{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T11:16:42Z","timestamp":1790162202598,"version":"4.1.0"},"reference-count":32,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2012,1,3]],"date-time":"2012-01-03T00:00:00Z","timestamp":1325548800000},"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":[[2012,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Mouse hepatocarcinogenesis is associated with mutations in Hras, but infrequently in Kras. The effect on carcinogenesis of developmental age at the time of ras mutation remains unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>We sought to compare quantitatively the effects of expressing mutant H\u2010 or Kras genes in fetal vs. adult mouse liver.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We established an inducible system of gene expression in mouse liver to define disease pathogenesis associated with activation of oncogene expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Diffuse expression of either oncogene in fetal or adult hepatocytes caused hepatomegaly. For mutant Hras<jats:sup>G12V<\/jats:sup>, this phenotype was almost fully reversible and accompanied by apoptosis, indicating that maintenance of hepatomegaly requires continuous Hras<jats:sup>G12V<\/jats:sup> expression. We also examined the effect of ras expression on growth of transplanted hepatocytes in an <jats:italic>in vivo<\/jats:italic> system that allows us to quantify hepatocyte growth effects in both permissive and restrictive hepatic growth environments. Mutant Kras<jats:sup>G12D<\/jats:sup> had no effect on hepatocyte growth in this system. In contrast, Hras<jats:sup>G12V<\/jats:sup> induced increased hepatocyte focus growth in quiescent liver, the hallmark of a cell autonomous growth stimulus. Hras<jats:sup>G12V<\/jats:sup> also increased the fraction of donor hepatocyte foci that displayed extreme growth, a characteristic of preneoplastic lesions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The primary effect of diffuse, whole\u2010liver expression of either mutant ras gene in fetal or adult mouse liver is diffuse and progressive hepatic growth. Hras<jats:sup>G12V<\/jats:sup> mutation influences hepatocarcinogenesis by conferring cell autonomous growth potential upon foci of expressing cells and by increasing the risk of neoplastic progression. Kras<jats:sup>G12D<\/jats:sup> does not share these latter carcinogenic effects in mouse liver.<\/jats:p><\/jats:sec>","DOI":"10.1111\/j.1478-3231.2011.02732.x","type":"journal-article","created":{"date-parts":[[2012,1,5]],"date-time":"2012-01-05T01:45:34Z","timestamp":1325727934000},"page":"582-591","source":"Crossref","is-referenced-by-count":5,"title":["Mutant Hras<sup>G12V<\/sup> and Kras<sup>G12D<\/sup> have overlapping, but non\u2010identical effects on hepatocyte growth and transformation frequency in transgenic mice"],"prefix":"10.1111","volume":"32","author":[{"given":"Marxa L.","family":"Figueiredo","sequence":"first","affiliation":[{"name":"Department of Pathobiological Sciences School of Veterinary Medicine University of Wisconsin\u2010Madison Madison WI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy J.","family":"Stein","sequence":"additional","affiliation":[{"name":"Department of Pathobiological Sciences School of Veterinary Medicine University of Wisconsin\u2010Madison Madison WI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Jochem","sequence":"additional","affiliation":[{"name":"Department of Pathobiological Sciences School of Veterinary Medicine University of Wisconsin\u2010Madison Madison WI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,1,3]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.21.5.1441-1443.2001"},{"key":"e_1_2_6_3_1","first-page":"55","article-title":"Mutations in ras genes in experimental tumours of rodents","volume":"146","author":"Sills RC","year":"1999","journal-title":"IARC Sci 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