Overexpression of insulin receptor substrate-1 and hepatitis Bx genes causes premalignant alterations in the liver.
Overexpression of insulin receptor substrate-1 and hepatitis Bx genes causes premalignant alterations in the liver.
复制标题
DOI：
10.1002/hep.22856
复制
发表时间：
2009-06
期刊：
影响因子：
13.5
通讯作者：
Wands, Jack R.
中科院分区：
文献类型：
--
作者：
Longato, Lisa;de la Monte, Suzanne;Kuzushita, Noriyoshi;Horimoto, Masayoshi;Rogers, Arlin B.;Slagle, Betty L.;Wands, Jack R.
在与持续病毒感染相关的肝细胞癌中，胰岛素(IN)/胰岛素受体-1/丝裂原活化蛋白激酶(INS-1/MAPK)和WNT/β-连环蛋白信号转导通路频繁发生。本研究的目的是在转基因小鼠中表达乙肝病毒(HBx)蛋白的背景下，通过IRS-1提供慢性增殖刺激，并确定这些基因的结构性表达是否足以导致肝细胞异型增生和细胞转化。我们建立了在肝脏特异性启动子下表达HBX(ATX)和/或IRS-1(ATX+/IRS-1)基因的转基因小鼠。我们还通过qRT-PCR评估了组织学和氧化损伤以及与这些信号转导级联相关的分子的上调。单独转基因(ATX或IRS-1)的小鼠未发生肿瘤，而ATX+/IRS-1+双转基因小鼠肝细胞不典型增生的发生率增加，并发生肝细胞癌。所有三个转基因株系均显著提高了IGF-1、WNT-1和WNT-3的mRNA水平，以及DNA损伤和氧化应激的证据。Atx+/irs+双转基因小鼠具有最高水平的WNT3和Frizzled7活性，并选择性地增加IGFII、增殖细胞核抗原和天冬氨酸天门冬氨酸氨基β羟基酶(Aah)的表达，这是一种与细胞迁移增加相关的基因。这些结果表明，ATX或IRS-1转基因的持续表达可以促进肝细胞的转化，但不足以引发肝脏的肿瘤性变化。然而，激活IN/IRS-1/MAPK和Wnt/β-catenin级联反应的双重表达足以在以前正常的肝脏中引起不典型增生和肝癌。
Activation of the insulin (IN)/IRS-1/MAPK and the Wnt/β-catenin signaling cascades occurs frequently in hepatocellular carcinoma (HCC) associated with persistent viral infection. The aims of this study were to provide a chronic proliferative stimulus via IRS-1 in the context of hepatitis Bx (HBx) protein expression in transgenic mice and determine if constitutive expression of these genes is sufficient to cause hepatocyte dysplasia and cellular transformation. We generated transgenic mice in which the HBx (ATX), IRS-1 or both (ATX+/IRS-1) genes were expressed under a liver specific promoter. We also assessed histology and oxidative damage as well as upregulation of molecules related to these signal transduction cascades in the liver by qRT-PCR. Whereas mice with a single transgene (ATX or IRS-1) did not develop tumors, ATX+/IRS-1+ double transgenic livers had increased frequency of hepatocellular dysplasia and developed HCC. All three transgenic lines had significantly increased IGF-1, Wnt 1 and Wnt 3 mRNA levels, and evidence of DNA damage and oxidative stress. The ATX+/IRS+ double transgenic mice were distinguished by having the highest level of activation of Wnt 3 and Frizzled 7 and selectively increased expression of IGF-II, PCNA, and aspartyl (-asparaginyl)-β-hydroxylase (AAH) a gene associated with increased cell migration. These results suggest that continued expression of the ATX or IRS-1 transgenes can contribute to hepatocyte transformation but are not sufficient to trigger neoplastic changes in the liver. However, dual expression that activates both the IN/IRS-1/MAPK and Wnt/β-catenin cascades is sufficient to cause dysplasia and HCC in a previously normal liver.
登录
查看更多内容
影响因子：
15.9
作者：
Lavaissiere, L;Jia, S;Friedman, PA
通讯作者：
Friedman, PA
影响因子：
--
作者：
Maeda, T;Taguchi, K;de la Monte, SM
通讯作者：
de la Monte, SM
影响因子：
25.7
作者：
de la Monte, SM;Tamaki, S;Wands, JR
通讯作者：
Wands, JR
DOI：
10.1073/pnas.91.22.10350
发表时间：
1994-10-25
影响因子：
11.1
作者：
BENN, J;SCHNEIDER, RJ
通讯作者：
SCHNEIDER, RJ
影响因子：
5.8
作者：
Alexia, C;Fallot, G;Groyer, A
通讯作者：
Groyer, A