Borlak Jürgen, Meier Tatiana, Halter Roman, Spanel Reinhard, Spanel-Borowski Katharina
Department of Pharmacology and Molecular Medicine, Fraunhofer Institute of Toxicology and Experimental Medicine, Nikolai-Fuchsstr. 1, 30625 Hannover, Germany.
Oncogene. 2005 Mar 10;24(11):1809-19. doi: 10.1038/sj.onc.1208196.
Epidermal growth factor is an important mitogen for hepatocytes. Its overexpression promotes hepatocellular carcinogenesis. To identify the network of genes regulated through EGF, we investigated the liver transcriptome during various stages of hepatocarcinogenesis in EGF2B transgenic mice. Targeted overexpression of IgEGF induced distinct hepatocellular lesions and eventually solid tumours at the age of 6-8 months, as evidenced by histopathology. We used the murine MG U74Av2 oligonucleotide microarrays to identify transcript signatures in 12 tumours of small (n=5, pooled), medium (n=4) and large sizes (n=3), and compared the findings with three nontumorous transgenic livers and four control livers. Global gene expression analysis at successive stages of carcinogenesis revealed hallmarks linked to tumour size. A comparison of gene expression profiles of nontumorous transgenic liver versus control liver provided insight into the initial events predisposing liver cells to malignant transformation, and we found overexpression of c-fos, eps-15, TGIF, IGFBP1, Alcam, ets-2 and repression of Gas-1 as distinct events. Further, when gene expression profiles of small manifested tumours were compared with nontumorous transgenic liver, additional changes were obvious and included overexpression of junB, Id-1, minopontin, villin, claudin-7, RR M2, p34cdc2, cyclinD1 and cyclinB1 among others. These genes are therefore strongly associated with tumour formation. Our study provided new information on the tumour stage-dependent network of EGF-regulated genes, and we identified candidate genes linked to tumorigenes and progression of disease.
表皮生长因子是肝细胞的一种重要促有丝分裂原。其过度表达会促进肝细胞癌的发生。为了确定通过表皮生长因子调控的基因网络，我们研究了表皮生长因子2B转基因小鼠肝癌发生不同阶段的肝脏转录组。IgEGF的靶向过表达在6 - 8个月大时诱导出明显的肝细胞病变并最终形成实体瘤，组织病理学证实了这一点。我们使用鼠类MG U74Av2寡核苷酸微阵列来鉴定12个小（n = 5，混合）、中（n = 4）和大（n = 3）肿瘤的转录特征，并将结果与三个非肿瘤转基因肝脏和四个对照肝脏进行比较。致癌连续阶段的全基因表达分析揭示了与肿瘤大小相关的特征。非肿瘤转基因肝脏与对照肝脏基因表达谱的比较为使肝细胞易于发生恶性转化的初始事件提供了见解，我们发现c - fos、eps - 15、TGIF、IGFBP1、Alcam、ets - 2的过度表达以及Gas - 1的抑制是明显的事件。此外，当将小的显性肿瘤的基因表达谱与非肿瘤转基因肝脏进行比较时，其他明显变化包括junB、Id - 1、minopontin、绒毛蛋白、claudin - 7、RR M2、p34cdc2、细胞周期蛋白D1和细胞周期蛋白B1等的过度表达。因此，这些基因与肿瘤形成密切相关。我们的研究提供了关于表皮生长因子调控基因的肿瘤阶段依赖性网络的新信息，并且我们鉴定出了与肿瘤发生和疾病进展相关的候选基因。
