Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice.
Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice.
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DOI：
10.1053/j.gastro.2012.09.002
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发表时间：
2012-12
期刊：
影响因子：
29.4
通讯作者：
Llovet JM
中科院分区：
文献类型：
--
作者：
Villanueva A;Alsinet C;Yanger K;Hoshida Y;Zong Y;Toffanin S;Rodriguez-Carunchio L;Solé M;Thung S;Stanger BZ;Llovet JM
Notch信号通路在白血病和实体瘤（如肺癌）中被激活，但对其在肝癌中的作用知之甚少。在白蛋白和甲胎蛋白增强子和启动子（AFP-NICD）的控制下，通过Cre表达，Notch的细胞内结构域在小鼠成肝细胞及其后代（肝细胞和胆管细胞）中有条件地表达。我们使用比较功能基因组学来整合来自AFP-NICD小鼠和人肝细胞癌（HCC）样本（n=683）的转录组数据。使用最近模板预测方法产生Notch基因标记。AFP-NICD小鼠在12个月大时发生了100%转移率的HCC。Notch信号的激活与胰岛素样生长因子2（Igf 2）的3个启动子的激活相关;这些过程似乎有助于肝癌的发生。比较功能基因组分析在来自患者的30%的HCC样品中鉴定了Notch激活的特征。这些样本改变了Notch途径基因的表达和IGF信号的激活，尽管与癌症相关的NOTCH 1区域的突变频率较低。使用γ-分泌酶抑制剂或通过表达MAML的显性阴性形式阻断肝癌细胞中的Notch活化信号传导降低了它们的体外增殖。Notch信号在人HCC样品中被激活，并促进小鼠肝肿瘤的形成。Notch标签是体外对Notch抑制的响应的生物标志物。
The Notch signaling pathway is activated in leukemia and solid tumors (such as lung cancer), but little is known about its role in liver cancer. The intracellular domain of Notch was conditionally expressed in hepatoblasts and their progeny (hepatocytes and cholangiocytes) in mice, through Cre expression, under the control of an albumin and α-fetoprotein enhancer and promoter (AFP-NICD). We used comparative functional genomics to integrate transcriptome data from AFP-NICD mice and human hepatocellular carcinoma (HCC) samples (n=683). A Notch gene signature was generated using the nearest template prediction method. AFP-NICD mice developed HCC with 100% penetrance when they were 12 months old. Activation of Notch signaling correlated with activation of 3 promoters of insulin-like growth factor 2 (Igf2); these processes appeared to contribute to hepatocarcinogenesis. Comparative functional genomic analysis identified a signature of Notch activation in 30% of HCC samples from patients. These samples had altered expression in Notch pathway genes and activation of IGF signaling, despite a low frequency of mutations in regions of NOTCH1 associated with cancer. Blocking Notch signaling in liver cancer cells with the Notch activation signature using γ-secretase inhibitors or by expressing a dominant negative form of MAML reduced their proliferation in vitro. Notch signaling is activated in human HCC samples and promotes formation of liver tumors in mice. The Notch signature is a biomarker of response to Notch inhibition in vitro.
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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：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
DOI：
10.1056/nejmoa0804525
发表时间：
2008-11-06
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hoshida Y;Villanueva A;Kobayashi M;Peix J;Chiang DY;Camargo A;Gupta S;Moore J;Wrobel MJ;Lerner J;Reich M;Chan JA;Glickman JN;Ikeda K;Hashimoto M;Watanabe G;Daidone MG;Roayaie S;Schwartz M;Thung S;Salvesen HB;Gabriel S;Mazzaferro V;Bruix J;Friedman SL;Kumada H;Llovet JM;Golub TR
通讯作者：
Golub TR
影响因子：
15.9
作者：
Kaposi-Novak, Pal;Lee, Ju-Seog;Thorgeirsson, Snorri S.
通讯作者：
Thorgeirsson, Snorri S.
影响因子：
45.3
作者：
Altekruse, Sean F.;McGlynn, Katherine A.;Reichman, Marsha E.
通讯作者：
Reichman, Marsha E.