{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,2,11]],"date-time":"2024-02-11T15:20:29Z","timestamp":1707664829476},"reference-count":24,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2011,8,4]],"date-time":"2011-08-04T00:00:00Z","timestamp":1312416000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2011,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:italic>Background<\/jats:italic>: Liver carcinogenesis is associated with multiple genetic changes in affected cells, including alterations in the Hras signalling pathway. <jats:italic>Aim<\/jats:italic>: To define the biological contributions of Hras to mouse hepatocarcinogenesis, we quantified <jats:italic>in vivo<\/jats:italic> interactions between mutant Hras and other genetic alterations frequently associated with liver cancer, including overexpression of the transcription factor c\u2010myc and the epidermal growth factor receptor ligand transforming growth factor alpha (<jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u03b1). <jats:italic>Methods<\/jats:italic>: To accomplish this aim, we initiated expression of an activated Hras in hepatocytes of adult mice with or without simultaneous overexpression of either c\u2010myc or <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u03b1. Potential interactions also were assessed through the use of the comparative hepatocyte growth assay, a hepatocyte transplantation assay that measures effects of altered gene expression on hepatocyte growth <jats:italic>in vivo<\/jats:italic>. <jats:italic>Results<\/jats:italic>: Hras expression caused diffuse liver enlargement (hepatomegaly), and this phenotype was not changed by coexpression of c\u2010myc or <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u03b1. Using the transplant system, we found that expression of mutant Hras alone was sufficient to induce hepatocyte focus growth in a quiescent liver. Paradoxically, adding expression of <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u03b1 or c\u2010myc reversed this Hras effect. Finally, the frequencies of transplant foci with the preneoplastic feature of extreme growth potential and of liver neoplasms were increased for Hras and both combinations when compared with control hepatocytes, but did not differ among oncogene\u2010expressing groups. <jats:italic>Conclusions<\/jats:italic>: Hras\u2010associated hepatocyte growth deregulation is not complemented by activation of c\u2010myc or <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u03b1 growth signalling pathways in mouse liver. This finding emphasizes the tissue\u2010specific character of molecular growth regulation.<\/jats:p>","DOI":"10.1111\/j.1478-3231.2011.02596.x","type":"journal-article","created":{"date-parts":[[2011,8,4]],"date-time":"2011-08-04T14:17:04Z","timestamp":1312467424000},"page":"1298-1305","source":"Crossref","is-referenced-by-count":3,"title":["Minimal cooperation between mutant Hras and c\u2010myc or TGF\u03b1 in the regulation of mouse hepatocyte growth or transformation <i>in vivo<\/i>"],"prefix":"10.1111","volume":"31","author":[{"given":"Timothy J.","family":"Stein","sequence":"first","affiliation":[{"name":"Department of Pathobiological Sciences School of Veterinary Medicine University of Wisconsin\u2010Madison Madison WI USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margaret","family":"Bowden","sequence":"additional","affiliation":[{"name":"Department of Pathobiological Sciences School of Veterinary Medicine University of Wisconsin\u2010Madison Madison WI USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric P.","family":"Sandgren","sequence":"additional","affiliation":[{"name":"Department of Pathobiological Sciences School of Veterinary Medicine University of Wisconsin\u2010Madison Madison WI USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2011,8,4]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0300-483X(95)03112-S"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.83.1.33"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.3629242"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.83.16.5825"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.20.9302"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.12.5547"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23682"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2009.12.034"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-3357"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1209556"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90075-P"},{"key":"e_1_2_6_13_1","first-page":"715","article-title":"Oncogene\u2010induced liver neoplasia in transgenic mice","volume":"4","author":"Sandgren EP","year":"1989","journal-title":"Oncogene"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1159\/000128344"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3835(97)00187-0"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1999.9417"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.8108734"},{"key":"e_1_2_6_18_1","first-page":"1963","article-title":"Hepatocyte transplantation into diseased mouse liver","volume":"157","author":"Weglarz TC","year":"2000","journal-title":"Kinetics of parenchymal repopulation and identification of the proliferative capacity of tetraploid and octaploid hepatocytes. 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