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Published on: September 12, 2019
WWC1 and NF2 Prevent the Development of Intrahepatic Cholangiocarcinoma by Regulating YAP/TAZ Activity through LATS
Jaeoh Park1, Jeong Sik Kim1, Ji Hae Nahm2,3
1Department of Biological Sciences, National Creative Research Initiatives Center, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea.
Abstract:
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 Drosophila 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 in vivo are not fully understood. Here, we show that deletion of both Wwc1 and Nf2 in the liver accelerates intrahepatic cholangiocarcinoma (iCCA) development through activation of YAP/TAZ. Additionally, biliary epithelial cell-specific deletion of both Lats1 and Lats2 using a Sox9-CreERT2 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.
Insights
WW C1 and NF2 suppress liver cancer by inhibiting YAP/TAZ oncogenic activity via LATS1/2. Deleting these genes accelerates intrahepatic cholangiocarcinoma (iCCA) in mice.
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- The Hippo signaling pathway is a tumor suppressor, inhibiting cell proliferation.
- YAP and TAZ are transcriptional coactivators activated in many cancers, promoting proliferation.
- Mammalian orthologs WWC1, FRMD6, and NF2 regulate LATS1/2, but their role in liver cancer is unclear.
Purpose of the Study:
- To investigate the in vivo roles of WWC1, FRMD6, and NF2 in regulating LATS1/2 activity.
- To determine the involvement of WWC1 and NF2 in liver tumorigenesis, specifically intrahepatic cholangiocarcinoma (iCCA).
Main Methods:
- Liver-specific deletion of Wwc1 and Nf2 in mice.
- Biliary epithelial cell-specific deletion of Lats1 and Lats2 using a Sox9-CreERT2 system.
- Analysis of YAP/TAZ activation and iCCA development.
Main Results:
- Deletion of Wwc1 and Nf2 accelerated iCCA development through YAP/TAZ activation.
- Deletion of Lats1 and Lats2 in biliary epithelial cells also led to iCCA via YAP/TAZ hyperactivation.
- WWC1 and NF2 were identified as crucial suppressors of iCCA.
Conclusions:
- WWC1 and NF2 cooperate to suppress cholangiocarcinoma development.
- This suppression is mediated by inhibiting the oncogenic activity of YAP/TAZ through LATS1/2.
- The WWC1-NF2-LATS1/2 axis is a potential therapeutic target for iCCA.
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