Department of Biological Sciences, National Creative Research Initiatives Center, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea.
Department of Pathology, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul 06273, Korea.
Mol Cells. 2020 May 31;43(5):491-499. doi: 10.14348/molcells.2020.0093.
Hippo signaling acts as a tumor suppressor pathway by inhibiting the proliferation of adult stem cells and progenitor cells in various organs. Liver-specific deletion of Hippo pathway components in mice induces liver cancer development through activation of the transcriptional coactivators, YAP and TAZ, which exhibit nuclear enrichment and are activated in numerous types of cancer. The upstream-most regulators of Warts, the ortholog of mammalian LATS1/2, are Kibra, Expanded, and Merlin. However, the roles of the corresponding mammalian orthologs, WWC1, FRMD6 and NF2, in the regulation of LATS1/2 activity and liver tumorigenesis are not fully understood. Here, we show that deletion of both and in the liver accelerates intrahepatic cholangiocarcinoma (iCCA) development through activation of YAP/TAZ. Additionally, biliary epithelial cell-specific deletion of both and using a Sox9-Cre system resulted in iCCA development through hyperactivation of YAP/TAZ. These findings suggest that WWC1 and NF2 cooperate to promote suppression of cholangiocarcinoma development by inhibiting the oncogenic activity of YAP/TAZ via LATS1/2.
Hippo 信号通路通过抑制各种器官中成体干细胞和祖细胞的增殖来发挥肿瘤抑制作用。在小鼠中特异性敲除 Hippo 通路成分会通过激活转录共激活因子 YAP 和 TAZ 诱导肝癌的发生，YAP 和 TAZ 在多种类型的癌症中表现出核富集和激活。Warts 的上游调控因子，即哺乳动物 LATS1/2 的同源物，是 Kibra、Expanded 和 Merlin。然而，相应的哺乳动物同源物 WWCl、FRMD6 和 NF2 在调节 LATS1/2 活性和肝肿瘤发生中的作用尚未完全阐明。在这里，我们表明，肝脏中 WWCl 和 NF2 的缺失通过激活 YAP/TAZ 加速了肝内胆管细胞癌（iCCA）的发展。此外，使用 Sox9-Cre 系统特异性敲除胆管上皮细胞中的 WWCl 和 NF2 导致 iCCA 的发展，这是通过 YAP/TAZ 的过度激活实现的。这些发现表明，WWC1 和 NF2 通过抑制 YAP/TAZ 的致癌活性，与 LATS1/2 合作促进了胆管癌的发展。
