{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T21:48:42Z","timestamp":1791323322234,"version":"4.3.1"},"reference-count":39,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2009,3,31]],"date-time":"2009-03-31T00:00:00Z","timestamp":1238457600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Deutsche Krebshilfe to AKB"},{"name":"Medical Faculty of the University of Regensburg"}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2009,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Striking similarities exist between molecular mechanisms driving embryonic liver development and progression of hepatocellular carcinoma (HCC). Bone morphogenetic proteins (BMPs), particularly BMP4, have been proposed to regulate embryonic hepatic development. BMP expression has been observed in neoplasia but the expression and biological role of BMP4 in human HCC are unknown. We found increased <jats:italic>BMP4<\/jats:italic> mRNA and protein in HCC cell lines and tissue samples compared to primary human hepatocytes and corresponding non\u2010tumourous tissue. Hypoxia further induced BMP4 expression in HCC cells, which was abolished by transfection of a dominant negative form of HIF\u20101alpha (dnHIF\u20101alpha). However, gel shift assays revealed only minor binding activity in nuclear extracts from (hypoxic) HCC cells to a putative hypoxia\u2010response element in the <jats:italic>BMP4<\/jats:italic> promoter. Sequence analysis of the <jats:italic>BMP4<\/jats:italic> promoter revealed two Ets\u20101 binding sites, and Ets\u20101 activity was increased in HCC cells under hypoxic conditions. Transfection of dnHIF\u20101alpha completely abrogated hypoxia\u2010induced Ets\u20101 activity as well as BMP4 expression. Overexpression of Ets\u20101 markedly enhanced <jats:italic>BMP4<\/jats:italic> promoter activity, while antisense Ets\u20101 almost completely abolished basal as well as hypoxia\u2010induced BMP4 expression. These data demonstrate that Ets\u20101 activity contributes to baseline expression of the <jats:italic>BMP4<\/jats:italic> gene and is the predominant mediator of the HIF\u2010dependent BMP4 induction under hypoxic conditions. To determine the functional relevance of BMP4 expression, HCC cell lines were treated with antisense BMP4 constructs or siRNA against BMP4. BMP4 suppression resulted in a strong reduction of the migratory and invasive potential and anchorage\u2010independent growth. Furthermore, tube formation assays indicated that BMP4 expressed by HCC cells promotes vasculogenesis. Our findings demonstrate that BMP4 is increased in HCC and promotes HCC progression. Therefore, BMP4 expression may have clinical relevance, and interfering with BMP4 signalling appears as an attractive therapeutic target for this highly aggressive tumour. Copyright \u00a9 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.2563","type":"journal-article","created":{"date-parts":[[2009,3,31]],"date-time":"2009-03-31T04:34:25Z","timestamp":1238474065000},"page":"520-529","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":73,"title":["Bone morphogenetic protein 4 is induced in hepatocellular carcinoma by hypoxia and promotes tumour progression"],"prefix":"10.1002","volume":"218","author":[{"given":"Ulrike","family":"Maegdefrau","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Amann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Winklmeier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Braig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Schubert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas S","family":"Weiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Schardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Warnecke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claus","family":"Hellerbrand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja\u2010Katrin","family":"Bosserhoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2009,5,8]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-437X(96)80064-5"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2443.2002.00599.x"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.448.65.2"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1993.1105"},{"key":"e_1_2_6_6_2","first-page":"497","article-title":"Expression of bone morphogenetic proteins of human neoplastic epithelial cells","volume":"42","author":"Hatakeyama S","year":"1997","journal-title":"Biochem Mol Biol Int"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(99)70024-7"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.21509"},{"key":"e_1_2_6_9_2","first-page":"1129","article-title":"Bone morphogenetic proteins and their receptor signaling in prostate cancer","volume":"22","author":"Ye L","year":"2007","journal-title":"Histol Histopathol"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-006-9362-1"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgm015"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.21148"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M600526200"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2006.12.020"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210182"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1007\/2789_2007_044"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00160.2003"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V97.2.516"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2008.03.016"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-06-0712"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.01913"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.000281"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.904601"},{"key":"e_1_2_6_24_2","doi-asserted-by":"publisher","DOI":"10.4161\/cbt.3.7.965"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature05349"},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2007.129544"},{"key":"e_1_2_6_27_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2184.2002.00248.x"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-003-3337-8"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.04-1640fje"},{"key":"e_1_2_6_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/0076-6879(83)01039-3"},{"key":"e_1_2_6_31_2","first-page":"373","article-title":"Expression of integrin alpha10 is induced in malignant melanoma","volume":"29","author":"Wenke AK","year":"2007","journal-title":"Cell Oncol"},{"key":"e_1_2_6_32_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2001.5927"},{"key":"e_1_2_6_33_2","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v11.i11.1705"},{"key":"e_1_2_6_34_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-002-0380-0"},{"key":"e_1_2_6_35_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M700063200"},{"key":"e_1_2_6_36_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4652(200002)182:2<239::AID-JCP13>3.0.CO;2-W"},{"key":"e_1_2_6_37_2","doi-asserted-by":"publisher","DOI":"10.1159\/000025634"},{"key":"e_1_2_6_38_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.24.11740"},{"key":"e_1_2_6_39_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.10309"},{"key":"e_1_2_6_40_2","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-051x.2001.028005465.x"}],"container-title":["The Journal of Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fpath.2563","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fpath.2563","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.2563","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T12:37:38Z","timestamp":1761050258000},"score":1,"resource":{"primary":{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/10.1002\/path.2563"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,5,8]]},"references-count":39,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2009,8]]}},"alternative-id":["10.1002\/path.2563"],"URL":"https:\/\/doi.org\/10.1002\/path.2563","archive":["Portico"],"relation":{},"ISSN":["0022-3417","1096-9896"],"issn-type":[{"value":"0022-3417","type":"print"},{"value":"1096-9896","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,5,8]]},"assertion":[{"value":"2008-11-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2009-03-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2009-05-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}