Review Article | Published:

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

Nature Reviews Gastroenterology & Hepatology (2018) | Download Citation


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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  1. 1.

    Clevers, H. & Nusse, R. Wnt/β-catenin signaling and disease. Cell 149, 1192–1205 (2012).

  2. 2.

    Logan, C. Y. & Nusse, R. The Wnt signaling pathway in development and disease. Annu. Rev. Cell Dev. Biol. 20, 781–810 (2004).

  3. 3.

    Kretzschmar, K. & Clevers, H. Wnt/β-catenin signaling in adult mammalian epithelial stem cells. Dev. Biol. 428, 273–282 (2017).

  4. 4.

    Moon, R. T., Kohn, A. D., De Ferrari, G. V. & Kaykas, A. WNT and β-catenin signalling: diseases and therapies. Nat. Rev. Genet. 5, 691–701 (2004).

  5. 5.

    Nusse, R. & Clevers, H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell 169, 985–999 (2017).

  6. 6.

    MacDonald, B. T., Tamai, K. & He, X. Wnt/β-catenin signaling: components, mechanisms, and diseases. Dev. Cell 17, 9–26 (2009).

  7. 7.

    Brembeck, F. H., Rosario, M. & Birchmeier, W. Balancing cell adhesion and Wnt signaling, the key role of β-catenin. Curr. Opin. Genet. Dev. 16, 51–59 (2006).

  8. 8.

    Niessen, C. M. & Gottardi, C. J. Molecular components of the adherens junction. Biochim. Biophys. Acta 1778, 562–571 (2008).

  9. 9.

    Stamos, J. L. & Weis, W. I. The β-catenin destruction complex. Cold Spring Harb. Perspect. Biol. 5, a007898 (2013).

  10. 10.

    Cong, F., Schweizer, L. & Varmus, H. Wnt signals across the plasma membrane to activate the β-catenin pathway by forming oligomers containing its receptors, Frizzled and LRP. Development 131, 5103–5115 (2004).

  11. 11.

    Zeng, X. et al. A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation. Nature 438, 873–877 (2005).

  12. 12.

    Davidson, G. et al. Casein kinase 1γ couples Wnt receptor activation to cytoplasmic signal transduction. Nature 438, 867–872 (2005).

  13. 13.

    Schwarz-Romond, T. et al. The DIX domain of Dishevelled confers Wnt signaling by dynamic polymerization. Nat. Struct. Mol. Biol. 14, 484–492 (2007).

  14. 14.

    Gao, C. & Chen, Y. G. Dishevelled: the hub of Wnt signaling. Cell. Signal. 22, 717–727 (2010).

  15. 15.

    Vlad, A., Rohrs, S., Klein-Hitpass, L. & Muller, O. The first five years of the Wnt targetome. Cell. Signal. 20, 795–802 (2008).

  16. 16.

    Cadigan, K. M. & Waterman, M. L. TCF/LEFs and Wnt signaling in the nucleus. Cold Spring Harb. Perspect. Biol. 4, a007906 (2012).

  17. 17.

    Valenta, T., Hausmann, G. & Basler, K. The many faces and functions of β-catenin. EMBO J. 31, 2714–2736 (2012).

  18. 18.

    Kaidi, A., Williams, A. C. & Paraskeva, C. Interaction between β-catenin and HIF-1 promotes cellular adaptation to hypoxia. Nat. Cell Biol. 9, 210–217 (2007).

  19. 19.

    Essers, M. A. et al. Functional interaction between β-catenin and FOXO in oxidative stress signaling. Science 308, 1181–1184 (2005).

  20. 20.

    Kormish, J. D., Sinner, D. & Zorn, A. M. Interactions between SOX factors and Wnt/β-catenin signaling in development and disease. Dev. Dyn. 239, 56–68 (2010).

  21. 21.

    Cruciat, C. M. & Niehrs, C. Secreted and transmembrane wnt inhibitors and activators. Cold Spring Harb. Perspect. Biol. 5, a015081 (2013).

  22. 22.

    Koo, B. K. et al. Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature 488, 665–669 (2012).

  23. 23.

    Hao, H. X. et al. ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Nature 485, 195–200 (2012).

  24. 24.

    van Amerongen, R. Alternative Wnt pathways and receptors. Cold Spring Harb. Perspect. Biol. 4, a007914 (2012).

  25. 25.

    Mlodzik, M. Planar cell polarization: do the same mechanisms regulate Drosophila tissue polarity and vertebrate gastrulation? Trends Genet. 18, 564–571 (2002).

  26. 26.

    Wang, H. Y. & Malbon, C. C. Wnt signaling, Ca2+, and cyclic GMP: visualizing Frizzled functions. Science 300, 1529–1530 (2003).

  27. 27.

    Chen, A. E., Ginty, D. D. & Fan, C. M. Protein kinase A signalling via CREB controls myogenesis induced by Wnt proteins. Nature 433, 317–322 (2005).

  28. 28.

    Thompson, M. D. & Monga, S. P. WNT/β-catenin signaling in liver health and disease. Hepatology 45, 1298–1305 (2007).

  29. 29.

