Wnt/β-Catenin Signalling during Liver Metabolism, Chronic Liver Disease and Hepatocarcinogenesis

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Gayatri D. Shirolkar
Sara Pasic
Jully Gogoi-Tiwari
Manoj K. Bhat
John K. Olynyk
Arun Dharmarajan
Janina E. E. Tirnitz-Parker


chronic liver disease, hepatocellular carcinoma, liver progenitor cells, metabolic syndrome, Wnt/β-catenin signalling


Chronic liver diseases (CLDs) are increasing in prevalence and their end-stage complications, namely, cirrhosis, liver failure and hepatocellular carcinoma represent major global challenges. The most common initiators of progressive CLD are viral hepatitis and long-term alcohol abuse as well as steatosis and steatohepatitis. Irrespective of the underlying aetiology, a common feature of CLD is the formation of hepatic ductular reactions, involving the proliferation of liver progenitor cells (LPCs) and their signalling to fibrosis-driving hepatic stellate cells. The Wnt/β-catenin pathway has been found to regulate development, stemness and differentiation, and alterations in its activity have been associated with tumour development. Recent data highlight the role of Wnt/β-catenin signalling in hepatic metabolism, steatosis and cancer, and suggest targeting of this pathway as a promising molecular strategy to potentially inhibit CLD progression and hepatocarcinogenesis.


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1. Fernandez-Iglesias A, Gracia-Sancho J. How to face chronic liver disease: The sinusoidal perspective. Front Med (Lausanne). 2017;4:7. http://dx.doi.org/10.3389/fmed.2017.00007
2. Williams R, Aspinall R, Bellis M, Camps-Walsh G, Cramp M, Dhawan A, et al. Addressing liver disease in the UK: A blueprint for attaining excellence in health care and reducing premature mortality from lifestyle issues of excess consumption of alcohol, obesity, and viral hepatitis. Lancet. 2014 Nov 29;384(9958):1953–97. http://dx.doi.org/10.1016/S0140-6736(14)61838-9
3. Ozakyol A. Global epidemiology of hepatocellular carcinoma (HCC epidemiology). J Gastrointest Cancer. 2017 Jun 19. http://dx.doi.org/10.1007/s12029-017-9959-0
4. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018 Jan 4. http://dx.doi.org/10.1016/S0140-6736(18)30010-2
5. Elsegood CL, Tirnitz-Parker JE, Olynyk JK, Yeoh GC. Immune checkpoint inhibition: Prospects for prevention and therapy of hepatocellular carcinoma. Clin Transl Immunology. 2017 Nov;6(11):e161. http://dx.doi.org/10.1038/cti.2017.47
6. Williams MJ, Clouston AD, Forbes SJ. Links between hepatic fibrosis, ductular reaction, and progenitor cell expansion. Gastroenterology. 2014 Feb;146(2):349–56. http://dx.doi.org/10.1053/j.gastro.2013.11.034
7. Gouw AS, Clouston AD, Theise ND. Ductular reactions in human liver: Diversity at the interface. Hepatology. 2011 Nov;54(5):1853–63. http://dx.doi.org/10.1002/hep.24613
8. Kohn-Gaone J, Dwyer BJ, Grzelak CA, Miller G, Shackel NA, Ramm GA, et al. Divergent inflammatory, fibrogenic, and liver progenitor cell dynamics in two common mouse models of chronic liver injury. Am J Pathol. 2016 Jul;186(7):1762–74. http://dx.doi.org/10.1016/j.ajpath.2016.03.005
