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Cited by 64Wnt/β-catenin signaling in development and cancerLiver physiology and pathologyHepatocellular Carcinoma Treatment and Prognosis

Wnt signaling in liver regeneration, disease, and cancer

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Zou, Gengyi, Park, Jae-Il·2023·Clinical and Molecular Hepatology
DOI 10.3350/cmh.2022.0058PMC PMC9845677
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Abstract

The liver exhibits the highest recovery rate from acute injuries. However, in chronic liver disease, the long-term loss of hepatocytes often leads to adverse consequences such as fibrosis, cirrhosis, and liver cancer. The Wnt signaling plays a pivotal role in both liver regeneration and tumorigenesis. Therefore, manipulating the Wnt signaling has become an attractive approach to treating liver disease, including cancer. Nonetheless, given the crucial roles of Wnt signaling in physiological processes, blocking Wnt signaling can also cause several adverse effects. Recent studies have identified cancer-specific regulators of Wnt signaling, which would overcome the limitation of Wnt signaling target approaches. In this review, we discussed the role of Wnt signaling in liver regeneration, precancerous lesion, and liver cancer. Furthermore, we summarized the basic and clinical approaches of Wnt signaling blockade and proposed the therapeutic prospects of cancer-specific Wnt signaling blockade for liver cancer treatment.

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Crossref · 10.3350/cmh.2022.0058

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  • The Wnt/β-catenin signaling pathway is activated within liver sinusoidal endothelial cells in response to liver injury.

    “The Wnt/β-catenin signaling pathway is activated within LSECs in response to liver injury.”

    From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [49]

    The ‘Wnt SIGNALING IN LIVER REGENERATION’ section says endothelial cells produce Wnts during liver regeneration, but specifies that these activate Wnt/β-catenin signaling in hepatocytes. The Introduction also identifies sinusoidal endothelial cells as Wnt-ligand sources. Neither passage establishes that the pathway is activated within LSECs in response to injury; page numbers were not provided in our copy. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • The Wnt/β-catenin pathway regulates not only hepatocyte proliferation but also liver metabolism, detoxification, and immune responses.

    “Importantly, the Wnt/β-catenin pathway regulates not only hepatocyte proliferation but also liver metabolism, detoxification, and immune responses.”

    From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [49]

    The 'Wnt signaling in liver regeneration' section links Wnt/β-catenin signaling to hepatocyte proliferation, and the Concluding remarks identify a role for Wnt signaling in metabolic zonation. The Introduction mentions inflammation in liver disease, but our copy does not establish that Wnt/β-catenin regulates immune responses or detoxification. No page numbers were supplied for these passages. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Following tissue damage, β-catenin levels rise significantly, which may be linked to shear stress, and it plays a crucial role in transcription of genes essential for cell proliferation.

    “Following tissue damage, β-catenin levels rise significantly, which may be linked to shear stress, and it plays a crucial role in transcription of genes essential for cell proliferation[49].”

    From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [49]

    The Wnt SIGNALING IN LIVER REGENERATION section reports that β-catenin levels rise after partial hepatectomy, followed by nuclear translocation and expression of genes for hepatocyte proliferation. It also says shear-stressed endothelial cells produce Wnts that activate the pathway. The claim extends these liver-specific findings to tissue damage generally, which the cited passages do not establish. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • The elevation of β-catenin represents an early event in liver regeneration and significantly impacts the activation of the hepatocyte cell cycle.

    “The elevation of β-catenin represents an early event in LR and significantly impacts the activation of the hepatocyte cell cycle.”

    From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [49]