    Monga, S. P. β-catenin signaling and roles in liver homeostasis, injury, and tumorigenesis. Gastroenterology 148, 1294–1310 (2015).

  30. 30.

    Loh, K. M., van Amerongen, R. & Nusse, R. Generating cellular diversity and spatial form: Wnt signaling and the evolution of multicellular animals. Dev. Cell 38, 643–655 (2016).

  31. 31.

    Si-Tayeb, K., Lemaigre, F. P. & Duncan, S. A. Organogenesis and development of the liver. Dev. Cell 18, 175–189 (2010).

  32. 32.

    Yamaguchi, T. P. Heads or tails: Wnts and anterior-posterior patterning. Curr. Biol. 11, R713–724 (2001).

  33. 33.

    Lade, A. G. & Monga, S. P. β-catenin signaling in hepatic development and progenitors: which way does the WNT blow? Dev. Dyn. 240, 486–500 (2011).

  34. 34.

    Nejak-Bowen, K. & Monga, S. P. Wnt/β-catenin signaling in hepatic organogenesis. Organogenesis 4, 92–99 (2008).

  35. 35.

    Perea-Gomez, A. et al. Nodal antagonists in the anterior visceral endoderm prevent the formation of multiple primitive streaks. Dev. Cell 3, 745–756 (2002).

  36. 36.

    Haramoto, Y. et al. Xenopus tropicalis nodal-related gene 3 regulates BMP signaling: an essential role for the pro-region. Dev. Biol. 265, 155–168 (2004).

  37. 37.

    Onuma, Y. et al. Xnr2 and Xnr5 unprocessed proteins inhibit Wnt signaling upstream of dishevelled. Dev. Dyn. 234, 900–910 (2005).

  38. 38.

    Jung, J., Zheng, M., Goldfarb, M. & Zaret, K. S. Initiation of mammalian liver development from endoderm by fibroblast growth factors. Science 284, 1998–2003 (1999).

  39. 39.

    Zhang, W., Yatskievych, T. A., Baker, R. K. & Antin, P. B. Regulation of Hex gene expression and initial stages of avian hepatogenesis by Bmp and Fgf signaling. Dev. Biol. 268, 312–326 (2004).

  40. 40.

    Finley, K. R., Tennessen, J. & Shawlot, W. The mouse secreted frizzled-related protein 5 gene is expressed in the anterior visceral endoderm and foregut endoderm during early post-implantation development. Gene Expr. Patterns 3, 681–684 (2003).

  41. 41.

    Dessimoz, J., Opoka, R., Kordich, J. J., Grapin-Botton, A. & Wells, J. M. FGF signaling is necessary for establishing gut tube domains along the anterior-posterior axis in vivo. Mech. Dev. 123, 42–55 (2006).

  42. 42.

    Zaret, K. Early liver differentiation: genetic potentiation and multilevel growth control. Curr. Opin. Genet. Dev. 8, 526–531 (1998).

  43. 43.

    Martinez Barbera, J. P. et al. The homeobox gene Hex is required in definitive endodermal tissues for normal forebrain, liver and thyroid formation. Development 127, 2433–2445 (2000).

  44. 44.

    Bort, R., Signore, M., Tremblay, K., Martinez Barbera, J. P. & Zaret, K. S. Hex homeobox gene controls the transition of the endoderm to a pseudostratified, cell emergent epithelium for liver bud development. Dev. Biol. 290, 44–56 (2006).

  45. 45.

    Monga, S. P. et al. β-catenin antisense studies in embryonic liver cultures: role in proliferation, apoptosis, and lineage specification. Gastroenterology 124, 202–216 (2003).

  46. 46.

    Suksaweang, S. et al. Morphogenesis of chicken liver: identification of localized growth zones and the role of β-catenin/Wnt in size regulation. Dev. Biol. 266, 109–122 (2004).

  47. 47.

    Tan, X. et al. β-catenin deletion in hepatoblasts disrupts hepatic morphogenesis and survival during mouse development. Hepatology 47, 1667–1679 (2008).

  48. 48.

    Pettinato, G. et al. Scalable differentiation of human iPSCs in a multicellular spheroid-based 3D culture into hepatocyte-like cells through direct Wnt/β-catenin pathway inhibition. Sci. Rep. 6, 32888 (2016).

  49. 49.

    Hussain, S. Z. et al. Wnt impacts growth and differentiation in ex vivo liver development. Exp. Cell Res. 292, 157–169 (2004).

  50. 50.

    Decaens, T. et al. Stabilization of β-catenin affects mouse embryonic liver growth and hepatoblast fate. Hepatology 47, 247–258 (2008).

  51. 51.

    Gerard, C., Tys, J. & Lemaigre, F. P. Gene regulatory networks in differentiation and direct reprogramming of hepatic cells. Semin. Cell Dev. Biol. 66, 43–50 (2017).

  52. 52.

    Matsumoto, K., Miki, R., Nakayama, M., Tatsumi, N. & Yokouchi, Y. Wnt9a secreted from the walls of hepatic sinusoids is essential for morphogenesis, proliferation, and glycogen accumulation of chick hepatic epithelium. Dev. Biol. 319, 234–247 (2008).