9. Dwyer BJ, Olynyk JK, Ramm GA, Tirnitz-Parker JE. TWEAK and LTbeta signaling during chronic liver disease. Front Immunol. 2014;5:39. http://dx.doi.org/10.3389/fimmu.2014.00039
10. Elsegood CL, Chan CW, Degli-Esposti MA, Wikstrom ME, Domenichini A, Lazarus K, et al. Kupffer cell-monocyte communication is essential for initiating murine liver progenitor cell-mediated liver regeneration. Hepatology. 2015 Oct;62(4):1272–84. http://dx.doi.org/10.1002/hep.27977
11. Grzelak CA, Martelotto LG, Sigglekow ND, Patkunanathan B, Ajami K, Calabro SR, et al. The intrahepatic signalling niche of hedgehog is defined by primary cilia positive cells during chronic liver injury. J Hepatol. 2014 Jan;60(1):143–51. http://dx.doi.org/10.1016/j.jhep.2013.08.012
12. Ruddell RG, Knight B, Tirnitz-Parker JE, Akhurst B, Summerville L, Subramaniam VN, et al. Lymphotoxin-beta receptor signaling regulates hepatic stellate cell function and wound healing in a murine model of chronic liver injury. Hepatology. 2009 Jan;49(1):227–39. http://dx.doi.org/10.1002/hep.22597
13. Tirnitz-Parker JE, Olynyk JK, Ramm GA. Role of TWEAK in coregulating liver progenitor cell and fibrogenic responses. Hepatology. 2014 Mar;59(3):1198–201. http://dx.doi.org/10.1002/hep.26701
14. Kohn-Gaone J, Gogoi-Tiwari J, Ramm GA, Olynyk JK, Tirnitz-Parker JE. The role of liver progenitor cells during liver regeneration, fibrogenesis, and carcinogenesis. Am J Physiol Gastrointest Liver Physiol. 2016 Feb 1;310(3):G143–54. http://dx.doi.org/10.1152/ajpgi.00215.2015
15. Gogoi-Tiwari J, Kohn-Gaone J, Giles C, Schmidt-Arras D, Gratte FD, Elsegood CL, et al. The murine choline-deficient, ethionine-supplemented (CDE) diet model of chronic liver injury. J Vis Exp. 2017 Oct 21(128). http://dx.doi.org/10.3791/56138
16. Espanol-Suner R, Carpentier R, Van Hul N, Legry V, Achouri Y, Cordi S, et al. Liver progenitor cells yield functional hepatocytes in response to chronic liver injury in mice. Gastroenterology. 2012 Dec;143(6):1564–75.e7. http://dx.doi.org/10.1053/j.gastro.2012.08.024
17. Shin S, Upadhyay N, Greenbaum LE, Kaestner KH. Ablation of foxl1-cre-labeled hepatic progenitor cells and their descendants impairs recovery of mice from liver injury. Gastroenterology. 2015 Jan;148(1):192–202.e3. http://dx.doi.org/10.1053/j.gastro.2014.09.039
18. Lu WY, Bird TG, Boulter L, Tsuchiya A, Cole AM, Hay T, et al. Hepatic progenitor cells of biliary origin with liver repopulation capacity. Nat Cell Biol. 2015 Aug;17(8):971–83. http://dx.doi.org/10.1038/ncb3203
19. Raven A, Lu WY, Man TY, Ferreira-Gonzalez S, O’Duibhir E, Dwyer BJ, et al. Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration. Nature. 2017 Jul 20;547(7663):350–4. http://dx.doi.org/10.1038/nature23015
20. Prakoso E, Tirnitz-Parker JE, Clouston AD, Kayali Z, Lee A, Gan EK, et al. Analysis of the intrahepatic ductular reaction and progenitor cell responses in hepatitis C virus recurrence after liver transplantation. Liver Transpl. 2014 Dec;20(12):1508–19. http://dx.doi.org/10.1002/lt.24007
