LITHOCHOLIC ACID INHIBITS THE EXPRESSION OF HLA CLASS-I GENES IN COLON ADENOCARCINOMA CELLS - DIFFERENTIAL EFFECT ON HLA-A, HLA-B AND HLA-CLOCI

Loss of HLA antigen expression is Considered to be one of the mechanis ms whereby tumor cells escape immune surveillance. We recently observe d reduced or lost expression of HLA antigens during human colon carcin ogenesis. We studied the effect of bile acids (BAs), long implicated i n the pathogenesis of colon cancer, on the expression of HLA class I a ntigens in human colon adenocarcinoma cells. Lithocholic acid (LCA) de creased by 42% the expression of HLA class I antigens on the surface o f these cells. This dose-dependent reduction was specific for both the target genes and the chemical structure of LCA, and was not evident i n cultured liver cells. None of the other BAs that were tested manifes ted this effect. LCA, and to a lesser. extent deoxycholic acid (DCA), decreased steady-state HLA class I mRNA levels. LCA decreased the rate of transcription of HLA-B (64%) and HLA-C (87%) but not HLA-A; DCA ha d a similar but less pronounced effect. In transient gene expression ( CAT assays) experiments, we evaluated the role of a 0.6-0.7kb Eco RI/X baI sequence from the 5' flanking region of HLA-A2, -B7 and -Cw7 genes in the regulation of class I gene expression by LCA. LCA down-regulat ed by 70% the expression of the reporter gene for all three genes. We interpret these results as indicating a differential regulation of the three HLA loci by LCA. Our findings, demonstrating a profound effect of LCA on HLA class I gene regulation, raise the possibility that such a mechanism may be operative in vivo.