Molecular mechanisms of hepatocarcinogenesis in transgenic mouse models of liver cancer
Molecular mechanisms of hepatocarcinogenesis in transgenic mouse models of liver cancer
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DOI：
10.1080/01926230590522095
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发表时间：
2005-01-01
影响因子：
1.5
通讯作者：
Thorgeirsson, SS
中科院分区：
文献类型：
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作者：
Calvisi, DF;Thorgeirsson, SS
c-myc和转化生长因子-α（transforming growth factor-alpha，TGF-α）在人肝细胞癌（hepatocellular carcinoma，HCC）中的过度表达是常见的。提示这些原癌基因在肝肿瘤发生中起关键作用。为了研究人类肝脏恶性转化背后的分子事件，我们已经产生了c-myc和c-myc/TGF-α转基因小鼠，这些小鼠容易发生肝癌。这些转基因小鼠发展出具有不同发病率、动力学和组织病理学特征的HCC。事实上，当与各自的单一转基因系相比时，c-myc和TGF-α转基因的共表达导致对肝肿瘤发育的显著协同作用，包括更短的潜伏期和更积极的表型。c-myc/TGF-α HCC更恶性的组织病理学特征是与单一亲本系相比，该肝癌模型中增殖增加和凋亡减少的结果。因此，c-myc和c-myc/TGF-α转基因小鼠显示出不同的HCC分子发病机制。重要的是，参与c-myc和c-myc/TGF-α肝癌发展的遗传和分子机制是人类肝癌发生中的主要致癌事件，表明这些小鼠模型代表了解剖和阐明人类HCC分子基础的有用工具。
Overexpression of c-myc and transforming growth factor-alpha (TGF-alpha) has been frequently observed in human hepatocellular carcinoma (HCC). suggesting a pivotal role played by these protooncogenes in liver oncogenesis. In order to investigate the molecular events underlying human hepatic malignant transformation, we have generated c-myc and c-myc/TGF-alpha transgenic mice that are prone to liver cancer. These transgenic mice develop HCCs with different incidence, kinetics and histopathological features. Indeed, co-expression of c-myc and TGF-alpha transgenes results in a dramatic synergistic effect on liver turner development when compared with respective single transgenic lines, including a shorter latency period and a more aggressive phenotype. The more malignant histopathological features characteristic of c-myc/TGF-alpha HCCs are the result of the increased proliferation and reduced apoptosis in this model of liver cancer when compared with single parental lines. Accordingly, c-myc and c-myc/TGF-alpha transgenic mice display a different molecular pathogenesis of HCC. Importantly, the genetic and molecular mechanisms that are involved in c-myc and c-myc/TGF-alpha liver cancer development are major oncogenic events in human hepatocarcinogenesis, indicating that these mouse models represent a useful tool to dissect and elucidate the molecular basis of human HCC.