Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway.
Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway.
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DOI：
10.1084/jem.20110198
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发表时间：
2011-09-26
期刊：
影响因子：
--
通讯作者：
Sage J
中科院分区：
文献类型：
--
作者：
Viatour P;Ehmer U;Saddic LA;Dorrell C;Andersen JB;Lin C;Zmoos AF;Mazur PK;Schaffer BE;Ostermeier A;Vogel H;Sylvester KG;Thorgeirsson SS;Grompe M;Sage J
在肝脏中缺乏所有三种Rb基因的小鼠会发展出类似于人类肝细胞癌的特定亚群的肿瘤，而Notch活性似乎抑制了这些肿瘤的生长和进展。肝细胞癌（HCC）是全球第三大癌症杀手，每年有超过60万人死亡。虽然主要的危险因素是已知的，但患者的治疗选择仍然有限，部分原因是我们对影响HCC发展的细胞和分子机制的理解不完全。有证据表明，视网膜母细胞瘤（RB）通路在大多数HCC病例中通过遗传、表观遗传和/或病毒机制功能失活。为了研究这一观察结果的功能相关性，我们通过删除Rb（Rb 1）基因家族的三个成员：Rb，p107和p130来灭活成年小鼠肝脏中的RB通路。Rb家族三基因敲除小鼠发生的肝肿瘤具有与人HCC相似的组织病理学特征和基因表达谱。在该小鼠模型中，癌症的发生与肝干/祖细胞群体的特异性扩增相关，表明RB途径可以通过维持成体肝祖细胞的静止来预防HCC的发展。此外，我们发现在肿瘤进展过程中，通过E2 F转录因子激活Notch通路可作为减缓HCC生长的负反馈机制。Notch活性水平还能够预测肝癌患者的生存期，这表明了诊断和治疗肝癌的新方法。
Mice lacking all three Rb genes in the liver develop tumors resembling specific subgroups of human hepatocellular carcinomas, and Notch activity appears to suppress the growth and progression of these tumors. Hepatocellular carcinoma (HCC) is the third cancer killer worldwide with >600,000 deaths every year. Although the major risk factors are known, therapeutic options in patients remain limited in part because of our incomplete understanding of the cellular and molecular mechanisms influencing HCC development. Evidence indicates that the retinoblastoma (RB) pathway is functionally inactivated in most cases of HCC by genetic, epigenetic, and/or viral mechanisms. To investigate the functional relevance of this observation, we inactivated the RB pathway in the liver of adult mice by deleting the three members of the Rb (Rb1) gene family: Rb, p107, and p130. Rb family triple knockout mice develop liver tumors with histopathological features and gene expression profiles similar to human HCC. In this mouse model, cancer initiation is associated with the specific expansion of populations of liver stem/progenitor cells, indicating that the RB pathway may prevent HCC development by maintaining the quiescence of adult liver progenitor cells. In addition, we show that during tumor progression, activation of the Notch pathway via E2F transcription factors serves as a negative feedback mechanism to slow HCC growth. The level of Notch activity is also able to predict survival of HCC patients, suggesting novel means to diagnose and treat HCC.
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