21. Knight B, Tirnitz-Parker JE, Olynyk JK. C-kit inhibition by imatinib mesylate attenuates progenitor cell expansion and inhibits liver tumor formation in mice. Gastroenterology. 2008 Sep;135(3):969–79, 979.e1. http://dx.doi.org/10.1053/j.gastro.2008.05.077
22. Ziol M, Nault JC, Aout M, Barget N, Tepper M, Martin A, et al. Intermediate hepatobiliary cells predict an increased risk of hepatocarcinogenesis in patients with hepatitis C virus-related cirrhosis. Gastroenterology. 2010 Jul;139(1):335–43.e2. http://dx.doi.org/10.1053/j.gastro.2010.04.012
23. Pozniak KN, Pearen MA, Pereira TN, Kramer CSM, Kalita-De Croft P, Nawaratna SK, et al. Taurocholate induces biliary differentiation of liver progenitor cells causing hepatic stellate cell chemotaxis in the ductular reaction: Role in pediatric cystic fibrosis liver disease. Am J Pathol. 2017 Dec;187(12):2744–57. http://dx.doi.org/10.1016/j.ajpath.2017.08.024
24. Haraguchi N, Utsunomiya T, Inoue H, Tanaka F, Mimori K, Barnard GF, et al. Characterization of a side population of cancer cells from human gastrointestinal system. Stem Cells. 2006 Mar;24(3):506–13. http://dx.doi.org/10.1634/stemcells.2005-0282
25. Chiba T, Kita K, Zheng YW, Yokosuka O, Saisho H, Iwama A, et al. Side population purified from hepatocellular carcinoma cells harbors cancer stem cell-like properties. Hepatology. 2006 Jul;44(1):240–51. http://dx.doi.org/10.1002/hep.21227
26. Ma S, Chan KW, Hu L, Lee TK, Wo JY, Ng IO, et al. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology. 2007 Jun;132(7):2542–56. http://dx.doi.org/10.1053/j.gastro.2007.04.025
27. Suetsugu A, Nagaki M, Aoki H, Motohashi T, Kunisada T, Moriwaki H. Characterization of CD133+ hepatocellular carcinoma cells as cancer stem/progenitor cells. Biochem Biophys Res Commun. 2006 Dec 29;351(4):820–4. http://dx.doi.org/10.1016/j.bbrc.2006.10.128
28. Yin S, Li J, Hu C, Chen X, Yao M, Yan M, et al. CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity. Int J Cancer. 2007 Apr 1;120(7):1444–50. http://dx.doi.org/10.1002/ijc.22476
29. Piao LS, Hur W, Kim TK, Hong SW, Kim SW, Choi JE, et al. CD133+ liver cancer stem cells modulate radioresistance in human hepatocellular carcinoma. Cancer Lett. 2012 Feb 28;315(2):129–37. http://dx.doi.org/10.1016/j.canlet.2011.10.012
30. Zhu Z, Hao X, Yan M, Yao M, Ge C, Gu J, et al. Cancer stem/progenitor cells are highly enriched in CD133+CD44+ population in hepatocellular carcinoma. Int J Cancer. 2010 May 1;126(9):2067–78. http://dx.doi.org/10.1002/ijc.24868
31. Lee TK, Castilho A, Cheung VC, Tang KH, Ma S, Ng IO. CD24(+) liver tumor-initiating cells drive self-renewal and tumor initiation through STAT3-mediated NANOG regulation. Cell Stem Cell. 2011 Jul 8;9(1):50–63. http://dx.doi.org/10.1016/j.stem.2011.06.005
32. Yang ZF, Ho DW, Ng MN, Lau CK, Yu WC, Ngai P, et al. Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell. 2008 Feb;13(2):153–66. http://dx.doi.org/10.1016/j.ccr.2008.01.013
33. Dolle L, Theise ND, Schmelzer E, Boulter L, Gires O, van Grunsven LA. EpCAM and the biology of hepatic stem/progenitor cells. Am J Physiol Gastrointest Liver Physiol. 2015 Feb 15;308(4):G233–50. http://dx.doi.org/10.1152/ajpgi.00069.2014