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  1. [1]Clemens MM McGill MR Apte U Mechanisms and biomarkers of liver regeneration after drug-induced liver injury Adv Pharmacol 2019 85 241 262 31307589 PMC7641498
  2. [2]Michalopoulos GK Hepatostat: liver regeneration and normal liver tissue maintenance Hepatology 2017 65 1384 1392 27997988
  3. [3]Ko S Russell JO Molina LM Monga SP Liver progenitors and adult cell plasticity in hepatic injury and repair: knowns and unknowns Annu Rev Pathol 2020 15 23 50 31399003 PMC7212705
  4. [4]Duncan AW Taylor MH Hickey RD Hanlon Newell AE Lenzi ML Olson SB The ploidy conveyor of mature hepatocytes as a source of genetic variation Nature 2010 467 707 710 20861837 PMC2967727
  5. [5]Anti M Marra G Rapaccini GL Rumi C Bussa S Fadda G DNA ploidy pattern in human chronic liver diseases and hepatic nodular lesions. Flow cytometric analysis on echoguided needle liver biopsy Cancer 1994 73 281 288 8293389
  6. [6]Duncan AW Hanlon Newell AE Smith L Wilson EM Olson SB Thayer MJ Frequent aneuploidy among normal human hepatocytes Gastroenterology 2012 142 25 28 22057114 PMC3244538
  7. [7]Siegel RL Miller KD Fuchs HE Jemal A Cancer statistics, 2022 CA Cancer J Clin 2022 72 7 33 35020204
  8. [8]Llovet JM Zucman-Rossi J Pikarsky E Sangro B Schwartz M Sherman M Hepatocellular carcinoma Nat Rev Dis Primers 2016 2 16018 27158749
  9. [9]Tortelote GG Reis RR de Almeida Mendes F Abreu JG Complexity of the Wnt/β-catenin pathway: searching for an activation model Cell Signal 2017 40 30 43 28844868
  10. [10]Xia XH Xiao CJ Shan H Facilitation of liver cancer SMCC7721 cell aging by sirtuin 4 via inhibiting JAK2/STAT3 signal pathway Eur Rev Med Pharmacol Sci 2017 21 1248 1253 28387906
  11. [11]Chen J Gingold JA Su X Immunomodulatory TGF-β signaling in hepatocellular carcinoma Trends Mol Med 2019 25 1010 1023 31353124
  12. [12]Czauderna C Castven D Mahn FL Marquardt JU Context-dependent role of NF-κB signaling in primary liver cancer-from tumor development to therapeutic implications Cancers (Basel) 2019 11 1053 31349670 PMC6721782
  13. [13]Russell JO Monga SP Wnt/β-catenin signaling in liver development, homeostasis, and pathobiology Annu Rev Pathol 2018 13 351 378 29125798 PMC5927358
  14. [14]Cheng JH She H Han YP Wang J Xiong S Asahina K Wnt antagonism inhibits hepatic stellate cell activation and liver fibrosis Am J Physiol Gastrointest Liver Physiol 2008 294 G39 G49 18006602
  15. [15]Zeng G Awan F Otruba W Muller P Apte U Tan X Wnt’er in liver: expression of Wnt and frizzled genes in mouse Hepatology 2007 45 195 204 17187422
  16. [16]Ma R Martínez-Ramírez AS Borders TL Gao F Sosa-Pineda B Metabolic and non-metabolic liver zonation is established non-synchronously and requires sinusoidal Wnts Elife 2020 9 e46206 32154783 PMC7067564
  17. [17]Monga SP β-catenin signaling and roles in liver homeostasis, injury, and tumorigenesis Gastroenterology 2015 148 1294 1310 25747274 PMC4494085
  18. [18]Nusse R Clevers H Wnt/β-catenin signaling, disease, and emerging therapeutic modalities Cell 2017 169 985 999 28575679
  19. [19]Clevers H Nusse R Wnt/β-catenin signaling and disease Cell 2012 149 1192 1205 22682243
  20. [20]Scheibner K Bakhti M Bastidas-Ponce A Lickert H Wnt signaling: implications in endoderm development and pancreas organogenesis Curr Opin Cell Biol 2019 61 48 55 31377680
  21. [21]Steinhart Z Angers S Wnt signaling in development and tissue homeostasis Development 2018 145 dev146589 29884654
  22. [22]Hu S Monga SP Wnt/-catenin signaling and liver regeneration: circuit, biology, and opportunities Gene Expr 2021 20 189 199 33472727 PMC8201651
  23. [24]Raslan AA Yoon JK WNT signaling in lung repair and regeneration Mol Cells 2020 43 774 783 32807748 PMC7528681
  24. [25]Girardi F Le Grand F Wnt signaling in skeletal muscle development and regeneration Prog Mol Biol Transl Sci 2018 153 157 179 29389515
  25. [27]Monga SP Pediaditakis P Mule K Stolz DB Michalopoulos GK Changes in WNT/beta-catenin pathway during regulated growth in rat liver regeneration Hepatology 2001 33 1098 1109 11343237 PMC1821078
  26. [28]Stolz DB Mars WM Petersen BE Kim TH Michalopoulos GK Growth factor signal transduction immediately after two-thirds partial hepatectomy in the rat Cancer Res 1999 59 3954 3960 10463591
  27. [29]Köhler C Bell AW Bowen WC Monga SP Fleig W Michalopoulos GK Expression of notch-1 and its ligand Jagged-1 in rat liver during liver regeneration Hepatology 2004 39 1056 1065 15057910 PMC1769555
  28. [31]Nikfarjam M Malcontenti-Wilson C Fanartzis M Daruwalla J Christophi C A model of partial hepatectomy in mice J Invest Surg 2004 17 291 294 15385262
  29. [32]Sadler KC Krahn KN Gaur NA Ukomadu C Liver growth in the embryo and during liver regeneration in zebrafish requires the cell cycle regulator, uhrf1 Proc Natl Acad Sci U S A 2007 104 1570 1575 17242348 PMC1785278
