A mouse model of hepatocellular carcinoma - Ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice
A mouse model of hepatocellular carcinoma - Ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice
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DOI：
10.1016/s0002-9440(10)61177-7
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发表时间：
2002-06-01
影响因子：
6
通讯作者：
French, DM
中科院分区：
文献类型：
--
作者：
Nicholes, K;Guillet, S;French, DM
大多数小鼠肝细胞癌模型都表达了在肝脏特异性启动子控制下的生长因子和癌基因。与此相反，我们在这里描述了在骨骼肌中过度表达人成纤维细胞生长因子19（FGF 19）的转基因小鼠中肝肿瘤的形成。FGF 19转基因小鼠早在2月龄时就有肝甲胎蛋白mRNA升高，10月龄时肝细胞癌明显。通过在肿瘤形成前FGF 19转基因小鼠和注射重组FGF 19蛋白的非转基因小鼠中掺入5-溴-2 '-脱氧尿苷，证实了中心周围肝细胞增殖的增加。小细胞发育不良的区域最初在中央周围明显，整个肝小叶的发育不良/肿瘤灶为谷氨酰胺合成酶阳性，提示中央周围起源。与Wingless/Wnt通路的慢性激活一致，来自FGF 19转基因小鼠的44%的肝细胞肿瘤具有β-连环蛋白的核染色。对编码β-连环蛋白的肿瘤DNA进行测序，发现了导致氨基酸取代的点突变。这些发现表明FGF 19在肝细胞癌中的作用是以前未知的。
Most mouse models of hepatocellular carcinoma have expressed growth factors and oncogenes under the control of a liver-specific promoter. In contrast, we describe here the formation of liver tumors in transgenic mice overexpressing human fibroblast growth factor 19 (FGF19) in skeletal muscle. FGF19 transgenic mice had elevated hepatic a-fetoprotein mRNA as early as 2 months of age, and hepatocellular carcinomas were evident by 10 months of age. Increased proliferation of pericentral hepatocytes was demonstrated by 5-bromo-2'-deoxyuridine incorporation in the FGF19 transgenic mice before tumor formation and in nontransgenic mice injected with recombinant FGF19 protein. Areas of small cell dysplasia were initially evident pericentrally, and dysplastic/neoplastic foci throughout the hepatic lobule were glutamine synthetase-positive, suggestive of a pericentral origin. Consistent with chronic activation of the Wingless/Wnt pathway, 44% of the hepatocellular tumors from FGF19 transgenic mice had nuclear staining for beta-catenin. Sequencing of the tumor DNA encoding beta-catenin revealed point mutations that resulted in amino acid substitutions. These findings suggest a previously unknown role for FGF19 in hepatocellular carcinomas.