  53. 53.

    Sekhon, S. S., Tan, X., Micsenyi, A., Bowen, W. C. & Monga, S. P. Fibroblast growth factor enriches the embryonic liver cultures for hepatic progenitors. Am. J. Pathol. 164, 2229–2240 (2004).

  54. 54.

    Cordi, S. et al. Role of β-catenin in development of bile ducts. Differentiation 91, 42–49 (2016).

  55. 55.

    Merino-Azpitarte, M. et al. SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma. J. Hepatol. 67, 72–83 (2017).

  56. 56.

    Jungermann, K. & Katz, N. Functional specialization of different hepatocyte populations. Physiol. Rev. 69, 708–764 (1989).

  57. 57.

    Benhamouche, S. et al. Apc tumor suppressor gene is the “zonation-keeper” of mouse liver. Dev. Cell 10, 759–770 (2006).

  58. 58.

    Yang, J. et al. β-catenin signaling in murine liver zonation and regeneration: a Wnt-Wnt situation! Hepatology 60, 964–976 (2014).

  59. 59.

    Wang, B., Zhao, L., Fish, M., Logan, C. Y. & Nusse, R. Self-renewing diploid Axin2+ cells fuel homeostatic renewal of the liver. Nature 524, 180–185 (2015).

  60. 60.

    Rocha, A. S. et al. The angiocrine factor rspondin3 is a key determinant of liver zonation. Cell Rep. 13, 1757–1764 (2015).

  61. 61.

    Planas-Paz, L. et al. The RSPO-LGR4/5-ZNRF3/RNF43 module controls liver zonation and size. Nat. Cell Biol. 18, 467–479 (2016).

  62. 62.

    Nejak-Bowen, K. N. & Monga, S. P. β-catenin signaling, liver regeneration and hepatocellular cancer: sorting the good from the bad. Semin. Cancer Biol. 21, 44–58 (2011).

  63. 63.

    Apte, U. et al. Wnt/β-catenin signaling mediates oval cell response in rodents. Hepatology 47, 288–295 (2008).

  64. 64.

    Williams, J. M. et al. The role of the Wnt family of secreted proteins in rat oval “stem” cell-based liver regeneration: Wnt1 drives differentiation. Am. J. Pathol. 176, 2732–2742 (2010).

  65. 65.

    Ji, X. K. et al. GSK-3β suppresses the proliferation of rat hepatic oval cells through modulating Wnt/β-catenin signaling pathway. Acta Pharmacol. Sin. 36, 334–342 (2015).

  66. 66.

    Kim, J. Y. et al. CWP232228 targets liver cancer stem cells through Wnt/β-catenin signaling: a novel therapeutic approach for liver cancer treatment. Oncotarget 7, 20395–20409 (2016).

  67. 67.

    Monga, S. P., Pediaditakis, P., Mule, K., Stolz, D. B. & Michalopoulos, G. K. Changes in WNT/β-catenin pathway during regulated growth in rat liver regeneration. Hepatology 33, 1098–1109 (2001).

  68. 68.

    Sodhi, D. et al. Morpholino oligonucleotide-triggered β-catenin knockdown compromises normal liver regeneration. J. Hepatol. 43, 132–141 (2005).

  69. 69.

    Tan, X., Behari, J., Cieply, B., Michalopoulos, G. K. & Monga, S. P. Conditional deletion of β-catenin reveals its role in liver growth and regeneration. Gastroenterology 131, 1561–1572 (2006).

  70. 70.

    Koch, A. et al. Childhood hepatoblastomas frequently carry a mutated degradation targeting box of the β-catenin gene. Cancer Res. 59, 269–273 (1999).

  71. 71.

    Forbes, S. A. et al. COSMIC: somatic cancer genetics at high-resolution. Nucleic Acids Res. 45, D777–D783 (2017).

  72. 72.

    Wei, Y. et al. Activation of β-catenin in epithelial and mesenchymal hepatoblastomas. Oncogene 19, 498–504 (2000).

  73. 73.

    Lopez-Terrada, D. et al. Towards an international pediatric liver tumor consensus classification: proceedings of the Los Angeles COG liver tumors symposium. Mod. Pathol. 27, 472–491 (2014).

  74. 74.

    Bell, D., Ranganathan, S., Tao, J. & Monga, S. P. Novel advances in understanding of molecular pathogenesis of hepatoblastoma: a Wnt/β-catenin perspective. Gene Expr. 17, 141–154 (2017).

  75. 75.

    Adesina, A. M. et al. Gene expression profiling reveals signatures characterizing histologic subtypes of hepatoblastoma and global deregulation in cell growth and survival pathways. Hum. Pathol. 40, 843–853 (2009).

  76. 76.

    Cairo, S. et al. Hepatic stem-like phenotype and interplay of Wnt/β-catenin and Myc signaling in aggressive childhood liver cancer. Cancer Cell 14, 471–484 (2008).

  77. 77.

    Armengol, C., Cairo, S., Fabre, M. & Buendia, M. A. Wnt signaling and hepatocarcinogenesis: the hepatoblastoma model. Int. J. Biochem. Cell Biol. 43, 265–270 (2011).

