Accelerated liver regeneration and hepatocarcinogenesis in mice overexpressing serine-45 mutant beta-catenin.
Accelerated liver regeneration and hepatocarcinogenesis in mice overexpressing serine-45 mutant beta-catenin.
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过度表达丝氨酸 45 突变体 β-连环蛋白的小鼠加速肝再生和肝癌发生。
DOI：
10.1002/hep.23538
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发表时间：
2010-05
期刊：
影响因子：
13.5
通讯作者：
Monga, Satdarshan P. S.
中科院分区：
文献类型：
--
作者：
Nejak-Bowen, Kari N.;Thompson, Michael D.;Singh, Sucha;Bowen, William C., Jr.;Dar, Mohd Jamal;Khillan, Jaspal;Dai, Chunsun;Monga, Satdarshan P. S.
Wnt/β-catenin通路参与肝细胞癌（HCC）的发病机制。我们在FVB品系中开发了在肝细胞中过表达Ser 45突变的β-catenin的转基因小鼠（TG），以研究其对肝再生和癌症的影响。在两个独立的TG系中，成年小鼠显示肝细胞膜上的β-连环蛋白升高，而Wnt途径靶点细胞周期蛋白-D1或谷氨酰胺合成酶未增加。然而，与野生型FVB小鼠（WT）的肝细胞相比，培养后的TG肝细胞在第5天（D5）的胸苷掺入量增加了2倍。当进行部分肝切除术（PH）时，在TG（40小时）和WT（72小时）中，S期肝细胞数量显著增加。与较早发生的增殖相一致，我们观察到TG肝脏中β-catenin的核转位沿着总的和核细胞周期蛋白-D1蛋白在40小时时的增加。为了测试β-连环蛋白的刺激是否诱导再生，我们利用Wnt-1裸DNA的流体动力学递送至对照小鼠，这促使Wnt-1、β-连环蛋白和已知靶点-GS和细胞周期蛋白-D1的增加，沿着细胞增殖的增加。β-连环蛋白过表达的TG小鼠在随访12个月时未显示自发性肿瘤发生的迹象。然而，腹腔内递送二乙基亚硝胺（一种已知的致癌物（DEN））仅在TG小鼠中在6个月时诱导HCC。TG肝脏中的肿瘤显示β-连环蛋白、细胞周期蛋白-D1和独特的遗传畸变的上调，而其他典型靶点不显著。总之，β-连环蛋白过表达在肝再生过程中提供生长优势。此外，虽然没有明显的自发性HCC，但β-连环蛋白过表达使TG小鼠对DEN诱导的HCC易感。
The Wnt/β-catenin pathway is implicated in the pathogenesis of hepatocellular cancer (HCC). We have developed a transgenic mouse (TG) in FVB strain that overexpresses Ser45-mutated-β-catenin in hepatocytes to study the effects on liver regeneration and cancer. In the two independent TG lines, adult mice show elevated β-catenin at hepatocyte membrane with no increase in Wnt pathway targets cyclin-D1 or glutamine synthetase. However, TG hepatocytes upon culture exhibit a 2-fold increase in thymidine incorporation at day 5 (D5) when compared to hepatocytes from wild-type FVB mice (WT). When subjected to partial hepatectomy (PH), dramatic increases in the number of hepatocytes in S-phase are evident in TG at 40 and WT at 72 hours. Coincident with the earlier onset of proliferation, we observe nuclear translocation of β-catenin along with increase in total and nuclear cyclin-D1 protein at 40 hours in TG livers. To test if stimulation of β-catenin induces regeneration, we utilized hydrodynamic delivery of Wnt-1 naked DNA to control mice, which prompted an increase in Wnt-1, β-catenin and known targets-GS and cyclin-D1, along with a concomitant increase in cell proliferation. β-Catenin overexpressing TG mice, when followed up to 12 months showed no signs of spontaneous tumorigenesis. However, intra-peritoneal delivery of diethylnitrosamine, a known carcinogen (DEN) induced HCC at 6 months in TG mice only. Tumors in TG livers showed upregulation of β-catenin, cyclin-D1 and unique genetic aberrations while other canonical targets were unremarkable. In conclusion, β-catenin overexpression offers growth advantage during liver regeneration. Also, while no spontaneous HCC is evident, β-catenin overexpression makes TG mice susceptible to DEN-induced HCC.
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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
影响因子：
7.7
作者：
Haramis, APG;Hurlstone, A;Clevers, HC
通讯作者：
Clevers, HC
影响因子：
5.3
作者：
Hsu, SC;Galceran, J;Grosschedl, R
通讯作者：
Grosschedl, R
DOI：
10.1073/pnas.96.4.1603
发表时间：
1999-02-16
影响因子：
11.1
作者：
Mann, B;Gelos, M;Hanski, C
通讯作者：
Hanski, C
影响因子：
6
作者：
Apte, Udayan;Singh, Sucha;Monga, Satdarshan P. S.
通讯作者：
Monga, Satdarshan P. S.