  30. [33]Curado S Stainier DY Anderson RM Nitroreductase-mediated cell/tissue ablation in zebrafish: a spatially and temporally controlled ablation method with applications in developmental and regeneration studies Nat Protoc 2008 3 948 954 18536643 PMC2705989
  31. [34]Teschke R Vierke W Goldermann L Carbon tetrachloride (CCl4) levels and serum activities of liver enzymes following acute CCl4 intoxication Toxicol Lett 1983 17 175 180 6623503
  32. [35]Preisegger KH Factor VM Fuchsbichler A Stumptner C Denk H Thorgeirsson SS Atypical ductular proliferation and its inhibition by transforming growth factor beta1 in the 3,5-diethoxycarbonyl-1,4-dihydrocollidine mouse model for chronic alcoholic liver disease Lab Invest 1999 79 103 109 10068199
  33. [36]Oderberg IM Goessling W Partial hepatectomy in adult zebrafish J Vis Exp 2021 170 10 3791/62349 PMC8139180 33871461
  34. [37]North TE Babu IR Vedder LM Lord AM Wishnok JS Tannenbaum SR PGE2-regulated Wnt signaling and N-acetylcysteine are synergistically hepatoprotective in zebrafish acetaminophen injury Proc Natl Acad Sci U S A 2010 107 17315 17320 20855591 PMC2951415
  35. [38]Sekine S Gutiérrez PJ Lan BY Feng S Hebrok M Liver-specific loss of beta-catenin results in delayed hepatocyte proliferation after partial hepatectomy Hepatology 2007 45 361 368 17256747
  36. [39]Goessling W North TE Lord AM Ceol C Lee S Weidinger G APC mutant zebrafish uncover a changing temporal requirement for wnt signaling in liver development Dev Biol 2008 320 161 174 18585699
  37. [41]Huch M Dorrell C Boj SF van Es JH Li VS van de Wetering M In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration Nature 2013 494 247 250 23354049 PMC3634804
  38. [42]Carmon KS Lin Q Gong X Thomas A Liu Q LGR5 interacts and cointernalizes with Wnt receptors to modulate Wnt/ β-catenin signaling Mol Cell Biol 2012 32 2054 2064 22473993 PMC3372227
  39. [43]Jho EH Zhang T Domon C Joo CK Freund JN Costantini F Wnt/beta-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway Mol Cell Biol 2002 22 1172 1183 11809808 PMC134648
  40. [44]Lustig B Jerchow B Sachs M Weiler S Pietsch T Karsten U Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors Mol Cell Biol 2002 22 1184 1193 11809809 PMC134640
  41. [45]Jung YS Jun S Kim MJ Lee SH Suh HN Lien EM TMEM9 promotes intestinal tumorigenesis through vacuolarATPase-activated Wnt/β-catenin signalling Nat Cell Biol 2018 20 1421 1433 30374053 PMC6261670
  42. [46]Jung YS Stratton SA Lee SH Kim MJ Jun S Zhang J TMEM9-v-ATPase activates Wnt/β-catenin signaling via APC lysosomal degradation for liver regeneration and tumorigenesis Hepatology 2021 73 776 794 32380568 PMC7647947
  43. [47]Kudo Y Sugimoto M Arias E Kasashima H Cordes T Linares JF PKCλ/ι loss induces autophagy, oxidative phosphorylation, and NRF2 to promote liver cancer progression Cancer Cell 2020 38 247 262.e11 32589943 PMC7423690
  44. [48]Wang Z Li Z Ye Y Xie L Li W Oxidative stress and liver cancer: etiology and therapeutic targets Oxid Med Cell Longev 2016 2016 7891574 27957239 PMC5121466
  45. [49]Funato Y Michiue T Asashima M Miki H The thioredoxinrelated redox-regulating protein nucleoredoxin inhibits Wntbeta-catenin signalling through dishevelled Nat Cell Biol 2006 8 501 508 16604061
  46. [50]Zhou T Zhou KK Lee K Gao G Lyons TJ Kowluru R The role of lipid peroxidation products and oxidative stress in activation of the canonical wingless-type MMTV integration site (WNT) pathway in a rat model of diabetic retinopathy Diabetologia 2011 54 459 468 20978740 PMC3017315
  47. [51]Sun HC Zhang W Qin LX Zhang BH Ye QH Wang L Positive serum hepatitis B e antigen is associated with higher risk of early recurrence and poorer survival in patients after curative resection of hepatitis B-related hepatocellular carcinoma J Hepatol 2007 47 684 690 17854945
  48. [52]Rein DB Wittenborn JS Weinbaum CM Sabin M Smith BD Lesesne SB Forecasting the morbidity and mortality associated with prevalent cases of pre-cirrhotic chronic hepatitis C in the United States Dig Liver Dis 2011 43 66 72 20739252
  49. [53]Yang JD Kim WR Coelho R Mettler TA Benson JT Sanderson SO Cirrhosis is present in most patients with hepatitis B and hepatocellular carcinoma Clin Gastroenterol Hepatol 2011 9 64 70 20831903 PMC3951426
  50. [54]Roudot-Thoraval F Epidemiology of hepatitis C virus infection Clin Res Hepatol Gastroenterol 2021 45 101596 33610022
  51. [55]Mavilia MG Wu GY HBV-HCV coinfection: viral interactions, management, and viral reactivation J Clin Transl Hepatol 2018 6 296 305 30271742 PMC6160312
  52. [56]Levrero M Zucman-Rossi J Mechanisms of HBV-induced hepatocellular carcinoma J Hepatol 2016 64 1 Suppl S84 S101 27084040
  53. [57]Arbuthnot P Kew M Hepatitis B virus and hepatocellular carcinoma Int J Exp Pathol 2001 82 77 100 11454100 PMC2517704