  78. 78.

    Goga, A., Yang, D., Tward, A. D., Morgan, D. O. & Bishop, J. M. Inhibition of CDK1 as a potential therapy for tumors over-expressing MYC. Nat. Med. 13, 820–827 (2007).

  79. 79.

    Ilmer, M. et al. Targeting the neurokinin-1 receptor compromises canonical Wnt signaling in hepatoblastoma. Mol. Cancer Ther. 14, 2712–2721 (2015).

  80. 80.

    Cairo, S., Armengol, C. & Buendia, M. A. Activation of Wnt and Myc signaling in hepatoblastoma. Front. Biosci. 4, 480–486 (2012).

  81. 81.

    Lopez-Terrada, D. et al. Histologic subtypes of hepatoblastoma are characterized by differential canonical Wnt and Notch pathway activation in DLK+ precursors. Hum. Pathol. 40, 783–794 (2009).

  82. 82.

    Tao, J. et al. Activation of β-catenin and Yap1 in human hepatoblastoma and induction of hepatocarcinogenesis in mice. Gastroenterology 147, 690–701 (2014).

  83. 83.

    Forner, A., Reig, M. & Bruix, J. Hepatocellular carcinoma. Lancet 391, 1301–1314 (2018).

  84. 84.

    Taipale, J. & Beachy, P. A. The Hedgehog and Wnt signalling pathways in cancer. Nature 411, 349–354 (2001).

  85. 85.

    Kelleher, F. C., Fennelly, D. & Rafferty, M. Common critical pathways in embryogenesis and cancer. Acta Oncol. 45, 375–388 (2006).

  86. 86.

    Russell, J. O. & Monga, S. S. Wnt/β-catenin signaling in liver development, homeostasis, and pathobiology. Annu. Rev. Pathol. 13, 351–378 (2017).

  87. 87.

    Ihara, A., Koizumi, H., Hashizume, R. & Uchikoshi, T. Expression of epithelial cadherin and α- and β-catenins in nontumoral livers and hepatocellular carcinomas. Hepatology 23, 1441–1447 (1996).

  88. 88.

    Satoh, S. et al. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat. Genet. 24, 245–250 (2000).

  89. 89.

    Waisberg, J. & Saba, G. T. Wnt−/−β-catenin pathway signaling in human hepatocellular carcinoma. World J. Hepatol. 7, 2631–2635 (2015).

  90. 90.

    Rebouissou, S. et al. Genotype-phenotype correlation of CTNNB1 mutations reveals different ss-catenin activity associated with liver tumor progression. Hepatology 64, 2047–2061 (2016).

  91. 91.

    Ding, S. L. et al. Integrative analysis of aberrant Wnt signaling in hepatitis B virus-related hepatocellular carcinoma. World J. Gastroenterol. 21, 6317–6328 (2015).

  92. 92.

    Tornesello, M. L. et al. Mutations in TP53, CTNNB1 and PIK3CA genes in hepatocellular carcinoma associated with hepatitis B and hepatitis C virus infections. Genomics 102, 74–83 (2013).

  93. 93.

    Schulze, K. et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat. Genet. 47, 505–511 (2015).

  94. 94.

    Lau, C. C. et al. Viral-human chimeric transcript predisposes risk to liver cancer development and progression. Cancer Cell 25, 335–349 (2014).

  95. 95.

    Jia, Y. et al. SOX17 antagonizes WNT/β-catenin signaling pathway in hepatocellular carcinoma. Epigenetics 5, 743–749 (2010).

  96. 96.

    Tsao, C. M. et al. SOX1 functions as a tumor suppressor by antagonizing the WNT/β-catenin signaling pathway in hepatocellular carcinoma. Hepatology 56, 2277–2287 (2012).

  97. 97.

    Quan, H. et al. Hepatitis C virus core protein epigenetically silences SFRP1 and enhances HCC aggressiveness by inducing epithelial-mesenchymal transition. Oncogene 33, 2826–2835 (2014).

  98. 98.

    Wang, Y. et al. The long noncoding RNA lncTCF7 promotes self-renewal of human liver cancer stem cells through activation of Wnt signaling. Cell Stem Cell 16, 413–425 (2015).

  99. 99.

    Carotenuto, P. et al. Wnt signalling modulates transcribed-ultraconserved regions in hepatobiliary cancers. Gut 66, 1268–1277 (2017).

  100. 100.

    Ying, Y. & Tao, Q. Epigenetic disruption of the WNT/β-catenin signaling pathway in human cancers. Epigenetics 4, 307–312 (2009).

  101. 101.

    Braconi, C. et al. Expression and functional role of a transcribed noncoding RNA with an ultraconserved element in hepatocellular carcinoma. Proc. Natl Acad. Sci. USA 108, 786–791 (2011).

  102. 102.

    Wang, W. et al. Blocking Wnt secretion reduces growth of hepatocellular carcinoma cell lines mostly independent of β-catenin signaling. Neoplasia 18, 711–723 (2016).

  103. 103.

    Debebe, A. et al. Wnt/β-catenin activation and macrophage induction during liver cancer development following steatosis. Oncogene 36, 6020–6029 (2017).

