Review Article | Published:

Wnt–β-catenin signalling in liver development, health and disease

Nature Reviews Gastroenterology & Hepatologyvolume 16pages121136 (2019) | Download Citation

Abstract

The canonical Wnt–β-catenin pathway is a complex, evolutionarily conserved signalling mechanism that regulates fundamental physiological and pathological processes. Wnt–β-catenin signalling tightly controls embryogenesis, including hepatobiliary development, maturation and zonation. In the mature healthy liver, the Wnt–β-catenin pathway is mostly inactive but can become re-activated during cell renewal and/or regenerative processes, as well as in certain pathological conditions, diseases, pre-malignant conditions and cancer. In hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), the two most prevalent primary liver tumours in adults, Wnt–β-catenin signalling is frequently hyperactivated and promotes tumour growth and dissemination. A substantial proportion of liver tumours (mainly HCC and, to a lesser extent, CCA) have mutations in genes encoding key components of the Wnt–β-catenin signalling pathway. Likewise, hepatoblastoma, the most common paediatric liver cancer, is characterized by Wnt–β-catenin activation, mostly as a result of β-catenin mutations. In this Review, we discuss the most relevant molecular mechanisms of action and regulation of Wnt–β-catenin signalling in liver development and pathophysiology. Moreover, we highlight important preclinical and clinical studies and future directions in basic and clinical research.

Key points

  • Wnt–β-catenin signalling is a highly-conserved and tightly-controlled molecular pathway that regulates cell fate during embryogenesis and hepatobiliary development, as well as liver homeostasis and repair in adulthood.

  • Abnormal Wnt–β-catenin signalling promotes the development and/or progression of different liver diseases, including cancer.

  • Mutations in key regulatory genes of the Wnt–β-catenin pathway are characteristic of hepatobiliary tumours and promote their growth, dedifferentiation and dissemination.

  • Targeting Wnt–β-catenin signalling is a new opportunity for personalized medicine currently under clinical investigation for liver cancer.

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COSMIC: http://cancer.sanger.ac.uk/cosmic

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Acknowledgements

J.M.B., M.J.P. and J.J.G.M. are supported by the Spanish Ministry of Economy and Competitiveness (J.M.B.: FIS PI12/00380, FIS PI15/01132 and Miguel Servet Programme CON14/00129; M.J.P.: FIS PI14/00399, PI17/00022 and “Ramon y Cajal” Programme RYC-2015-17755; J.J.G.M.: FIS PI16/00598; SAF2016-75197-R) cofinanced by “Fondo Europeo de Desarrollo Regional” (FEDER). J.M.B., M.J.P., J.J.G.M. and L.B. are also supported by ISCIII (CIBERehd), Spain. J.M.B. is supported by “Diputación Foral Gipuzkoa” (DFG15/010, DFG16/004) and “Fundación Científica de la Asociación Española Contra el Cáncer” (AECC Scientific Foundation). M.J.P. is supported by the Department of Health of the Basque Country (2015111100). P.O. and I.L. were funded by the Basque Government (PRE_2016_1_0152 and PRE_2016_1_0269, respectively), and A.E.-B. by the University of the Basque Country (UPV/EHU: PIF2014/11).

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Affiliations

  1. Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute — Donostia University Hospital — University of the Basque Country (UPV/EHU), San Sebastian, Spain

    • Maria J. Perugorria
    • , Paula Olaizola
    • , Ibone Labiano
    • , Aitor Esparza-Baquer
    • , Luis Bujanda
    •  & Jesus M. Banales
  2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health (ISCIII), Madrid, Spain

    • Maria J. Perugorria
    • , Jose J. G. Marin
    • , Luis Bujanda
    •  & Jesus M. Banales
  3. Ikerbasque, Basque Foundation for Science, Bilbao, Spain

    • Maria J. Perugorria
    •  & Jesus M. Banales
  4. Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy

    • Marco Marzioni
  5. Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain

    • Jose J. G. Marin

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Contributions

J.M.B., M.J.P., P.O., I.L. and A.E-B. contributed to all aspects of this manuscript. M.M., J.J.G.M. and L.B. made substantial contributions to discussion of content, wrote the manuscript and reviewed and edited the manuscript before submission.

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The authors declare no competing interests.

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Correspondence to Jesus M. Banales.

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https://doi.org/10.1038/s41575-018-0075-9