  54. [58]Neuveut C Wei Y Buendia MA Mechanisms of HBV-related hepatocarcinogenesis J Hepatol 2010 52 594 604 20185200
  55. [59]Tian X Li J Ma ZM Zhao C Wan DF Wen YM Role of hepatitis B surface antigen in the development of hepatocellular carcinoma: regulation of lymphoid enhancer-binding factor 1 J Exp Clin Cancer Res 2009 28 58 19402906 PMC2678988
  56. [60]Javanmard D Najafi M Babaei MR Karbalaie Niya MH Esghaei M Panahi M Investigation of CTNNB1 gene mutations and expression in hepatocellular carcinoma and cirrhosis in association with hepatitis B virus infection Infect Agent Cancer 2020 15 37 32514293 PMC7268324
  57. [61]Zucman-Rossi J Benhamouche S Godard C Boyault S Grimber G Balabaud C Differential effects of inactivated Axin1 and activated beta-catenin mutations in human hepatocellular carcinomas Oncogene 2007 26 774 780 16964294
  58. [62]Galy O Chemin I Le Roux E Villar S Le Calvez-Kelm F Lereau M Mutations in TP53 and CTNNB1 in relation to hepatitis B and C infections in hepatocellular carcinomas from Thailand Hepat Res Treat 2011 2011 697162 21760996 PMC3132492
  59. [63]Hsieh A Kim HS Lim SO Yu DY Jung G Hepatitis B viral X protein interacts with tumor suppressor adenomatous polyposis coli to activate Wnt/β-catenin signaling Cancer Lett 2011 300 162 172 20971552
  60. [64]Feitelson MA Duan LX Hepatitis B virus X antigen in the pathogenesis of chronic infections and the development of hepatocellular carcinoma Am J Pathol 1997 150 1141 1157 9094970 PMC1858185
  61. [65]Lau CC Sun T Ching AK He M Li JW Wong AM Viralhuman chimeric transcript predisposes risk to liver cancer development and progression Cancer Cell 2014 25 335 349 24582836
  62. [66]Moradpour D Penin F Hepatitis C virus proteins: from structure to function Curr Top Microbiol Immunol 2013 369 113 142 23463199
  63. [67]Fukutomi T Zhou Y Kawai S Eguchi H Wands JR Li J Hepatitis C virus core protein stimulates hepatocyte growth: correlation with upregulation of Wnt-1 expression Hepatology 2005 41 1096 1105 15841445
  64. [68]Liu J Ding X Tang J Cao Y Hu P Zhou F Enhancement of canonical Wnt/β-catenin signaling activity by HCV core protein promotes cell growth of hepatocellular carcinoma cells PLoS One 2011 6 e27496 22110662 PMC3216985
  65. [69]Umer M Qureshi SA Hashmi ZY Raza A Ahmad J Rahman M Promoter hypermethylation of Wnt pathway inhibitors in hepatitis C virus - induced multistep hepatocarcinogenesis Virol J 2014 11 117 24947038 PMC4076499
  66. [70]Quan H Zhou F Nie D Chen Q Cai X Shan X Hepatitis C virus core protein epigenetically silences SFRP1 and enhances HCC aggressiveness by inducing epithelial-mesenchymal transition Oncogene 2014 33 2826 2835 23770846
  67. [71]Ripoli M Barbano R Balsamo T Piccoli C Brunetti V Coco M Hypermethylated levels of E-cadherin promoter in Huh-7 cells expressing the HCV core protein Virus Res 2011 160 74 81 21640770
  68. [72]Jung YS Wang W Jun S Zhang J Srivastava M Kim MJ Deregulation of CRAD-controlled cytoskeleton initiates mucinous colorectal cancer via β-catenin Nat Cell Biol 2018 20 1303 1314 30361697 PMC6261439
  69. [73]Liu Y El-Serag HB Jiao L Lee J Moore D Franco LM WNT signaling pathway gene polymorphisms and risk of hepatic fibrosis and inflammation in HCV-infected patients PLoS One 2013 8 e84407 24386373 PMC3875538
  70. [74]Takahara Y Takahashi M Zhang QW Wagatsuma H Mori M Tamori A Serial changes in expression of functionally clustered genes in progression of liver fibrosis in hepatitis C patients World J Gastroenterol 2008 14 2010 2022 18395900 PMC2701521
  71. [75]Mercer KE Hennings L Ronis MJ Alcohol consumption, Wnt/ β-catenin signaling, and hepatocarcinogenesis Adv Exp Med Biol 2015 815 185 195 25427908 PMC5600155
  72. [76]Kim HS Kim SJ Bae J Wang Y Park SY Min YS The p90rsk-mediated signaling of ethanol-induced cell proliferation in HepG2 cell line Korean J Physiol Pharmacol 2016 20 595 603 27847436 PMC5106393
  73. [77]Wang F Yang JL Yu KK Xu M Xu YZ Chen L Activation of the NF-κB pathway as a mechanism of alcohol enhanced progression and metastasis of human hepatocellular carcinoma Mol Cancer 2015 14 10 25622857 PMC4320626
  74. [78]Yang CF Zhong YJ Ma Z Li L Shi L Chen L NOX4/ROS mediate ethanol-induced apoptosis via MAPK signal pathway in L-02 cells Int J Mol Med 2018 41 2306 2316 29336467
  75. [79]Zhang C Ellis JL Yin C Inhibition of vascular endothelial growth factor signaling facilitates liver repair from acute ethanol-induced injury in zebrafish Dis Model Mech 2016 9 1383 1396 27562099 PMC5117223
  76. [80]Mandrekar P Ambade A Lim A Szabo G Catalano D An essential role for monocyte chemoattractant protein-1 in alcoholic liver injury: regulation of proinflammatory cytokines and hepatic steatosis in mice Hepatology 2011 54 2185 2197 21826694 PMC3342822
