Modeling hepatitis B virus X-induced hepatocellular carcinoma in mice with the Sleeping Beauty transposon system.
Modeling hepatitis B virus X-induced hepatocellular carcinoma in mice with the Sleeping Beauty transposon system.
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DOI：
10.1002/hep.24091
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发表时间：
2011-03
期刊：
影响因子：
13.5
通讯作者：
Largaespada, David A.
中科院分区：
文献类型：
--
作者：
Keng, Vincent W.;Tschida, Barbara R.;Bell, Jason B.;Largaespada, David A.
B型肝炎病毒（HBV）诱导肝细胞癌（HCC）的机制尚不清楚，目前还没有成熟的动物模型来研究这种疾病。使用睡美人转座子作为递送系统，我们通过水动力尾静脉注射将HBV的致癌组分，即肝炎B病毒X（HBx）基因引入延胡索酰乙酰乙酸水解酶（Fah）突变小鼠的肝脏。从转座子载体的Fah cDNA的共表达允许在Fah突变小鼠中遗传校正的肝细胞的选择性再增殖。流体动力学递送过程诱导肝脏炎症，随后携带转基因的肝细胞的选择性再增殖可以提供关于HBV诱导的增生机制的有用遗传信息。针对Trp 53基因（shp 53）或其他肿瘤抑制基因和癌基因（如组成型活性NRASG 12 V）的短发夹RNA也可以与HBx共同递送，使用该系统确定是否存在致癌合作。在这项研究中，我们发现HBx的表达诱导了水动力注射肝脏中β-catenin表达的激活，表明其与HBV诱导的增生中的Wnt信号通路相关。HBx与shp 53共注射加速了这些小鼠肝脏增生的形成。正如预期的那样，单独的组成型活性NRASG 12 V足以诱导肝脏增生，当与shp 53共注射时，其致瘤性增强。有趣的是，HBx似乎不与组成型活性NRASG 12 V合作驱动肝脏肿瘤发生。该系统可用作研究体内系统中HBV对肝增生和最终HCC的各种遗传贡献的模型。
The mechanisms associated with hepatitis B viral (HBV) induced hepatocellular carcinoma (HCC) remain elusive and currently, there are no well-established animal models to study this disease. Using the Sleeping Beauty transposon as a delivery system, we introduced an oncogenic component of HBV, namely the hepatitis B virus X (HBx) gene to the livers of fumarylacetoacetate hydrolase (Fah) mutant mice via hydrodynamic tail vein injections. Coexpression of the Fah cDNA from the transposon vector allows for the selective repopulation of genetically corrected hepatocytes in Fah mutant mice. The process of hydrodynamic delivery induces liver inflammation and the subsequent selective repopulation of hepatocytes carrying the transgene(s) can provide useful genetic information on the mechanisms of HBV-induced hyperplasia. Short hairpin RNA directed against the Trp53 gene (shp53) or other tumor suppressor genes, and oncogenes, like the constitutively active NRASG12V, can also be codelivered with HBx using this system to determine if oncogenic cooperation exists. In this study, we find that expression of HBx induced activation of β-catenin expression in hydrodynamically injected livers, indicating its association with the Wnt signaling pathway in HBV-induced hyperplasia. HBx coinjected with shp53 accelerated the formation of liver hyperplasia in these mice. As expected, constitutively active NRASG12V alone was sufficient to induce liver hyperplasia and its tumorigenicity was augmented when coinjected with shp53. Interestingly, HBx does not seem to cooperate with constitutively active NRASG12V in driving liver tumorigenesis. This system can be used as a model for studying the various genetic contributions of HBV to liver hyperplasia and finally HCC in an in vivo system.
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影响因子：
11.2
作者：
Hoshida Y;Nijman SM;Kobayashi M;Chan JA;Brunet JP;Chiang DY;Villanueva A;Newell P;Ikeda K;Hashimoto M;Watanabe G;Gabriel S;Friedman SL;Kumada H;Llovet JM;Golub TR
通讯作者：
Golub TR
DOI：
10.1016/j.bbrc.2005.12.089
发表时间：
2006-02-17
影响因子：
3.1
作者：
Wu, BK;Li, CC;Tsai, TF
通讯作者：
Tsai, TF
影响因子：
46.9
作者：
Keng, Vincent W.;Villanueva, Augusto;Chiang, Derek Y.;Dupuy, Adam J.;Ryan, Barbara J.;Matise, Ilze;Silverstein, Kevin A. T.;Sarver, Aaron;Starr, Timothy K.;Akagi, Keiko;Tessarollo, Lino;Collier, Lara S.;Powers, Scott;Lowe, Scott W.;Jenkins, Nancy A.;Copeland, Neal G.;Llovet, Josep M.;Largaespada, David A.
通讯作者：
Largaespada, David A.
影响因子：
4.6
作者：
Bock, C. Thomas;Toan, Nguyen L.;Torresi, Joseph
通讯作者：
Torresi, Joseph
影响因子：
11.4
作者：
DORIA, M;KLEIN, N;SCHNEIDER, RJ
通讯作者：
SCHNEIDER, RJ