34. Yamashita T, Budhu A, Forgues M, Wang XW. Activation of hepatic stem cell marker EpCAM by Wnt-beta-catenin signaling in hepatocellular carcinoma. Cancer Res. 2007 Nov 15;67(22):10831–9. http://dx.doi.org/10.1158/0008-5472.CAN-07-0908
35. Hu M, Kurobe M, Jeong YJ, Fuerer C, Ghole S, Nusse R, et al. Wnt/beta-catenin signaling in murine hepatic transit amplifying progenitor cells. Gastroenterology. 2007 Nov;133(5):1579–91. http://dx.doi.org/10.1053/j.gastro.2007.08.036
36. Yang W, Yan HX, Chen L, Liu Q, He YQ, Yu LX, et al. Wnt/beta-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells. Cancer Res. 2008 Jun 1;68(11):4287–95. http://dx.doi.org/10.1158/0008-5472.CAN-07-6691
37. Tirnitz-Parker JE, Tonkin JN, Knight B, Olynyk JK, Yeoh GC. Isolation, culture and immortalisation of hepatic oval cells from adult mice fed a choline-deficient, ethionine-supplemented diet. Int J Biochem Cell Biol. 2007;39(12):2226–39. http://dx.doi.org/10.1016/j.biocel.2007.06.008
38. Boulter L, Govaere O, Bird TG, Radulescu S, Ramachandran P, Pellicoro A, et al. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nat Med. 2012 Mar 4;18(4):572–9. http://dx.doi.org/10.1038/nm.2667
39. Cai C, Zhu X. The Wnt/beta-catenin pathway regulates self-renewal of cancer stem-like cells in human gastric cancer. Mol Med Rep. 2012 May;5(5):1191–6. http://dx.doi.org/10.3892/mmr.2012.802
40. Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004;20:781–810. http://dx.doi.org/10.1146/annurev.cellbio.20.010403.113126
41. Pohl S, Scott R, Arfuso F, Perumal V, Dharmarajan A. Secreted frizzled-related protein 4 and its implications in cancer and apoptosis. Tumour Biol. 2015 Jan;36(1):143–52. http://dx.doi.org/10.1007/s13277-014-2956-z
42. Kikuchi A, Yamamoto H, Kishida S. Multiplicity of the interactions of Wnt proteins and their receptors. Cell Signal. 2007 Apr;19(4):659–71. http://dx.doi.org/10.1016/j.cellsig.2006.11.001
43. Tamai K, Semenov M, Kato Y, Spokony R, Liu C, Katsuyama Y, et al. LDL-receptor-related proteins in Wnt signal transduction. Nature. 2000 Sep 28;407(6803):530–5. http://dx.doi.org/10.1038/35035117
44. Monga SP. Beta-catenin signaling and roles in liver homeostasis, injury, and tumorigenesis. Gastroenterology. 2015 Jun;148(7):1294–310. http://dx.doi.org/10.1053/j.gastro.2015.02.056
45. Sethi JK, Vidal-Puig A. Wnt signalling and the control of cellular metabolism. Biochem J. 2010 Mar 15;427(1):1–17. http://dx.doi.org/10.1042/BJ20091866
46. Colletti M, Cicchini C, Conigliaro A, Santangelo L, Alonzi T, Pasquini E, et al. Convergence of Wnt signaling on the HNF4alpha-driven transcription in controlling liver zonation. Gastroenterology. 2009 Aug;137(2):660–72. http://dx.doi.org/10.1053/j.gastro.2009.05.038
47. Cadoret A, Ovejero C, Terris B, Souil E, Levy L, Lamers WH, et al. New targets of beta-catenin signaling in the liver are involved in the glutamine metabolism. Oncogene. 2002 Nov 28;21(54):8293–301. http://dx.doi.org/10.1038/sj.onc.1206118
