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Dysregulated YAP1/TAZ and TGF-β signaling mediate hepatocarcinogenesis in Mob1a/1b-deficient mice

Miki Nishio1, Keishi Sugimachi2, Hiroki Goto1

  • 1Medical Institute of Bioregulation, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 819-0395, Japan;

Proceedings of the National Academy of Sciences of the United States of America
|December 25, 2015
PubMed

Insights

Mps One Binder Kinase Activator (MOB)1A/1B deficiency in mouse liver causes severe liver cancer. Targeting YAP1/TAZ and TGF-β pathways with macrocyclic lactones shows potential for treating human liver cancers.

Area of Science:

  • Cell Biology
  • Oncology
  • Molecular Biology

Background:

  • Mps One Binder Kinase Activator (MOB)1A/1B are essential Hippo pathway components that coactivate large tumor suppressor homolog (LATS) kinases.
  • Liver-specific double deficiency of Mob1a/1b (LMob1DKO) in mice leads to severe liver pathologies, including hyperplasia and mortality.
  • This phenotype represents the most severe observed among mutations in Hippo signaling components, highlighting MOB1A/1B's critical role in mammalian liver Hippo signaling.

Purpose of the Study:

  • To investigate the role of MOB1A/1B in liver homeostasis and tumorigenesis.
  • To elucidate the molecular mechanisms underlying liver cancer development in LMob1DKO mice.
  • To identify potential therapeutic targets for liver cancers driven by Hippo pathway dysregulation.

Main Methods:

  • Generation of liver-specific Mob1a/1b double knockout (LMob1DKO) mice.
  • Histopathological analysis of liver tissues to assess cellular changes and tumor development.
  • Molecular analysis to determine the involvement of key signaling pathways, including YAP1, TAZ, and TGF-β.
  • In vitro and in vivo drug screening for potential therapeutic agents.

Main Results:

  • LMob1DKO mice exhibit hyperplasia, inflammation, fibrosis, and develop combined hepatocellular and cholangiocarcinomas (cHC-CCs) and intrahepatic cholangiocellular carcinomas (ICCs).
  • Liver cells in LMob1DKO mice display hyperproliferation, dedifferentiation, enhanced epithelial-mesenchymal transition, and increased TGF-β2/3 production.
  • The observed phenotype is critically dependent on Yes-Associated Protein-1 (Yap1) and partially on PDZ-binding motif (Taz) and Tgfbr2.
  • Antiparasitic macrocyclic lactones were identified as inhibitors of YAP1 activation in vitro and in vivo.

Conclusions:

  • MOB1A/1B are indispensable for maintaining liver homeostasis and preventing tumorigenesis.
  • YAP1 activation is a key driver of liver cancer in the context of MOB1A/1B deficiency.
  • Macrocyclic lactones targeting YAP1/TAZ, potentially combined with TGF-β pathway inhibition, represent a promising therapeutic strategy for cHC-CCs and ICCs.
Keywords:
Hippo pathwayMOB1TGF-betaivermectinliver cancer

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