Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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WWC1 and NF2 Prevent the Development of Intrahepatic Cholangiocarcinoma by Regulating YAP/TAZ Activity through LATS in Mice

  • Park, Jaeoh (Department of Biological Sciences, National Creative Research Initiatives Center, Korea Advanced Institute of Science and Technology (KAIST)) ;
  • Kim, Jeong Sik (Department of Biological Sciences, National Creative Research Initiatives Center, Korea Advanced Institute of Science and Technology (KAIST)) ;
  • Nahm, Ji Hae (Department of Pathology, Yonsei University College of Medicine, Gangnam Severance Hospital) ;
  • Kim, Sang-Kyum (Department of Pathology, Yonsei University College of Medicine, Severance Hospital Seoul) ;
  • Lee, Da-Hye (Center for Bioanalysis, Korea Research Institute for Standards and Science) ;
  • Lim, Dae-Sik (Department of Biological Sciences, National Creative Research Initiatives Center, Korea Advanced Institute of Science and Technology (KAIST))
  • Received : 2020.04.09
  • Accepted : 2020.04.13
  • Published : 2020.05.31
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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.

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References

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