  77. [81]Yuen MF Tanaka Y Fong DY Fung J Wong DK Yuen JC Independent risk factors and predictive score for the development of hepatocellular carcinoma in chronic hepatitis B J Hepatol 2009 50 80 88 18977053
  78. [82]Wong VW Chu WC Wong GL Chan RS Chim AM Ong A Prevalence of non-alcoholic fatty liver disease and advanced fibrosis in Hong Kong Chinese: a population study using proton-magnetic resonance spectroscopy and transient elastography Gut 2012 61 409 415 21846782
  79. [83]Bhala N Angulo P van der Poorten D Lee E Hui JM Saracco G The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: an international collaborative study Hepatology 2011 54 1208 1216 21688282 PMC3238674
  80. [84]Farrell GC van Rooyen D Gan L Chitturi S NASH is an inflammatory disorder: pathogenic, prognostic and therapeutic implications Gut Liver 2012 6 149 171 22570745 PMC3343154
  81. [86]Chettouh H Lequoy M Fartoux L Vigouroux C DesboisMouthon C Hyperinsulinaemia and insulin signalling in the pathogenesis and the clinical course of hepatocellular carcinoma Liver Int 2015 35 2203 2217 26123841
  82. [87]Jonatan D Spence JR Method AM Kofron M Sinagoga K Haataja L Sox17 regulates insulin secretion in the normal and pathologic mouse β cell PLoS One 2014 9 e104675 25144761 PMC4140688
  83. [88]Jia Y Yang Y Liu S Herman JG Lu F Guo M SOX17 antagonizes WNT/β-catenin signaling pathway in hepatocellular carcinoma Epigenetics 2010 5 743 749 20716954
  84. [89]Ackers I Malgor R Interrelationship of canonical and noncanonical Wnt signalling pathways in chronic metabolic diseases Diab Vasc Dis Res 2018 15 3 13 29113510 PMC5752873
  85. [90]Wang S Song K Srivastava R Dong C Go GW Li N Nonalcoholic fatty liver disease induced by noncanonical Wnt and its rescue by Wnt3a FASEB J 2015 29 3436 3445 25917329 PMC4511193
  86. [91]Kew MC Synergistic interaction between aflatoxin B1 and hepatitis B virus in hepatocarcinogenesis Liver Int 2003 23 405 409 14986813
  87. [92]Devereux TR Stern MC Flake GP Yu MC Zhang ZQ London SJ CTNNB1 mutations and beta-catenin protein accumulation in human hepatocellular carcinomas associated with high exposure to aflatoxin B1 Mol Carcinog 2001 31 68 73 11429783
  88. [93]Yang JD Hainaut P Gores GJ Amadou A Plymoth A Roberts LR A global view of hepatocellular carcinoma: trends, risk, prevention and management Nat Rev Gastroenterol Hepatol 2019 16 589 604 31439937 PMC6813818
  89. [94]Bengochea A de Souza MM Lefrançois L Le Roux E Galy O Chemin I Common dysregulation of Wnt/frizzled receptor elements in human hepatocellular carcinoma Br J Cancer 2008 99 143 150 18577996 PMC2453022
  90. [95]Boyault S Rickman DS de Reyniès A Balabaud C Rebouissou S Jeannot E Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets Hepatology 2007 45 42 52 17187432
  91. [96]Fodde R Smits R Clevers H APC, signal transduction and genetic instability in colorectal cancer Nat Rev Cancer 2001 1 55 67 11900252
  92. [97]Khemlina G Ikeda S Kurzrock R The biology of hepatocellular carcinoma: implications for genomic and immune therapies Mol Cancer 2017 16 149 28854942 PMC5577674
  93. [98]Satoh S Daigo Y Furukawa Y Kato T Miwa N Nishiwaki T AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1 Nat Genet 2000 24 245 250 10700176
  94. [99]Park JY Park WS Nam SW Kim SY Lee SH Yoo NJ Mutations of beta-catenin and AXIN I genes are a late event in human hepatocellular carcinogenesis Liver Int 2005 25 70 76 15698401
  95. [100]Zhu M Lu T Jia Y Luo X Gopal P Li L Somatic mutations increase hepatic clonal fitness and regeneration in chronic liver disease Cell 2019 177 608 621.e12 30955891 PMC6519461
  96. [101]Marquardt JU Seo D Andersen JB Gillen MC Kim MS Conner EA Sequential transcriptome analysis of human liver cancer indicates late stage acquisition of malignant traits J Hepatol 2014 60 346 353 24512821 PMC3943679
  97. [102]Rebouissou S Nault JC Advances in molecular classification and precision oncology in hepatocellular carcinoma J Hepatol 2020 72 215 229 31954487
  98. [103]Abitbol S Dahmani R Coulouarn C Ragazzon B Mlecnik B Senni N AXIN deficiency in human and mouse hepatocytes induces hepatocellular carcinoma in the absence of β-catenin activation J Hepatol 2018 68 1203 1213 29525529
  99. [104]Lazaridis KN Gores GJ Cholangiocarcinoma Boyer TD Manns MP Sanyal AJ Zakim and Boyer’s Hepatology 6th ed Philadelphia Saunders 2012 1032 1044
  100. [105]Boulter L Guest RV Kendall TJ Wilson DH Wojtacha D Robson AJ WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited J Clin Invest 2015 125 1269 1285 25689248 PMC4362247
  101. [106]Chen W Liang J Huang L Cai J Lei Y Lai J Characterizing the activation of the Wnt signaling pathway in hilar cholangiocarcinoma using a tissue microarray approach Eur J Histochem 2016 60 2536 26972709 PMC4800245
