{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T22:51:07Z","timestamp":1775256667293,"version":"3.50.1"},"reference-count":49,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2013,2,26]],"date-time":"2013-02-26T00:00:00Z","timestamp":1361836800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001868","name":"National Science Council","doi-asserted-by":"crossref","award":["NSC 100-2325-B-182 -006"],"award-info":[{"award-number":["NSC 100-2325-B-182 -006"]}],"id":[{"id":"10.13039\/501100001868","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001868","name":"National Science Council","doi-asserted-by":"crossref","award":["NSC 98-2314-B-016-035-MY2"],"award-info":[{"award-number":["NSC 98-2314-B-016-035-MY2"]}],"id":[{"id":"10.13039\/501100001868","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001868","name":"National Science Council","doi-asserted-by":"crossref","award":["NSC 99-3112-B-016-003"],"award-info":[{"award-number":["NSC 99-3112-B-016-003"]}],"id":[{"id":"10.13039\/501100001868","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001868","name":"National Science Council","doi-asserted-by":"crossref","award":["NSC 100-2320-B-016-011"],"award-info":[{"award-number":["NSC 100-2320-B-016-011"]}],"id":[{"id":"10.13039\/501100001868","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001868","name":"National Science Council","doi-asserted-by":"crossref","award":["NSC 99-2314-B-016-015-MY2"],"award-info":[{"award-number":["NSC 99-2314-B-016-015-MY2"]}],"id":[{"id":"10.13039\/501100001868","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004737","name":"National Health Research Institutes, Taiwan","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004737","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Tri-Service General Hospital, Taiwan, Republic of China","award":["TSGH-C100-010-014-S03"],"award-info":[{"award-number":["TSGH-C100-010-014-S03"]}]},{"name":"Liver Disease Prevention and Treatment Research Foundation, Taiwan, Republic of China"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Gastro and Hepatol"],"published-print":{"date-parts":[[2013,3]]},"abstract":"Abstract<\/jats:title>Background and Aim<\/jats:title>Except for genetic mutations, epigenetic changes are also involved in the development of human cancers. Recently, we have identified SOX<\/jats:styled-content>1<\/jats:italic>, SRY<\/jats:styled-content> (sex determining region Y<\/jats:styled-content>)\u2010box 1, is hypermethylated in cervical cancer and ovarian cancer. Therefore, we investigated whether promoter hypermethylation of SOX<\/jats:styled-content>1<\/jats:italic> is common in hepatocellular carcinoma (HCC<\/jats:styled-content>).<\/jats:p><\/jats:sec>Methods<\/jats:title>We used methylation\u2010specific polymerase chain reaction (MS<\/jats:styled-content>\u2010PCR<\/jats:styled-content>) and bisulfite sequencing to analyze the methyaltion level of the SOX<\/jats:styled-content>1<\/jats:italic> promoter in seven HCC<\/jats:styled-content> cell lines, 54 clinical HCC<\/jats:styled-content>s, 42 cirrhotic livers, 21 livers with chronic hepatitis, and 15 control livers. Then, we employed quantitative MS<\/jats:styled-content>\u2010PCR<\/jats:styled-content> (QMSP<\/jats:styled-content>) to validate in an independent set of samples (60 paired HCC<\/jats:styled-content>s and 30 control livers). Finally, we used luciferase reporter and colony formation assay to check the effect of SOX<\/jats:styled-content>1 in HCC<\/jats:styled-content>.<\/jats:p><\/jats:sec>Results<\/jats:title>Promoter methylation of SOX<\/jats:styled-content>1<\/jats:italic> was significantly frequent in HCC<\/jats:styled-content> cell lines and clinical HCC<\/jats:styled-content>s, cirrhotic livers, but not in control livers (P<\/jats:italic>\u2009<\u20090.0001). There is a significant correlation between downregulation of SOX<\/jats:styled-content>1<\/jats:italic> expression and promoter methylation. QMSP<\/jats:styled-content> results confirmed that promoter hypermethylation of SOX<\/jats:styled-content>1<\/jats:italic> is significantly more frequent in HCC<\/jats:styled-content>s than control livers (P<\/jats:italic>\u2009<\u20090.0001). The frequency of SOX<\/jats:styled-content>1<\/jats:italic> methylation in patients with secreted frizzled\u2010related proteins (SFRP<\/jats:styled-content><\/jats:italic>s) methylation is significantly higher than in patients without SFRP<\/jats:styled-content><\/jats:italic>s methylation (P<\/jats:italic>\u2009<\u20090.0001). Furthermore, ectopic expression of SOX<\/jats:styled-content>1<\/jats:italic> could suppress T<\/jats:styled-content>\u2010cell factor\u2010dependent transcriptional activity and colony formation number in HCC<\/jats:styled-content>s.<\/jats:p><\/jats:sec>Conclusions<\/jats:title>Concomitant epigenetic silencing of SOX<\/jats:styled-content>1<\/jats:italic> and SFRP<\/jats:styled-content>s<\/jats:italic> through promoter hypermethylation is frequent in HCC<\/jats:styled-content>s, and this might contribute to abnormal activation of canonical Wnt signal pathway.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jgh.12078","type":"journal-article","created":{"date-parts":[[2012,12,6]],"date-time":"2012-12-06T13:49:13Z","timestamp":1354801753000},"page":"551-559","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Frequent concomitant epigenetic silencing of SOX<\/scp>1<\/i> and secreted frizzled\u2010related proteins (SFRP<\/scp><\/i>s) in human hepatocellular carcinoma"],"prefix":"10.1111","volume":"28","author":[{"given":"Yu\u2010Lueng","family":"Shih","sequence":"first","affiliation":[{"name":"Division of Gastroenterology Department of Internal Medicine Tri\u2010Service General Hospital National Defense Medical Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chung\u2010Bao","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Division of General Surgery Department of Surgery Tri\u2010Service General Hospital National Defense Medical Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming\u2010De","family":"Yan","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology