tr anscriptional regulatory sequence (TRS) of either alpha-fetoprotein (A FP) or albumin has been used for targeting cancer cells. To examine th e feasibility of using TRSs of these genes for possible gene therapy o f HCCs, the cellular distribution of AFP and albumin gene transcripts was studied in 25 cases of surgically removed human HCCs. AFP gene exp ression was observed in HCC nodules of 13 cases. The expression in HCC was heterogeneous, and the distribution of the transcripts was mostly sparse and spotty. The higher the serum AFP levels, the larger popula tion of the AFP-expressing HCC cells tended to reflect. In noncancerou s liver, a slight AFP expression was found by Northern blot analysis, but the transcripts were not detected in the liver sections. In contra st, albumin expression was found in all HCCs as well as in noncancerou s hepatocytes. In HCC, the transcripts for albumin were distributed in cancer cells, and the expression varied with nodules. There were more albumin-expressing cancer cells than the AFP-expressing cells. Albumi n expression was retained even in poorly differentiated HCC, although the intensity of the signal was not as strong as in more-differentiate d HCCs. Metastatic HCC nodules revealed transcripts for both AFP and a lbumin genes, and those were clearly recognized in the lung tissue, Th ese results suggest that, for gene therapy for HCCs, neither AFP nor a lbumin are ideal options for targeting HCC cells. AFP-TRS may be used as a transcriptional regulator in selected cases in which AFP gene exp ression is observed in the cancer nodules. The serum AFP level appears to be an important indicator in selecting cases. Albumin-TRS in conju nction with retroviral vector might be used in limited cases such as H CCs with no AFP expression. However, careful consideration must be tak en, because albumin is constitutively expressed in normal hepatocytes, and AFP-expressing nonmalignant progenitor cells possibly exist.