  104. 104.

    Zhi, X. et al. βII-Spectrin (SPTBN1) suppresses progression of hepatocellular carcinoma and Wnt signaling by regulation of Wnt inhibitor kallistatin. Hepatology 61, 598–612 (2015).

  105. 105.

    Lai, K. K. Y. et al. Stearoyl-CoA desaturase promotes liver fibrosis and tumor development in mice via a Wnt positive-signaling loop by stabilization of low-density lipoprotein-receptor-related proteins 5 and 6. Gastroenterology 152, 1477–1491 (2017).

  106. 106.

    Nambotin, S. B. et al. Pharmacological inhibition of Frizzled-7 displays anti-tumor properties in hepatocellular carcinoma. J. Hepatol. 54, 288–299 (2011).

  107. 107.

    Pez, F. et al. Wnt signaling and hepatocarcinogenesis: molecular targets for the development of innovative anticancer drugs. J. Hepatol. 59, 1107–1117 (2013).

  108. 108.

    Chai, S. et al. Octamer 4/microRNA-1246 signaling axis drives Wnt/β-catenin activation in liver cancer stem cells. Hepatology 64, 2062–2076 (2016).

  109. 109.

    Gu, W., Li, X. & Wang, J. miR-139 regulates the proliferation and invasion of hepatocellular carcinoma through the WNT/TCF-4 pathway. Oncol. Rep. 31, 397–404 (2014).

  110. 110.

    Qu, C. et al. Salt-inducible Kinase (SIK1) regulates HCC progression and WNT/β-catenin activation. J. Hepatol. 64, 1076–1089 (2016).

  111. 111.

    Harada, N. et al. Lack of tumorigenesis in the mouse liver after adenovirus-mediated expression of a dominant stable mutant of β-catenin. Cancer Res. 62, 1971–1977 (2002).

  112. 112.

    Nejak-Bowen, K. N. et al. Accelerated liver regeneration and hepatocarcinogenesis in mice overexpressing serine-45 mutant β-catenin. Hepatology 51, 1603–1613 (2010).

  113. 113.

    Mokkapati, S. et al. β-catenin activation in a novel liver progenitor cell type is sufficient to cause hepatocellular carcinoma and hepatoblastoma. Cancer Res. 74, 4515–4525 (2014).

  114. 114.

    Tao, J. et al. Modeling a human hepatocellular carcinoma subset in mice through coexpression of met and point-mutant β-catenin. Hepatology 64, 1587–1605 (2016).

  115. 115.

    Tao, J. et al. Targeting β-catenin in hepatocellular cancers induced by coexpression of mutant β-catenin and K-Ras in mice. Hepatology 65, 1581–1599 (2017).

  116. 116.

    Colnot, S. et al. Liver-targeted disruption of Apc in mice activates β-catenin signaling and leads to hepatocellular carcinomas. Proc. Natl Acad. Sci. USA 101, 17216–17221 (2004).

  117. 117.

    Lam, S. H. & Gong, Z. Modeling liver cancer using zebrafish: a comparative oncogenomics approach. Cell Cycle 5, 573–577 (2006).

  118. 118.

    Ober, E. A., Verkade, H., Field, H. A. & Stainier, D. Y. Mesodermal Wnt2b signalling positively regulates liver specification. Nature 442, 688–691 (2006).

  119. 119.

    Evason, K. J. et al. Identification of chemical inhibitors of β-catenin-driven liver tumorigenesis in zebrafish. PLOS Genet. 11, e1005305 (2015).

  120. 120.

    Banales, J. M. et al. Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat. Rev. Gastroenterol. Hepatol. 13, 261–280 (2016).

  121. 121.

    Rizvi, S., Khan, S. A., Hallemeier, C. L., Kelley, R. K. & Gores, G. J. Cholangiocarcinoma — evolving concepts and therapeutic strategies. Nat. Rev. Clin. Oncol. 15, 95–111 (2018).

  122. 122.

    Valle, J. et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N. Engl. J. Med. 362, 1273–1281 (2010).

  123. 123.

    Tokumoto, N. et al. Immunohistochemical and mutational analyses of Wnt signaling components and target genes in intrahepatic cholangiocarcinomas. Int. J. Oncol. 27, 973–980 (2005).

  124. 124.

    Yothaisong, S. et al. Opisthorchis viverrini infection activates the PI3K/ AKT/PTEN and Wnt/β-catenin signaling pathways in a Cholangiocarcinogenesis model. Asian Pac. J. Cancer Prev. 15, 10463–10468 (2014).

  125. 125.

    Zhang, K. S., Zhou, Q., Wang, Y. F. & Liang, L. J. Inhibition of Wnt signaling induces cell apoptosis and suppresses cell proliferation in cholangiocarcinoma cells. Oncol. Rep. 30, 1430–1438 (2013).

  126. 126.

    Sugimachi, K. et al. Altered expression of β-catenin without genetic mutation in intrahepatic cholangiocarcinoma. Mod. Pathol. 14, 900–905 (2001).

  127. 127.