Department of Internal Medicine Wan Fang Hospital Taipei Medical University Taipei"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chun\u2010Ming","family":"Tsao","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences National Defense Medical Center"},{"name":"Bureau of Investigation Ministry of Justice New Taipei City Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsai\u2010Yuan","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology Department of Internal Medicine Tri\u2010Service General Hospital National Defense Medical Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chang\u2010Hsin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department and Graduate Institute of Microbiology and Immunology National Defense Medical Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ya\u2010Wen","family":"Lin","sequence":"additional","affiliation":[{"name":"Department and Graduate Institute of Microbiology and Immunology National Defense Medical Center"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2013,2,26]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2002.33411"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2004.09.013"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199903113401001"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cld.2004.12.009"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1934"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2007.06.016"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21651"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1593\/neo.07469"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1586\/egh.10.74"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.11.24.3286"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.126.2.345"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.14.15.1837"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.10.12.1443"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/382638a0"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1440-1746.2003.02973.x"},{"key":"e_1_2_6_17_1","doi-asserted-by":"crossref","first-page":"8847","DOI":"10.1073\/pnas.95.15.8847","article-title":"Somatic mutations of the beta\u2010catenin gene are frequent in mouse and human hepatocellular carcinomas","volume":"95","author":"La Coste A","year":"1998","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-03-1346"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.11197"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/73448"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.22023"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng892"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra023075"},{"key":"e_1_2_6_24_1","first-page":"4525","article-title":"Inactivation of the CDKN2\/p16\/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers","volume":"55","author":"Herman JG","year":"1995","journal-title":"Cancer Res."},{"key":"e_1_2_6_25_1","first-page":"4366","article-title":"Analysis of adenomatous polyposis coli promoter hypermethylation in human cancer","volume":"60","author":"Esteller M","year":"2000","journal-title":"Cancer Res."},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cr.7290177"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63469-4"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1206338"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1330"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.22750"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.23519"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.23957"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.22046"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1171104"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.02179-06"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.18.9821"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.2353\/jmoldx.2006.050135"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.25252"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.2353\/jmoldx.2006.060026"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-419X(03)00005-2"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00432-003-0431-0"},{"key":"e_1_2_6_43_1","first-page":"3225","article-title":"A gene hypermethylation profile of human cancer","volume":"61","author":"Esteller M","year":"2001","journal-title":"Cancer Res."},{"key":"e_1_2_6_44_1","first-page":"2765","article-title":"Frequent hypermethylation of the 5\u2032 CpG island of E\u2010cadherin in esophageal adenocarcinoma","volume":"7","author":"Corn PG","year":"2001","journal-title":"Clin. Cancer Res."},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.4.2727"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2000.19797"},{"key":"e_1_2_6_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1209439"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1208910"},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2008.04.019"},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2010.05.012"}],"container-title":["Journal of Gastroenterology and Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fjgh.12078","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fjgh.12078","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jgh.12078","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,15]],"date-time":"2023-10-15T10:29:32Z","timestamp":1697365772000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jgh.12078"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,2,26]]},"references-count":49,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2013,3]]}},"alternative-id":["10.1111\/jgh.12078"],"URL":"https:\/\/doi.org\/10.1111\/jgh.12078","archive":["Portico"],"relation":{},"ISSN":["0815-9319","1440-1746"],"issn-type":[{"value":"0815-9319","type":"print"},{"value":"1440-1746","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,2,26]]},"assertion":[{"value":"2012-09-24","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2013-02-26","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}