48. Benhamouche S, Decaens T, Godard C, Chambrey R, Rickman DS, Moinard C, et al. Apc tumor suppressor gene is the “zonation-keeper” of mouse liver. Dev Cell. 2006 Jun;10(6):759–70. http://dx.doi.org/10.1016/j.devcel.2006.03.015
49. Burke ZD, Tosh D. The Wnt/beta-catenin pathway: Master regulator of liver zonation? Bioessays. 2006 Nov;28(11):1072–7. http://dx.doi.org/10.1002/bies.20485
50. Debebe A, Medina V, Chen CY, Mahajan IM, Jia C, Fu D, et al. Wnt/beta-catenin activation and macrophage induction during liver cancer development following steatosis. Oncogene. 2017 Oct 26;36(43):6020–9. http://dx.doi.org/10.1038/onc.2017.207
51. Liu H, Fergusson MM, Wu JJ, Rovira, II, Liu J, Gavrilova O, et al. Wnt signaling regulates hepatic metabolism. Sci Signal. 2011 Feb 1;4(158):ra6. http://dx.doi.org/10.1126/scisignal.2001249
52. Essers MA, de Vries-Smits LM, Barker N, Polderman PE, Burgering BM, Korswagen HC. Functional interaction between beta-catenin and FOXO in oxidative stress signaling. Science. 2005 May 20;308(5725):1181–4. http://dx.doi.org/10.1126/science.1109083
53. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA. 2001 May 16;285(19):2486–97.
54. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, et al. Nonalcoholic fatty liver disease: A feature of the metabolic syndrome. Diabetes. 2001 Aug;50(8):1844–50. http://dx.doi.org/10.2337/diabetes.50.8.1844
55. Bennett CN, Ross SE, Longo KA, Bajnok L, Hemati N, Johnson KW, et al. Regulation of Wnt signaling during adipogenesis. J Biol Chem. 2002 Aug 23;277(34):30998–1004. http://dx.doi.org/10.1074/jbc.M204527200
56. Ross SE, Hemati N, Longo KA, Bennett CN, Lucas PC, Erickson RL, et al. Inhibition of adipogenesis by Wnt signaling. Science. 2000 Aug 11;289(5481):950–3. http://dx.doi.org/10.1126/science.289.5481.950
57. Kennell JA, MacDougald OA. Wnt signaling inhibits adipogenesis through beta-catenin-dependent and -independent mechanisms. J Biol Chem. 2005 Jun 24;280(25):24004–10. http://dx.doi.org/10.1074/jbc.M501080200
58. Fairfield H, Falank C, Harris E, Demambro V, McDonald M, Pettitt JA, et al. The skeletal cell-derived molecule sclerostin drives bone marrow adipogenesis. J Cell Physiol. 2018 Feb;233(2):1156–67. http://dx.doi.org/10.1002/jcp.25976
59. Nault JC, Zucman-Rossi J. Genetics of hepatobiliary carcinogenesis. Semin Liver Dis. 2011 May;31(2):173–87. http://dx.doi.org/10.1055/s-0031-1276646
60. de La Coste A, Romagnolo B, Billuart P, Renard CA, Buendia MA, Soubrane O, et al. Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8847–51. http://dx.doi.org/10.1073/pnas.95.15.8847
61. Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad IB, et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet. 2012 May 6;44(6):694–8. http://dx.doi.org/10.1038/ng.2256
62. Huang H, Fujii H, Sankila A, Mahler-Araujo BM, Matsuda M, Cathomas G, et al. Beta-catenin mutations are frequent in human hepatocellular carcinomas associated with hepatitis C virus infection. Am J Pathol. 1999 Dec;155(6):1795–801. http://dx.doi.org/10.1016/S0002-9440(10)65496-X
