Accelerated hepatocellular carcinoma development in mice expressing the Pim-3 transgene selectively in the liver
Accelerated hepatocellular carcinoma development in mice expressing the Pim-3 transgene selectively in the liver
复制标题
DOI：
10.1038/onc.2009.504
复制
发表时间：
2010-04-01
期刊：
影响因子：
8
通讯作者：
Mukaida, N.
中科院分区：
文献类型：
--
作者：
Wu, Y.;Wang, Y. Y.;Mukaida, N.
PIM-3是一种具有丝氨酸/苏氨酸激酶活性的原癌基因，在肝细胞癌组织中表达增强。为了探讨Pim-3在肝细胞癌发生发展中的作用，我们制备了选择性表达人Pim-3的转基因小鼠。这些小鼠按孟德尔比例出生，具有生育能力，直到出生一年后肝脏才表现出任何明显的病理变化。PIM-3转基因小鼠肝细胞表现出更快的细胞周期进程。与观察到的野生型小鼠相比，在Pim-3转基因小鼠的早期阶段，给予有效的肝癌致癌物二乙基亚硝胺(DEN)诱导了肝细胞的加速增殖。治疗6个月后，DEN诱导脂滴堆积，增殖细胞数量增加。最终，野生型小鼠发生肝癌的频率为40%，直到治疗后10个月。与观察到的野生型小鼠相比，具有更高增殖细胞数量的Pim-3转基因小鼠的脂肪堆积速度加快。与野生型小鼠相比，PIM-3转基因小鼠发生肝癌的几率更高(80%)，负担更重，肿瘤内CD31阳性血管面积增加。这些观察表明，Pim-3单独不能引起，但可以加速肝癌的发展，当诱发肝癌的致癌物，如DEN。Oncogene(2010)29,2228-2237；doi：10.1038/onc.2009.504；2010年1月18日在线发布
Pim-3, a proto-oncogene with serine/threonine kinase activity, was enhanced in hepatocellular carcinoma (HCC) tissues. To address the roles of Pim-3 in HCC development, we prepared transgenic mice that express human Pim-3 selectively in liver. The mice were born at a Mendelian ratio, were fertile and did not exhibit any apparent pathological changes in the liver until 1 year after birth. Pim-3-transgenic mouse-derived hepatocytes exhibited accelerated cell cycle progression. The administration of a potent hepatocarcinogen, diethylnitrosamine (DEN), induced accelerated proliferation of liver cells in Pim-3 transgenic mice in the early phase, compared with that observed for wild-type mice. Treatment with DEN induced lipid droplet accumulation with increased proliferating cell numbers 6 months after the treatment. Eventually, wild-type mice developed HCC with a frequency of 40% until 10 month after the treatment. Lipid accumulation was accelerated in Pim-3 transgenic mice with higher proliferating cell numbers, compared with that observed for wild-type mice. Pim-3 transgenic mice developed HCC with a higher incidence (80%) and a heavier burden, together with enhanced intratumoral CD31-positive vascular areas, compared with that observed for wild-type mice. These observations indicate that Pim-3 alone cannot cause, but can accelerate HCC development when induced by a hepatocarcinogen, such as DEN. Oncogene (2010) 29, 2228-2237; doi: 10.1038/onc.2009.504; published online 18 January 2010