    Goeppert, B. et al. Global alterations of DNA methylation in cholangiocarcinoma target the Wnt signaling pathway. Hepatology 59, 544–554 (2014).

  128. 128.

    Goeppert, B. et al. Cadherin-6 is a putative tumor suppressor and target of epigenetically dysregulated miR-429 in cholangiocarcinoma. Epigenetics 11, 780–790 (2016).

  129. 129.

    Zhang, F. et al. Long noncoding RNA PCAT1 regulates extrahepatic cholangiocarcinoma progression via the Wnt/β-catenin-signaling pathway. Biomed. Pharmacother. 94, 55–62 (2017).

  130. 130.

    Loilome, W. et al. Activated macrophages promote Wnt/β-catenin signaling in cholangiocarcinoma cells. Tumour Biol. 35, 5357–5367 (2014).

  131. 131.

    Boulter, L. et al. WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited. J. Clin. Invest. 125, 1269–1285 (2015).

  132. 132.

    Shen, D. Y., Zhang, W., Zeng, X. & Liu, C. Q. Inhibition of Wnt/β-catenin signaling downregulates P-glycoprotein and reverses multi-drug resistance of cholangiocarcinoma. Cancer Sci. 104, 1303–1308 (2013).

  133. 133.

    Huang, G. L. et al. Oncogenic activity of retinoic acid receptor gamma is exhibited through activation of the Akt/NF-kappaB and Wnt/β-catenin pathways in cholangiocarcinoma. Mol. Cell. Biol. 33, 3416–3425 (2013).

  134. 134.

    Wang, J. et al. Underexpression of LKB1 tumor suppressor is associated with enhanced Wnt signaling and malignant characteristics of human intrahepatic cholangiocarcinoma. Oncotarget 6, 18905–18920 (2015).

  135. 135.

    Friedman, S. L. Evolving challenges in hepatic fibrosis. Nat. Rev. Gastroenterol. Hepatol. 7, 425–436 (2010).

  136. 136.

    Friedman, S. L. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol. Rev. 88, 125–172 (2008).

  137. 137.

    Liu, Y. et al. WNT signaling pathway gene polymorphisms and risk of hepatic fibrosis and inflammation in HCV-infected patients. PLOS ONE 8, e84407 (2013).

  138. 138.

    Ge, W. S. et al. β-catenin is overexpressed in hepatic fibrosis and blockage of Wnt/β-catenin signaling inhibits hepatic stellate cell activation. Mol. Med. Rep. 9, 2145–2151 (2014).

  139. 139.

    Jiang, F., Parsons, C. J. & Stefanovic, B. Gene expression profile of quiescent and activated rat hepatic stellate cells implicates Wnt signaling pathway in activation. J. Hepatol. 45, 401–409 (2006).

  140. 140.

    Xiong, W. J. et al. Wnt5a participates in hepatic stellate cell activation observed by gene expression profile and functional assays. World J. Gastroenterol. 18, 1745–1752 (2012).

  141. 141.

    Corbett, L., Mann, J. & Mann, D. A. Non-canonical Wnt predominates in activated rat hepatic stellate cells, influencing HSC survival and paracrine stimulation of Kupffer cells. PLOS ONE 10, e0142794 (2015).

  142. 142.

    Myung, S. J. et al. Wnt signaling enhances the activation and survival of human hepatic stellate cells. FEBS Lett. 581, 2954–2958 (2007).

  143. 143.

    Cheng, J. H. et al. Wnt antagonism inhibits hepatic stellate cell activation and liver fibrosis. Am. J. Physiol. Gastrointest. Liver Physiol. 294, G39–G49 (2008).

  144. 144.

    Chatani, N. et al. Secreted frizzled-related protein 5 (Sfrp5) decreases hepatic stellate cell activation and liver fibrosis. Liver Int. 35, 2017–2026 (2015).

  145. 145.

    Kweon, S. M., Chi, F., Higashiyama, R., Lai, K. & Tsukamoto, H. Wnt pathway stabilizes MeCP2 protein to repress PPAR-γ in activation of hepatic stellate cells. PLOS ONE 11, e0156111 (2016).

  146. 146.

    Tokunaga, Y. et al. Selective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model. Sci. Rep. 7, 325 (2017).

  147. 147.

    Zhu, N. L., Wang, J. & Tsukamoto, H. The Necdin-Wnt pathway causes epigenetic peroxisome proliferator-activated receptor γ repression in hepatic stellate cells. J. Biol. Chem. 285, 30463–30471 (2010).

  148. 148.

    Haughton, E. L. et al. Pregnane X receptor activators inhibit human hepatic stellate cell transdifferentiation in vitro. Gastroenterology 131, 194–209 (2006).

  149. 149.

    Yu, F., Guo, Y., Chen, B., Dong, P. & Zheng, J. MicroRNA-17-5p activates hepatic stellate cells through targeting of Smad7. Lab Invest. 95, 781–789 (2015).

  150. 150.

    Yu, F. et al. MicroRNA-17-5p-activated Wnt/β-catenin pathway contributes to the progression of liver fibrosis. Oncotarget 7, 81–93 (2016).

  151. 151.