  102. [107]Banales JM Marin JJG Lamarca A Rodrigues PM Khan SA Roberts LR Cholangiocarcinoma 2020: the next horizon in mechanisms and management Nat Rev Gastroenterol Hepatol 2020 17 557 588 32606456 PMC7447603
  103. [108]Vaquero J Guedj N Clapéron A Nguyen Ho-Bouldoires TH Paradis V Fouassier L Epithelial-mesenchymal transition in cholangiocarcinoma: from clinical evidence to regulatory networks J Hepatol 2017 66 424 441 27686679
  104. [109]Nitta T Mitsuhashi T Hatanaka Y Miyamoto M Oba K Tsuchikawa T Prognostic significance of epithelialmesenchymal transition-related markers in extrahepatic cholangiocarcinoma: comprehensive immunohistochemical study using a tissue microarray Br J Cancer 2014 111 1363 1372 25077440 PMC4183847
  105. [110]Chaw SY Abdul Majeed A Dalley AJ Chan A Stein S Farah CS Epithelial to mesenchymal transition (EMT) biomarkers--E-cadherin, beta-catenin, APC and vimentin--in oral squamous cell carcinogenesis and transformation Oral Oncol 2012 48 997 1006 22704062
  106. [111]Valenta T Hausmann G Basler K The many faces and functions of β-catenin EMBO J 2012 31 2714 2736 22617422 PMC3380220
  107. [112]Zhang GF Qiu L Yang SL Wu JC Liu TJ Wnt/β-catenin signaling as an emerging potential key pharmacological target in cholangiocarcinoma Biosci Rep 2020 40 BSR20193353 32140709 PMC7953494
  108. [113]Xue W Dong B Zhao Y Wang Y Yang C Xie Y Upregulation of TTYH3 promotes epithelial-to-mesenchymal transition through Wnt/β-catenin signaling and inhibits apoptosis in cholangiocarcinoma Cell Oncol (Dordr) 2021 44 1351 1361 34796468 PMC12980733
  109. [114]Carrillo-Reixach J Torrens L Simon-Coma M Royo L Domingo-Sàbat M Abril-Fornaguera J Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications J Hepatol 2020 73 328 341 32240714 PMC12452110
  110. [115]Gupta K Rane S Das A Marwaha RK Menon P Rao KL Relationship of β-catenin and postchemotherapy histopathologic changes with overall survival in patients with hepatoblastoma J Pediatr Hematol Oncol 2012 34 e320 e328 22735888
  111. [116]Crippa S Ancey PB Vazquez J Angelino P Rougemont AL Guettier C Mutant CTNNB1 and histological heterogeneity define metabolic subtypes of hepatoblastoma EMBO Mol Med 2017 9 1589 1604 28923827 PMC5666308
  112. [117]López-Terrada D Gunaratne PH Adesina AM Pulliam J Hoang DM Nguyen Y Histologic subtypes of hepatoblastoma are characterized by differential canonical Wnt and notch pathway activation in DLK+ precursors Hum Pathol 2009 40 783 794 19200579
  113. [118]Taniguchi K Roberts LR Aderca IN Dong X Qian C Murphy LM Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas Oncogene 2002 21 4863 4871 12101426
  114. [119]Shah K Panchal S Patel B Porcupine inhibitors: novel and emerging anti-cancer therapeutics targeting the Wnt signaling pathway Pharmacol Res 2021 167 105532 33677106
  115. [120]Liu J Pan S Hsieh MH Ng N Sun F Wang T Targeting Wnt-driven cancer through the inhibition of porcupine by LGK974 Proc Natl Acad Sci U S A 2013 110 20224 20229 24277854 PMC3864356
  116. [121]Madan B Ke Z Harmston N Ho SY Frois AO Alam J Wnt addiction of genetically defined cancers reversed by PORCN inhibition Oncogene 2016 35 2197 2207 26257057 PMC4650263
  117. [122]Proffitt KD Madan B Ke Z Pendharkar V Ding L Lee MA Pharmacological inhibition of the Wnt acyltransferase PORCN prevents growth of WNT-driven mammary cancer Cancer Res 2013 73 502 507 23188502
  118. [123]Wang W Xu L Liu P Jairam K Yin Y Chen K Blocking Wnt secretion reduces growth of hepatocellular carcinoma cell lines mostly independent of β-catenin signaling Neoplasia 2016 18 711 723 27851986 PMC5110474
  119. [124]Barrott JJ Cash GM Smith AP Barrow JR Murtaugh LC Deletion of mouse porcn blocks Wnt ligand secretion and reveals an ectodermal etiology of human focal dermal hypoplasia/Goltz syndrome Proc Natl Acad Sci U S A 2011 108 12752 12757 21768372 PMC3150921
  120. [125]Liu W Shaver TM Balasa A Ljungberg MC Wang X Wen S Deletion of porcn in mice leads to multiple developmental defects and models human focal dermal hypoplasia (Goltz syndrome) PLoS One 2012 7 e32331 22412863 PMC3295752
  121. [126]Funck-Brentano T Nilsson KH Brommage R Henning P Lerner UH Koskela A Porcupine inhibitors impair trabecular and cortical bone mass and strength in mice J Endocrinol 2018 238 13 23 29720540 PMC5987170
  122. [127]He X Semenov M Tamai K Zeng X LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way Development 2004 131 1663 1677 15084453
  123. [128]Wei W Chua MS Grepper S So SK Blockade of Wnt-1 signaling leads to anti-tumor effects in hepatocellular carcinoma cells Mol Cancer 2009 8 76 19778454 PMC2759906
  124. [129]Cruciat CM Niehrs C Secreted and transmembrane wnt inhibitors and activators Cold Spring Harb Perspect Biol 2013 5 a015081 23085770 PMC3578365
  125. [130]Niehrs C Function and biological roles of the Dickkopf family of Wnt modulators Oncogene 2006 25 7469 7481 17143291
