Altered gene expression of transcriptional regulatory factors in tumor marker-positive cells during chemically...

Glutathione-S-transferase placental form (GST-P) is markedly and specifically inducible in rat chemical hepatocarcinogenesis and is a reliable marker protein for pre-neoplasia. To gain insights into the molecular mechanisms at the early stage of hepatocarcinogenesis and hepatotoxicity, we investigated the gene expression profile by DNA microarray analysis. We prepared RNA from GST-P-positive foci in three individual rats and compared with normal liver sections from three individual rats, and labeled RNA was individually hybridized onto Affymetrix GeneChip Rat Expression Array 230A. DNA microarray analysis showed distinctly different profiles of dysregulated gene expression and supported the previous finding that some enzymes involved in metabolism and detoxification are overexpressed and suppressed. Here we discovered that several DNA-binding transcription factors and cofactors, including sterol-regulatory-element binding protein 1 (SREBP1) and Wilms' tumour 1 (WT1)-interacting protein, and their target genes were dysregulated in GST-P-positive foci. Moreover, genes involved in chromatin components, histone modification enzymes, and centrosome duplication were highly expressed. These genes were not previously known to be up-regulated during chemically induced hepatocarcinogenesis. DNA microarray analysis using RNA prepared from tumor marker-positive foci and control tissues provided a candidate gene link to the early stage of carcinogenesis and hepatotoxicity.