Mutant Hras(G12V) and Kras(G12D) have overlapping, but non-identical effects on hepatocyte growth and transformation frequency in transgenic mice.
Mutant Hras(G12V) and Kras(G12D) have overlapping, but non-identical effects on hepatocyte growth and transformation frequency in transgenic mice.
复制标题
突变体Hras(G12V)和Kras(G12D)对转基因小鼠的肝细胞生长和转化频率具有重叠但不相同的影响。
DOI：
10.1111/j.1478-3231.2011.02732.x
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Sandgren,EricP
中科院分区：
文献类型：
--
作者：
Figueiredo,MarxaL;Stein,TimothyJ;Jochem,Adam;Sandgren,EricP
BackgroundMouse 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.AimWe sought to compare quantitatively the effects of expressing mutant H‐ or Kras genes in fetal vs. adult mouse liver.MethodsWe established an inducible system of gene expression in mouse liver to define disease pathogenesis associated with activation of oncogene expression.ResultsDiffuse expression of either oncogene in fetal or adult hepatocytes caused hepatomegaly. For mutant HrasG12V, this phenotype was almost fully reversible and accompanied by apoptosis, indicating that maintenance of hepatomegaly requires continuous HrasG12Vexpression. We also examined the effect of ras expression on growth of transplanted hepatocytes in anin vivosystem that allows us to quantify hepatocyte growth effects in both permissive and restrictive hepatic growth environments. Mutant KrasG12Dhad no effect on hepatocyte growth in this system. In contrast, HrasG12Vinduced increased hepatocyte focus growth in quiescent liver, the hallmark of a cell autonomous growth stimulus. HrasG12Valso increased the fraction of donor hepatocyte foci that displayed extreme growth, a characteristic of preneoplastic lesions.ConclusionsThe primary effect of diffuse, whole‐liver expression of either mutant ras gene in fetal or adult mouse liver is diffuse and progressive hepatic growth. HrasG12Vmutation influences hepatocarcinogenesis by conferring cell autonomous growth potential upon foci of expressing cells and by increasing the risk of neoplastic progression. KrasG12Ddoes not share these latter carcinogenic effects in mouse liver.
