caa a22 4500 445853263 CHVBK 20180317145420.0 cr unu---uuuuu 170323e20111201xx s 000 0 eng 10.1007/s00204-011-0715-0 doi (NATIONALLICENCE)springer-10.1007/s00204-011-0715-0 Identification of biomarkers of chemically induced hepatocarcinogenesis in rasH2 mice by toxicogenomic analysis [Elektronische Daten] [Han-Jin Park, Jung-Hwa Oh, Se-Myo Park, Jae-Woo Cho, Young Yum, Sue Park, Do-Young Yoon, Seokjoo Yoon] Toxicogenomic approaches have been applied to chemical-induced heptocarcinogenesis rodent models for the identification of biomarkers of early-stage hepatocarcinogenesis and to help clarify the underlying carcinogenic mechanisms in the liver. In this study, we used toxiciogenomic methods to identify candidate biomarker genes associated with hepatocarcinogenesis in rasH2 mice. Blood chemical, histopathologic, and gene expression analyses of the livers of rasH2 mice were performed 7 and 91days after the administration of the genotoxic hepatocarcinogens 2-acetylaminofluorene (AAF) and diethylnitrosoamine (DEN), the genotoxic carcinogen melphalan (Mel), and the nongenotoxic noncarcinogen 1-naphthylisothiocynate (ANIT). Histopathologic lesions and a rise in accompanying serum marker levels were found in the DEN-treated rasH2 mice, whereas no neoplastic lesions were observed in the rasH2 mice. However, biological functional analysis using Ingenuity Pathways Analysis (IPA) software revealed that genes with comparable molecular and cellular functions were similarly deregulated in the AAF- and DEN-treated rasH2 mice. We selected 68 significantly deregulated genes that represented a hepatocarcinogen-specific signature; these genes were commonly deregulated in both the AAF- and DEN-treated rasH2 mice on days 7 and 91. Hierarchical clustering analysis indicated that the expression patterns of the selected genes in the hepatocarcinogen (AAF and DEN) groups were distinctive from the patterns in the control, Mel, and ANIT groups. Biomarker filter analysis using IPA software suggested that 28 of the 68 signature genes represent promising candidate biomarkers of cancer. Quantitative real-time PCR analysis confirmed that the deregulated genes, which exhibited sustained up- and down-regulation up to day 91, are likely involved in early-stage hepatocarcinogenesis. In summary, the common and significant gene expression changes induced by AAF and DEN may reflect early molecular events associated with hepatocarcinogenesis, and these "signature” genes may be useful as biomarkers of hepatocarcinogenesis in mice. Springer-Verlag, 2011 Biomarker nationallicence Hepatocarcinogenesis nationallicence rasH2 mice nationallicence Toxicogenomics nationallicence 2-acetylaminofluorene nationallicence Diethylnitrosoamine nationallicence Park Han-Jin Division of Research and Development, Korea Institute of Toxicology, 19 Shinsung-ro, 305-343, Yuseong-gu, Daejeon, Korea aut Oh Jung-Hwa Division of Research and Development, Korea Institute of Toxicology, 19 Shinsung-ro, 305-343, Yuseong-gu, Daejeon, Korea aut Park Se-Myo Division of Research and Development, Korea Institute of Toxicology, 19 Shinsung-ro, 305-343, Yuseong-gu, Daejeon, Korea aut Cho Jae-Woo Division of Pre-Clinical Study, Korea Institute of Toxicology, 19 Shinsung-ro, 305-343, Yuseong-gu, Daejeon, Korea aut Yum Young Toxicological Screening and Testing Division, NiFDS, Korea Food and Drug Administration, 187 Osongsaengmyeong2(i)-ro, Gangoe-myeon, 363-951, Cheongwon-gun, Chungcheongbuk-do, Korea aut Park Sue Hazardous Substances Analysis Division at Seoul Regional FDA, Korea Food and Drug Administration, 900-12, Mok-dong, Yangcheon-gu, 158-050, Seoul, Korea aut Yoon Do-Young Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong 1, Gwangjin-gu, 143-701, Seoul, Korea aut Yoon Seokjoo Division of Research and Development, Korea Institute of Toxicology, 19 Shinsung-ro, 305-343, Yuseong-gu, Daejeon, Korea aut Archives of Toxicology Springer-Verlag 85/12(2011-12-01), 1627-1640 0340-5761 85:12<1627 2011 85 204 https://doi.org/10.1007/s00204-011-0715-0 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00204-011-0715-0 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Park Han-Jin Division of Research and Development, Korea Institute of Toxicology, 19 Shinsung-ro, 305-343, Yuseong-gu, Daejeon, Korea aut NATIONALLICENCE 700 1- Oh Jung-Hwa Division of Research and Development, Korea Institute of Toxicology, 19 Shinsung-ro, 305-343, Yuseong-gu, Daejeon, Korea aut NATIONALLICENCE 700 1- Park Se-Myo Division of Research and Development, Korea Institute of Toxicology, 19 Shinsung-ro, 305-343, Yuseong-gu, Daejeon, Korea aut NATIONALLICENCE 700 1- Cho Jae-Woo Division of Pre-Clinical Study, Korea Institute of Toxicology, 19 Shinsung-ro, 305-343, Yuseong-gu, Daejeon, Korea aut NATIONALLICENCE 700 1- Yum Young Toxicological Screening and Testing Division, NiFDS, Korea Food and Drug Administration, 187 Osongsaengmyeong2(i)-ro, Gangoe-myeon, 363-951, Cheongwon-gun, Chungcheongbuk-do, Korea aut NATIONALLICENCE 700 1- Park Sue Hazardous Substances Analysis Division at Seoul Regional FDA, Korea Food and Drug Administration, 900-12, Mok-dong, Yangcheon-gu, 158-050, Seoul, Korea aut NATIONALLICENCE 700 1- Yoon Do-Young Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong 1, Gwangjin-gu, 143-701, Seoul, Korea aut NATIONALLICENCE 700 1- Yoon Seokjoo Division of Research and Development, Korea Institute of Toxicology, 19 Shinsung-ro, 305-343, Yuseong-gu, Daejeon, Korea aut NATIONALLICENCE 773 0- Archives of Toxicology Springer-Verlag 85/12(2011-12-01), 1627-1640 0340-5761 85:12<1627 2011 85 204 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer