Epidermal growth factor-induced hepatocellular carcinoma: gene expression profiles in precursor lesions, early stage and solitary tumours.
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.
Borlak
Jürgen
J
Department of Pharmacology and Molecular Medicine, Fraunhofer Institute of Toxicology and Experimental Medicine, Nikolai-Fuchsstr. 1, 30625 Hannover, Germany. Borlak@item.fraunhofer.de
Meier
Tatiana
T
Halter
Roman
R
Spanel
Reinhard
R
Spanel-Borowski
Katharina
K
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D004815:Epidermal Growth Factor / Q000235:genetics*; D020224:Expressed Sequence Tags; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016762:Genes, fos / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology; D050787:Proto-Oncogene Protein c-ets-2; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics; D014158:Transcription, Genetic
C494070:Ets2 protein, mouse; D018398:Homeodomain Proteins; D050787:Proto-Oncogene Protein c-ets-2; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C490797:Tgif1 protein, mouse; D015534:Trans-Activators; D004815:Epidermal Growth Factor