{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T15:11:05Z","timestamp":1778771465217,"version":"3.51.4"},"reference-count":49,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2013,12,14]],"date-time":"2013-12-14T00:00:00Z","timestamp":1386979200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2014,6,15]]},"abstract":"<jats:p>Hepatocellular carcinoma (HCC) is one of the most prevalent cancers and is rising in incidence worldwide. The molecular mechanisms leading to the development of HCC are complex and include both genetic and epigenetic events. To determine the relative contribution of these alterations in liver tumorigenesis, we evaluated epigenetic modifications at both global and gene specific levels, as well as the mutational profile of genes commonly altered in liver tumors. A mouse model of fibrosis\u2010associated liver cancer that was designed to emulate cirrhotic liver, a prevailing disease state observed in most humans with HCC, was used. Tumor and nontumor liver samples from B6C3F1 mice treated with <jats:italic>N<\/jats:italic>\u2010nitrosodiethylamine (DEN; a single <jats:italic>ip<\/jats:italic> injection of 1 mg\/kg at 14 days of age) and carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>; 0.2 ml\/kg, 2 times\/week <jats:italic>ip<\/jats:italic> starting at 8 weeks of age for 14 weeks), as well as corresponding vehicle control animals, were analyzed for genetic and epigenetic alterations. <jats:italic>H\u2010ras<\/jats:italic>, <jats:italic>Ctnnb1<\/jats:italic> and <jats:italic>Hnf1\u03b1<\/jats:italic> genes were not mutated in tumors in mice treated with DEN+CCl<jats:sub>4<\/jats:sub>. In contrast, the increased tumor incidence in mice treated with DEN+CCl<jats:sub>4<\/jats:sub> was associated with marked epigenetic changes in liver tumors and nontumor liver tissue, including demethylation of genomic DNA and repetitive elements, a decrease in histone 3 lysine 9 trimethylation (H3K9me3) and promoter hypermethylation and functional downregulation of <jats:italic>Riz1,<\/jats:italic> a histone lysine methyltransferase tumor suppressor gene. Additionally, the reduction in H3K9me3 was accompanied by increased expression of long interspersed nucleotide elements 1 and short interspersed nucleotide elements B2, which is an indication of genomic instability. In summary, our results suggest that epigenetic events, rather than mutations in known cancer\u2010related genes, play a prominent role in increased incidence of liver tumors in this mouse model of fibrosis\u2010associated liver cancer.<\/jats:p>","DOI":"10.1002\/ijc.28610","type":"journal-article","created":{"date-parts":[[2013,11,15]],"date-time":"2013-11-15T02:28:38Z","timestamp":1384482518000},"page":"2778-2788","source":"Crossref","is-referenced-by-count":44,"title":["Genetic and epigenetic changes in fibrosis\u2010associated hepatocarcinogenesis in mice"],"prefix":"10.1002","volume":"134","author":[{"given":"Grace","family":"Chappell","sequence":"first","affiliation":[{"name":"Department of Environmental Sciences and Engineering University of North Carolina Chapel Hill NC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristy","family":"Kutanzi","sequence":"additional","affiliation":[{"name":"Division of Biochemical Toxicology National Center for Toxicological Research Jefferson AR"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeki","family":"Uehara","sequence":"additional","affiliation":[{"name":"Department of Environmental Sciences and Engineering University of North Carolina Chapel Hill NC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Volodymyr","family":"Tryndyak","sequence":"additional","affiliation":[{"name":"Division of Biochemical Toxicology National Center for Toxicological Research Jefferson AR"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hue\u2010Hua","family":"Hong","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Pathology Branch National Institute of Environmental Health Sciences and National Toxicology Program Research Triangle Park NC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Hoenerhoff","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Pathology Branch National Institute of Environmental Health Sciences and National Toxicology Program Research Triangle Park NC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frederick A.","family":"Beland","sequence":"additional","affiliation":[{"name":"Division of Biochemical Toxicology National Center for Toxicological Research Jefferson AR"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivan","family":"Rusyn","sequence":"additional","affiliation":[{"name":"Department of Environmental Sciences and Engineering University of North Carolina Chapel Hill NC"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Igor P.","family":"Pogribny","sequence":"additional","affiliation":[{"name":"Division of Biochemical Toxicology National Center for Toxicological Research Jefferson AR"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2013,12,14]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.EPI-11-0643"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-13-2107"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1934"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-012-0931-2"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2004.09.014"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1590-8658(10)60511-7"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)61347-0"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2613.2009.00656.x"},{"key":"e_1_2_6_10_1","first-page":"4253","article-title":"Kinetics of diethylnitrosamine hepatocarcinogenesis in the infant mouse","volume":"43","author":"Vesselinovitch SD","year":"1983","journal-title":"Cancer Res"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-230X-10-79"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfs342"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0031-1276646"},{"key":"e_1_2_6_14_1","article-title":"Role of epigenetic aberrations in the development and progression of human hepatocellular carcinoma","author":"Pogribny IP","journal-title":"Cancer Lett"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1177\/0192623312467520"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2010.11.010"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1999.1187"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600545"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.18.9821"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.73"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgl050"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/0300-483X(95)03112-S"},{"key":"e_1_2_6_23_1","first-page":"313","article-title":"Alterations of oncogenes, tumor suppressor genes and growth factors in hepatocellular carcinoma: with relation to tumor size and invasiveness","volume":"111","author":"Tang Z","year":"1998","journal-title":"Chin Med J (Engl)"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.15.8847"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1001"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.2337\/db09-1819"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.14.1741"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20670"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22110"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.01.029"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2007.05767.x"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkt012"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.013"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2001.24798"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1202858"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.275.5307.1787"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24133"},{"key":"e_1_2_6_38_1","first-page":"55","volume-title":"Mutations in ras genes in experimental tumours of rodents. In: McGregor DB, Rice JM, Venitt S. The use of short\u2010 and medium\u2010term tests for carcinogens and data on genetic effects in carcinogenic hazard evaluationed","author":"Sills RC","year":"1999"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/15.5.1083"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13148-011-0032-8"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg1748"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01262"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/1098-2264(2000)9999:9999<::AID-GCC1066>3.0.CO;2-F"},{"key":"e_1_2_6_44_1","first-page":"8094","article-title":"Hypermethylation in human cancers of the RIZ1 tumor suppressor gene, a member of a histone\/protein methyltransferase superfamily","volume":"61","author":"Du Y","year":"2001","journal-title":"Cancer Res"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrfmmm.2010.07.013"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2010.05.012"},{"key":"e_1_2_6_47_1","first-page":"7619","article-title":"Inactivation of a histone methyltransferase by mutations in human cancers","volume":"63","author":"Kim KC","year":"2003","journal-title":"Cancer Res"},{"key":"e_1_2_6_48_1","first-page":"1171","article-title":"Hyper\u2010methylation of RIZ1 tumor suppressor gene is involved in the early tumorigenesis of hepatocellular carcinoma","volume":"23","author":"Piao GH","year":"2008","journal-title":"Histol Histopathol"},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21682"},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-380866-0.60010-1"}],"container-title":["International Journal of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fijc.28610","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ijc.28610","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,4]],"date-time":"2023-10-04T05:54:39Z","timestamp":1696398879000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ijc.28610"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,12,14]]},"references-count":49,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2014,6,15]]}},"alternative-id":["10.1002\/ijc.28610"],"URL":"https:\/\/doi.org\/10.1002\/ijc.28610","archive":["Portico"],"relation":{},"ISSN":["0020-7136","1097-0215"],"issn-type":[{"value":"0020-7136","type":"print"},{"value":"1097-0215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,12,14]]}}}