Hippo signaling interactions with Wnt/β-catenin and Notch signaling repress liver tumorigenesis
Hippo signaling interactions with Wnt/β-catenin and Notch signaling repress liver tumorigenesis
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DOI：
10.1172/jci88486
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发表时间：
2017-01-03
影响因子：
15.9
通讯作者：
Yang, Yingzi
中科院分区：
文献类型：
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作者：
Kim, Wantae;Khan, Sanjoy Kumar;Yang, Yingzi
恶性肿瘤的发生和发展经历了多个步骤，肿瘤的发生在肿瘤的预防、诊断和治疗中具有独特的重要性。然而，相互作用途径的信号网络抑制正常细胞增殖并阻止肿瘤发生的分子机制仍然知之甚少。在这里，我们报道了Hippo、Wnt/ β -连环蛋白和Notch通路形成一个相互作用的网络来维持肝脏大小和抑制肝细胞癌（HCC）。哺乳动物肝脏中Hippo激酶Mst1和Mst2的消融导致HCC快速形成，并激活含有转录调节因子1 （YAP/TAZ）、STAT3、Wnt/ β -catenin和Notch信号。先前的研究表明，这些下游通路的异常激活可导致HCC。严格的遗传实验表明，Notch信号与Hippo信号效应因子YAP/TAZ形成正反馈回路，促进严重肝肥大和HCC的快速发生和发展。令人惊讶的是，我们发现Wnt/ β -catenin信号激活通过抑制YAP/TAZ和Notch信号之间的正反馈回路来抑制HCC的形成。此外，我们发现当去除哺乳动物不育的20样激酶1和2 （Mst1和Mst2）时，肝细胞中的STAT3对于HCC的形成是必不可少的。我们已经确定的分子网络为HCC分子分类和治疗由不同基因突变引起的肝脏肿瘤的治疗发展提供了见解。
Malignant tumors develop through multiple steps of initiation and progression, and tumor initiation is of singular importance in tumor prevention, diagnosis, and treatment. However, the molecular mechanism whereby a signaling network of interacting pathways restrains proliferation in normal cells and prevents tumor initiation is still poorly understood. Here, we have reported that the Hippo, Wnt/beta-catenin, and Notch pathways form an interacting network to maintain liver size and suppress hepatocellular carcinoma (HCC). Ablation of the mammalian Hippo kinases Mst1 and Mst2 in liver led to rapid HCC formation and activated Yes-associated protein/WW domain containing transcription regulator 1 (YAP/TAZ), STAT3, Wnt/beta-catenin, and Notch signaling. Previous work has shown that abnormal activation of these downstream pathways can lead to HCC. Rigorous genetic experiments revealed that Notch signaling forms a positive feedback loop with the Hippo signaling effector YAP/TAZ to promote severe hepatomegaly and rapid HCC initiation and progression. Surprisingly, we found that Wnt/beta-catenin signaling activation suppressed HCC formation by inhibiting the positive feedback loop between YAP/TAZ and Notch signaling. Furthermore, we found that STAT3 in hepatocytes is dispensable for HCC formation when mammalian sterile 20-like kinase 1 and 2 (Mst1 and Mst2) were removed. The molecular network we have identified provides insights into HCC molecular classifications and therapeutic developments for the treatment of liver tumors caused by distinct genetic mutations.