  126. [131]Kawazoe M Kaneko K Nanki T Glucocorticoid therapy suppresses Wnt signaling by reducing the ratio of serum Wnt3a to Wnt inhibitors, sFRP-1 and Wif-1 Clin Rheumatol 2021 40 2947 2954 33420868
  127. [132]Hu J Dong A Fernandez-Ruiz V Shan J Kawa M MartínezAnsó E Blockade of Wnt signaling inhibits angiogenesis and tumor growth in hepatocellular carcinoma Cancer Res 2009 69 6951 6959 19690140
  128. [133]Glinka A Wu W Delius H Monaghan AP Blumenstock C Niehrs C Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction Nature 1998 391 357 362 9450748
  129. [134]Caneparo L Huang YL Staudt N Tada M Ahrendt R Kazanskaya O Dickkopf-1 regulates gastrulation movements by coordinated modulation of Wnt/beta catenin and Wnt/PCP activities, through interaction with the Dally-like homolog Knypek Genes Dev 2007 21 465 480 17322405 PMC1804334
  130. [135]Cha SW Tadjuidje E Tao Q Wylie C Heasman J Wnt5a and Wnt11 interact in a maternal Dkk1-regulated fashion to activate both canonical and non-canonical signaling in Xenopus axis formation Development 2008 135 3719 3729 18927149
  131. [136]Nambotin SB Lefrancois L Sainsily X Berthillon P Kim M Wands JR Pharmacological inhibition of frizzled-7 displays anti-tumor properties in hepatocellular carcinoma J Hepatol 2011 54 288 299 21055837
  132. [137]Jimeno A Gordon M Chugh R Messersmith W Mendelson D Dupont J A first-in-human phase I study of the anticancer stem cell agent ipafricept (OMP-54F28), a decoy receptor for wnt ligands, in patients with advanced solid tumors Clin Cancer Res 2017 23 7490 7497 28954784
  133. [138]Moore KN Gunderson CC Sabbatini P McMeekin DS MantiaSmaldone G Burger RA A phase 1b dose escalation study of ipafricept (OMP54F28) in combination with paclitaxel and carboplatin in patients with recurrent platinumsensitive ovarian cancer Gynecol Oncol 2019 154 294 301 31174889 PMC7397408
  134. [140]Wei W Chua MS Grepper S So SK Soluble frizzled-7 receptor inhibits Wnt signaling and sensitizes hepatocellular carcinoma cells towards doxorubicin Mol Cancer 2011 10 16 21314951 PMC3050858
  135. [141]Fischer MM Cancilla B Yeung VP Cattaruzza F Chartier C Murriel CL WNT antagonists exhibit unique combinatorial antitumor activity with taxanes by potentiating mitotic cell death Sci Adv 2017 3 e1700090 28691093 PMC5479655
  136. [143]Davis SL Cardin DB Shahda S Lenz HJ Dotan E O’Neil BH A phase 1b dose escalation study of Wnt pathway inhibitor vantictumab in combination with nab-paclitaxel and gemcitabine in patients with previously untreated metastatic pancreatic cancer Invest New Drugs 2020 38 821 830 31338636 PMC7211194
  137. [145]Gupta PB Onder TT Jiang G Tao K Kuperwasser C Weinberg RA Identification of selective inhibitors of cancer stem cells by high-throughput screening Cell 2009 138 645 659 19682730 PMC4892125
  138. [146]Huczynski A Salinomycin: a new cancer drug candidate Chem Biol Drug Des 2012 79 235 238 22145602
  139. [147]Lu D Choi MY Yu J Castro JE Kipps TJ Carson DA Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells Proc Natl Acad Sci U S A 2011 108 13253 13257 21788521 PMC3156152
  140. [148]Niwa AM Semprebon SC D’Epiro GFR Marques LA Zanetti TA Mantovani MS Salinomycin induces cell cycle arrest and apoptosis and modulates hepatic cytochrome P450 mRNA expression in HepG2/C3a cells Toxicol Mech Methods 2022 32 341 351 34806536
  141. [149]Liu Q Sun J Luo Q Ju Y Song G Salinomycin suppresses tumorigenicity of liver cancer stem cells and Wnt/beta-catenin signaling Curr Stem Cell Res Ther 2021 16 630 637 31971116
  142. [150]Huang SM Mishina YM Liu S Cheung A Stegmeier F Michaud GA Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling Nature 2009 461 614 620 19759537
  143. [151]Clevers H Wnt/beta-catenin signaling in development and disease Cell 2006 127 469 480 17081971
  144. [152]Rubinfeld B Albert I Porfiri E Fiol C Munemitsu S Polakis P Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly Science 1996 272 1023 1026 8638126
  145. [153]Ma Y Zhang P Zhang Q Wang X Miao Q Lyu X Dihydroartemisinin suppresses proliferation, migration, the Wnt/ β-catenin pathway and EMT via TNKS in gastric cancer Oncol Lett 2021 22 688 34457043 PMC8358739
  146. [154]Ma Z Han C Xia W Wang S Li X Fang P circ5615 functions as a ceRNA to promote colorectal cancer progression by upregulating TNKS Cell Death Dis 2020 11 356 32393760 PMC7214456
  147. [155]Ma L Wang X Jia T Wei W Chua MS So S Tankyrase inhibitors attenuate WNT/β-catenin signaling and inhibit growth of hepatocellular carcinoma cells Oncotarget 2015 6 25390 25401 26246473 PMC4694839
  148. [156]Wu X Luo F Li J Zhong X Liu K Tankyrase 1 inhibitior XAV939 increases chemosensitivity in colon cancer cell lines via inhibition of the Wnt signaling pathway Int J Oncol 2016 48 1333 1340 26820603 PMC4777596