    Zhou, D. D. et al. MicroRNA-145 inhibits hepatic stellate cell activation and proliferation by targeting ZEB2 through Wnt/β-catenin pathway. Mol. Immunol. 75, 151–160 (2016).

  152. 152.

    Yu, F., Fan, X., Chen, B., Dong, P. & Zheng, J. Activation of hepatic stellate cells is inhibited by microRNA-378a-3p via Wnt10a. Cell Physiol. Biochem. 39, 2409–2420 (2016).

  153. 153.

    Irvine, K. M. et al. Deletion of Wntless in myeloid cells exacerbates liver fibrosis and the ductular reaction in chronic liver injury. Fibrogen. Tissue Repair 8, 19 (2015).

  154. 154.

    Preziosi, M. E. et al. Mice lacking liver-specific β-catenin develop steatohepatitis and fibrosis after iron overload. J. Hepatol. 67, 360–369 (2017).

  155. 155.

    Huang, C. K. et al. Restoration of Wnt/β-catenin signaling attenuates alcoholic liver disease progression in a rat model. J. Hepatol. 63, 191–198 (2015).

  156. 156.

    Reccia, I. et al. Non-alcoholic fatty liver disease: a sign of systemic disease. Metabolism 72, 94–108 (2017).

  157. 157.

    Wong, V. W. et al. Pathogenesis and novel treatment options for non-alcoholic steatohepatitis. Lancet Gastroenterol. Hepatol. 1, 56–67 (2016).

  158. 158.

    Liu, S. et al. β-catenin is essential for ethanol metabolism and protection against alcohol-mediated liver steatosis in mice. Hepatology 55, 931–940 (2012).

  159. 159.

    Go, G. W. et al. The combined hyperlipidemia caused by impaired Wnt-LRP6 signaling is reversed by Wnt3a rescue. Cell Metab. 19, 209–220 (2014).

  160. 160.

    Wang, S. et al. Nonalcoholic fatty liver disease induced by noncanonical Wnt and its rescue by Wnt3a. Faseb J. 29, 3436–3445 (2015).

  161. 161.

    Liu, W. et al. Low density lipoprotein (LDL) receptor-related protein 6 (LRP6) regulates body fat and glucose homeostasis by modulating nutrient sensing pathways and mitochondrial energy expenditure. J. Biol. Chem. 287, 7213–7223 (2012).

  162. 162.

    Nobili, V. et al. Docosahexaenoic acid for the treatment of fatty liver: randomised controlled trial in children. Nutr. Metab. Cardiovasc. Dis. 23, 1066–1070 (2013).

  163. 163.

    Carpino, G. et al. Macrophage activation in pediatric nonalcoholic fatty liver disease (NAFLD) correlates with hepatic progenitor cell response via Wnt3a pathway. PLOS ONE 11, e0157246 (2016).

  164. 164.

    Allen, K., Jaeschke, H. & Copple, B. L. Bile acids induce inflammatory genes in hepatocytes: a novel mechanism of inflammation during obstructive cholestasis. Am. J. Pathol. 178, 175–186 (2011).

  165. 165.

    Yeh, T. H. et al. Liver-specific β-catenin knockout mice have bile canalicular abnormalities, bile secretory defect, and intrahepatic cholestasis. Hepatology 52, 1410–1419 (2010).

  166. 166.

    Lemberger, U. J. et al. Hepatocyte specific expression of an oncogenic variant of β-catenin results in cholestatic liver disease. Oncotarget 7, 86985–86998 (2016).

  167. 167.

    de Vries, E. & Beuers, U. Management of cholestatic disease in 2017. Liver Int. 37 (Suppl. 1), 123–129 (2017).

  168. 168.

    Tanaka, A. et al. Genomic analysis of differentially expressed genes in liver and biliary epithelial cells of patients with primary biliary cirrhosis. J. Autoimmun 17, 89–98 (2001).

  169. 169.

    Shackel, N. A., McGuinness, P. H., Abbott, C. A., Gorrell, M. D. & McCaughan, G. W. Identification of novel molecules and pathogenic pathways in primary biliary cirrhosis: cDNA array analysis of intrahepatic differential gene expression. Gut 49, 565–576 (2001).

  170. 170.

    Thompson, M. D., Awuah, P., Singh, S. & Monga, S. P. Disparate cellular basis of improved liver repair in β-catenin-overexpressing mice after long-term exposure to 3,5-diethoxycarbonyl-1,4-dihydrocollidine. Am. J. Pathol. 177, 1812–1822 (2010).

  171. 171.

    Okabe, H. et al. Wnt signaling regulates hepatobiliary repair following cholestatic liver injury in mice. Hepatology 64, 1652–1666 (2016).

  172. 172.

    Sackett, S. D. et al. Foxl1 promotes liver repair following cholestatic injury in mice. Lab Invest. 89, 1387–1396 (2009).

  173. 173.

    Perugorria, M. J. et al. Polycystic liver diseases: advanced insights into the molecular mechanisms. Nat. Rev. Gastroenterol. Hepatol. 11, 750–761 (2014).

  174. 174.

    Perugorria, M. J. & Banales, J. M. Genetics: Novel causative genes for polycystic liver disease. Nat. Rev. Gastroenterol. Hepatol. 14, 391–392 (2017).

