Oliva Joan, Bardag-Gorce Fawzia, French Barbara A, Li Jun, McPhaul Laron, Amidi Fataneh, Dedes Jeniffer, Habibi Amir, Nguyen Sheila, French Samuel W
Department of Pathology, Harbor-UCLA Medical Center, 1000 W. Carson Street Torrance, CA 90509, USA.
Exp Mol Pathol. 2008 Apr;84(2):102-12. doi: 10.1016/j.yexmp.2007.12.003. Epub 2008 Jan 11.
There is clinical evidence that chronic liver diseases in which MDBs (Mallory Denk Bodies) form progress to hepatocellular carcinoma. The present study provides evidence that links MDB formation induced by chronic drug injury, with preneoplasia and later to the formation of tumors, which develop long after drug withdrawal. Evidence indicated that this link was due to an epigenetic cellular memory induced by chronic drug ingestion. Microarray analysis showed that the expressions of many markers of preneoplasia (UBD, Alpha Fetoprotein, KLF6 and glutathione-S-transferase mu2) were increased together when the drug DDC was refed. These changes were suppressed by S-adenosylmethionine feeding, indicating that the drug was affecting DNA and histones methylation in an epigenetic manner. The link between MDB formation and neoplasia formation was likely due to the over expression of UBD (also called FAT10), which is up regulated in 90% of human hepatocellular carcinomas. Immunohistochemical staining of drug-primed mouse livers showed that FAT10 positive liver cells persisted up to 4 months after drug withdrawal and they were still found in the livers of mice, 14 months after drug withdrawal. The refeeding of DDC increased the percent of FAT10 hepatocytes.
有临床证据表明，形成Mallory小体（MDBs）的慢性肝病会进展为肝细胞癌。本研究提供了证据，将慢性药物损伤诱导的MDB形成与肿瘤形成前状态以及随后的肿瘤形成联系起来，这些肿瘤在停药很久之后才发生。证据表明，这种联系是由于慢性药物摄入诱导的表观遗传细胞记忆。微阵列分析表明，当再次给予药物二乙基亚硝胺（DDC）时，许多肿瘤形成前标志物（泛素结合蛋白D、甲胎蛋白、Kruppel样因子6和谷胱甘肽-S-转移酶μ2）的表达同时增加。这些变化被给予S-腺苷甲硫氨酸所抑制，表明该药物以表观遗传方式影响DNA和组蛋白甲基化。MDB形成与肿瘤形成之间的联系可能是由于泛素结合蛋白D（也称为FAT10）的过度表达，该蛋白在90%的人类肝细胞癌中上调。对用药物预处理过的小鼠肝脏进行免疫组织化学染色显示，FAT10阳性肝细胞在停药后持续存在长达4个月，并且在停药14个月后的小鼠肝脏中仍能发现。再次给予DDC增加了FAT10阳性肝细胞的比例。
