Differential down-regulation of the UDP-glucuronosyltransferase 1A locus is an early event in human liver and biliary cancer.
Differential down-regulation of the UDP-glucuronosyltransferase 1A locus is an early event in human liver and biliary cancer.
复制标题
DOI：
--
复制
发表时间：
1997-07
期刊：
影响因子：
11.2
通讯作者：
C. Strassburg;M. Manns;R. Tukey
中科院分区：
文献类型：
--
作者：
C. Strassburg;M. Manns;R. Tukey
控制细胞解毒的最重要过程之一是在内质网中通过葡萄糖醛酸化进行的，并且很可能在针对化学诱导的致癌作用的防御机制中发挥重要作用。人 UDP-葡萄糖醛酸基转移酶 UGT1A 基因座编码多达 12 种独特的转移酶，这些酶通过选择性外显子共享进行转录。人们对这个基因座在人体组织中如何受到调节知之甚少。我们提供的证据表明，UGT1A 基因产物在由肝细胞和胆管组织组成的正常肝组织以及恶性和癌前肿瘤组织中存在差异表达。在肝脏中，UGT1A1、UGT1A3、UGT1A4 和 UGT1A9 均有表达，并且在恶性肝细胞癌及其癌前病变肝腺瘤中均显着下调，但在良性局灶性结节性增生中则不然。 UGT1A6 在肝脏中大量表达，但在肝脏肿瘤中没有显着调节。 UGT1A10是一种新发现的UGT1A基因产物，仅在胆管组织而非肝细胞组织中表达，并且在胆管细胞癌中也显着下调。 UGT1A4 还观察到正常胆管组织和肿瘤之间的差异调节。这些发现暗示 UGT1A 基因座的调节是肝癌发生中的一个假定的早期事件，可区分良性和恶性肝肿瘤发生，并表明复杂的细胞控制模式是该基因座调节的基础。
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.