  175. 175.

    Masyuk, A. I. et al. Cholangiocyte autophagy contributes to hepatic cystogenesis in polycystic liver disease and represents a potential therapeutic target. Hepatology 67, 1088–1108 (2017).

  176. 176.

    Cnossen, W. R. et al. Whole-exome sequencing reveals LRP5 mutations and canonical Wnt signaling associated with hepatic cystogenesis. Proc. Natl Acad. Sci. USA 111, 5343–5348 (2014).

  177. 177.

    Wills, E. S. et al. Liver cyst gene knockout in cholangiocytes inhibits cilium formation and Wnt signaling. Hum. Mol. Genet. 26, 4190–4202 (2017).

  178. 178.

    Spirli, C. et al. Protein kinase A-dependent pSer(675) -β-catenin, a novel signaling defect in a mouse model of congenital hepatic fibrosis. Hepatology 58, 1713–1723 (2013).

  179. 179.

    Locatelli, L. et al. Macrophage recruitment by fibrocystin-defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis. Hepatology 63, 965–982 (2016).

  180. 180.

    Kaffe, E. et al. β-catenin and IL-1β dependent CXCL10 production drives progression of disease in a mouse model of congenital hepatic fibrosis. Hepatology 67, 1903–1919 (2017).

  181. 181.

    Krishnamurthy, N. & Kurzrock, R. Targeting the Wnt/β-catenin pathway in cancer: Update on effectors and inhibitors. Cancer Treat. Rev. 62, 50–60 (2017).

  182. 182.

    US National Library of Medicine. (2014).

  183. 183.

    US National Library of Medicine. (2016).

  184. 184.

    US National Library of Medicine. (2015).

  185. 185.

    Shi, X. D. et al. Dickkopf-1 expression is associated with tumorigenity and lymphatic metastasis in human hilar cholangiocarcinoma. Oncotarget 7, 70378–70387 (2016).

  186. 186.

    Yu, B. et al. Elevated expression of DKK1 is associated with cytoplasmic/nuclear β-catenin accumulation and poor prognosis in hepatocellular carcinomas. J. Hepatol. 50, 948–957 (2009).

  187. 187.

    Kagey, M. H. & He, X. Rationale for targeting the Wnt signalling modulator Dickkopf-1 for oncology. Br. J. Pharmacol. 174, 4637–4650 (2017).

  188. 188.

    US National Library of Medicine. (2014).

  189. 189.

    Ganesh, S. et al. Direct pharmacological inhibition of β-catenin by RNA interference in tumors of diverse origin. Mol. Cancer Ther. 15, 2143–2154 (2016).

  190. 190.

    Sebio, A., Kahn, M. & Lenz, H. J. The potential of targeting Wnt/β-catenin in colon cancer. Expert Opin. Ther. Targets 18, 611–615 (2014).

  191. 191.

    Palmer, H. G. et al. Vitamin D3 promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of β-catenin signaling. J. Cell Biol. 154, 369–387 (2001).

  192. 192.

    Osei-Sarfo, K. & Gudas, L. J. Retinoic acid suppresses the canonical Wnt signaling pathway in embryonic stem cells and activates the noncanonical Wnt signaling pathway. Stem Cells 32, 2061–2071 (2014).

  193. 193.

    Chen, J. et al. Vitamin D deficiency promotes liver tumor growth in transforming growth factor-β/Smad3-deficient mice through Wnt and Toll-like Receptor 7 pathway modulation. Sci. Rep. 6, 30217 (2016).

  194. 194.

    Chiang, K. C. et al. Chemopreventive and chemotherapeutic effect of dietary supplementation of vitamin D on cholangiocarcinoma in a chemical-induced animal model. Oncotarget 5, 3849–3861 (2014).

  195. 195.

    Xia, H. & Hui, K. M. Emergence of aspirin as a promising chemopreventive and chemotherapeutic agent for liver cancer. Cell Death Dis. 8, e3112 (2017).

  196. 196.

    Choi, J. et al. Aspirin use and the risk of cholangiocarcinoma. Hepatology 64, 785–796 (2016).

  197. 197.

    Rahman, M. A. et al. Sulindac and exisulind exhibit a significant antiproliferative effect and induce apoptosis in human hepatocellular carcinoma cell lines. Cancer Res. 60, 2085–2089 (2000).

  198. 198.

    Wentz, S. C. et al. Sulindac prevents carcinogen-induced intrahepatic cholangiocarcinoma formation in vivo. J. Surg. Res. 157, e87–95 (2009).

  199. 199.

    US National Library of Medicine. (2013).

  200. 200.

    US National Library of Medicine. (2016).

  201. 201.

    US National Library of Medicine. (2013).

  202. 202.

    Kahn, M. Can we safely target the WNT pathway? Nat. Rev. Drug Discov. 13, 513–532 (2014).

  203. 203.

    Zhang, X. & Hao, J. Development of anticancer agents targeting the Wnt/β-catenin signaling. Am. J. Cancer Res. 5, 2344–2360 (2015).

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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).

Author information


  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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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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