Minimal cooperation between mutant Hras and c-myc or TGFα in the regulation of mouse hepatocyte growth or transformation in vivo.
Minimal cooperation between mutant Hras and c-myc or TGFα in the regulation of mouse hepatocyte growth or transformation in vivo.
复制标题
突变体 Hras 和 c-myc 或 TGFα 在调节小鼠肝细胞生长或体内转化方面的最小合作。
DOI：
10.1111/j.1478-3231.2011.02596.x
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Sandgren,EricP
中科院分区：
文献类型：
--
作者：
Stein,TimothyJ;Bowden,Margaret;Sandgren,EricP
Background: Liver carcinogenesis is associated with multiple genetic changes in affected cells, including alterations in the Hras signalling pathway.Aim: To define the biological contributions of Hras to mouse hepatocarcinogenesis, we quantifiedin vivointeractions between mutant Hras and other genetic alterations frequently associated with liver cancer, including overexpression of the transcription factor c‐myc and the epidermal growth factor receptor ligand transforming growth factor alpha (TGFα).Methods: To accomplish this aim, we initiated expression of an activated Hras in hepatocytes of adult mice with or without simultaneous overexpression of either c‐myc or TGFα. 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 growthin vivo.Results: Hras expression caused diffuse liver enlargement (hepatomegaly), and this phenotype was not changed by coexpression of c‐myc or TGFα. 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 TGFα or c‐myc 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‐expressing groups.Conclusions: Hras‐associated hepatocyte growth deregulation is not complemented by activation of c‐myc or TGFα growth signalling pathways in mouse liver. This finding emphasizes the tissue‐specific character of molecular growth regulation.
