Differential Down-Regulation of the UDP-Glucuronosyltransferase 1A Locus Is an Early Event in Human Liver and Biliary Cancer

Abstract

One of the most important processes controlling cellular detoxification is carried out in the endoplasmic reticulum by glucuronidation, and most likely plays an important role in the defense mechanism against chemical-induced carcinogenesis. The human UDP-glucuronosyltransferase UGT1A locus encodes up to 12 unique transferases that are transcribed through selective exon sharing. Little is known about how this locus is regulated in human tissues. We present evidence that the UGT1A gene products are differentially expressed in normal liver tissue, which is composed of hepatocellular and biliary tissue, as well as in malignant and premalignant tumor tissue. In liver, UGT1A1, UGT1A3, UGT1A4, and UGT1A9 are expressed, and are all significantly down-regulated in malignant hepatocellular carcinoma and its premalignant precursor, hepatic adenoma, but not in benign focal nodular hyperplasia. UGT1A6, which is expressed abundantly in liver, is not significantly regulated in liver tumors. UGT1A10, a newly discovered UGT1A gene product, is expressed only in biliary and not hepatocellular tissue and is also significantly down-regulated in cholangiocellular carcinoma. Differential regulation between normal biliary tissue and tumor is also observed with UGT1A4. These findings implicate the regulation of the UGT1A locus as a putative early event in hepatocarcinogenesis that discriminates between benign and malignant hepatotumorigenesis and indicates that a complex mode of cellular control underlies the regulation of this locus.