63. Yamamoto Y, Sakamoto M, Fujii G, Tsuiji H, Kenetaka K, Asaka M, et al. Overexpression of orphan G-protein-coupled receptor, Gpr49, in human hepatocellular carcinomas with beta-catenin mutations. Hepatology. 2003 Mar;37(3):528–33. http://dx.doi.org/10.1053/jhep.2003.50029
64. Zucman-Rossi J, Benhamouche S, Godard C, Boyault S, Grimber G, Balabaud C, et al. Differential effects of inactivated Axin1 and activated beta-catenin mutations in human hepatocellular carcinomas. Oncogene. 2007 Feb 1;26(5):774–80. http://dx.doi.org/10.1038/sj.onc.1209824
65. Harada N, Oshima H, Katoh M, Tamai Y, Oshima M, Taketo MM. Hepatocarcinogenesis in mice with beta-catenin and Ha-ras gene mutations. Cancer Res. 2004 Jan 1;64(1):48–54. http://dx.doi.org/10.1158/0008-5472.CAN-03-2123
66. Boyault S, Rickman DS, de Reynies A, Balabaud C, Rebouissou S, Jeannot E, et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology. 2007 Jan;45(1):42–52. http://dx.doi.org/10.1002/hep.21467
67. Loeppen S, Schneider D, Gaunitz F, Gebhardt R, Kurek R, Buchmann A, et al. Overexpression of glutamine synthetase is associated with beta-catenin-mutations in mouse liver tumors during promotion of hepatocarcinogenesis by phenobarbital. Cancer Res. 2002 Oct 15;62(20):5685–8.
68. Hailfinger S, Jaworski M, Braeuning A, Buchmann A, Schwarz M. Zonal gene expression in murine liver: Lessons from tumors. Hepatology. 2006 Mar;43(3):407–14. http://dx.doi.org/10.1002/hep.21082
69. Pez F, Lopez A, Kim M, Wands JR, Caron de Fromentel C, Merle P. Wnt signaling and hepatocarcinogenesis: Molecular targets for the development of innovative anticancer drugs. J Hepatol. 2013 Nov;59(5):1107–17. http://dx.doi.org/10.1016/j.jhep.2013.07.001
70. Yuzugullu H, Benhaj K, Ozturk N, Senturk S, Celik E, Toylu A, et al. Canonical Wnt signaling is antagonized by noncanonical Wnt5a in hepatocellular carcinoma cells. Mol Cancer. 2009 Oct 22;8:90. http://dx.doi.org/10.1186/1476-4598-8-90
71. Huang J, Zhang YL, Teng XM, Lin Y, Zheng DL, Yang PY, et al. Down-regulation of SFRP1 as a putative tumor suppressor gene can contribute to human hepatocellular carcinoma. BMC Cancer. 2007 Jul 12;7:126. http://dx.doi.org/10.1186/1471-2407-7-126
72. Deng Y, Yu B, Cheng Q, Jin J, You H, Ke R, et al. Epigenetic silencing of WIF-1 in hepatocellular carcinomas. J Cancer Res Clin Oncol. 2010 Aug;136(8):1161–7. http://dx.doi.org/10.1007/s00432-010-0763-5
73. Sato H, Suzuki H, Toyota M, Nojima M, Maruyama R, Sasaki S, et al. Frequent epigenetic inactivation of DICKKOPF family genes in human gastrointestinal tumors. Carcinogenesis. 2007 Dec;28(12):2459–66. http://dx.doi.org/10.1093/carcin/bgm178
74. Fatima S, Lee NP, Tsang FH, Kolligs FT, Ng IO, Poon RT, et al. Dickkopf 4 (DKK4) acts on Wnt/beta-catenin pathway by influencing beta-catenin in hepatocellular carcinoma. Oncogene. 2012 Sep 20;31(38):4233–44. http://dx.doi.org/10.1038/onc.2011.580
75. Chouhan S, Singh S, Athavale D, Ramteke P, Pandey V, Joseph J, et al. Glucose induced activation of canonical Wnt signaling pathway in hepatocellular carcinoma is regulated by DKK4. Sci Rep. 2016 Jun 8;6:27558. http://dx.doi.org/10.1038/srep27558

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