  149. [157]Huang J Qu Q Guo Y Xiang Y Feng D Tankyrases/β-catenin signaling pathway as an anti-proliferation and anti-metastatic target in hepatocarcinoma cell lines J Cancer 2020 11 432 440 31897238 PMC6930431
  150. [158]Ghany MG Strader DB Thomas DL Seeff LB Diagnosis, management, and treatment of hepatitis C: an update Hepatology 2009 49 1335 1374 19330875 PMC7477893
  151. [159]Lee D Chung YH Kim JA Park WH Jin YJ Shim JH Safety and efficacy of adjuvant pegylated interferon therapy for metastatic tumor antigen 1-positive hepatocellular carcinoma Cancer 2013 119 2239 2246 23564564
  152. [160]Thompson MD Dar MJ Monga SP Pegylated interferon alpha targets Wnt signaling by inducing nuclear export of β-catenin J Hepatol 2011 54 506 512 21093092 PMC3052972
  153. [161]Deng J Hua L Han T Tian M Wang D Tang H The CREB-binding protein inhibitor ICG-001: a promising therapeutic strategy in sporadic meningioma with NF2 mutations Neurooncol Adv 2020 2 vdz055 32642722 PMC7212891
  154. [162]Takahashi-Yanaga F Kahn M Targeting Wnt signaling: can we safely eradicate cancer stem cells? Clin Cancer Res 2010 16 3153 3162 20530697
  155. [163]Delgado ER Yang J So J Leimgruber S Kahn M Ishitani T Identification and characterization of a novel smallmolecule inhibitor of β-catenin signaling Am J Pathol 2014 184 2111 2122 24819961 PMC4076560
  156. [164]Wei W Chua MS Grepper S So S Small molecule antagonists of Tcf4/beta-catenin complex inhibit the growth of HCC cells in vitro and in vivo Int J Cancer 2010 126 2426 2436 19662654
  157. [165]Gedaly R Galuppo R Daily MF Shah M Maynard E Chen C Targeting the Wnt/β-catenin signaling pathway in liver cancer stem cells and hepatocellular carcinoma cell lines with FH535 PLoS One 2014 9 e99272 24940873 PMC4062395
  158. [166]Handeli S Simon JA A small-molecule inhibitor of Tcf/beta-catenin signaling down-regulates PPARgamma and PPARdelta activities Mol Cancer Ther 2008 7 521 529 18347139
  159. [167]Gwak J Lee JH Chung YH Song GY Oh S Small moleculebased promotion of PKCα-mediated β-catenin degradation suppresses the proliferation of CRT-positive cancer cells PLoS One 2012 7 e46697 23071615 PMC3465275
  160. [168]Chen X Yang J Evans PM Liu C Wnt signaling: the good and the bad Acta Biochim Biophys Sin (Shanghai) 2008 40 577 594 18604449 PMC2532600
  161. [169]Chen D Xie R Shu B Landay AL Wei C Reiser J Wnt signaling in bone, kidney, intestine, and adipose tissue and interorgan interaction in aging Ann N Y Acad Sci 2019 1442 48 60 30101565 PMC6372353
  162. [170]Behari J The Wnt/β-catenin signaling pathway in liver biology and disease Expert Rev Gastroenterol Hepatol 2010 4 745 756 21108594 PMC3298845
  163. [171]Bowman EJ Graham LA Stevens TH Bowman BJ The bafilomycin/concanamycin binding site in subunit c of the v-ATPases from Neurospora crassa and Saccharomyces cerevisiae J Biol Chem 2004 279 33131 33138 15180988
  164. [172]Huss M Ingenhorst G König S Gassel M Dröse S Zeeck A Concanamycin A, the specific inhibitor of v-ATPases, binds to the v(o) subunit c J Biol Chem 2002 277 40544 40548 12186879
  165. [173]Capurro M Martin T Shi W Filmus J Glypican-3 binds to frizzled and plays a direct role in the stimulation of canonical Wnt signaling J Cell Sci 2014 127 Pt 7 1565 1575 24496449
  166. [174]Guo M Zhang H Zheng J Liu Y Glypican-3: a new target for diagnosis and treatment of hepatocellular carcinoma J Cancer 2020 11 2008 2021 32127929 PMC7052944
  167. [175]Capurro MI Xiang YY Lobe C Filmus J Glypican-3 promotes the growth of hepatocellular carcinoma by stimulating canonical Wnt signaling Cancer Res 2005 65 6245 6254 16024626
  168. [176]Gao W Kim H Feng M Phung Y Xavier CP Rubin JS Inactivation of Wnt signaling by a human antibody that recognizes the heparan sulfate chains of glypican-3 for liver cancer therapy Hepatology 2014 60 576 587 24492943 PMC4083010

Cited by

Sorted by citations

Authors
Zou, G., & Park, J.-I.
Affiliations
The University of Texas MD Anderson Cancer Center (US)
Corresponding author
Zou, Gengyi
ORCID
Venue
Clinical and Molecular Hepatology
Publisher
The Korean Association for the Study of the Liver
Published
2023-01-01
Volume
29
Issue
1
Pages
33-50
ISSN
  • 2287-2728 (ISSN-L)
  • 2287-285X
DOI
10.3350/cmh.2022.0058
PMC
PMC9845677
OpenAlex
W4283789381
Cited by
64
References
4
Citations by year
2026: 9 · 2025: 26 · 2024: 18 · 2023: 11
FWCI
1.43
Type
journal article
Language
en
Open access
Licence
Locations
  • Clinical and Molecular Hepatology (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Cancer Prevention and Research Institute of Texas (RP200315)
  • National Cancer Institute (CA193297, CA256207)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
Keywords
Wnt signaling, liver regeneration, chronic liver disease, liver cancer, hepatocellular carcinoma, liver fibrosis, liver cirrhosis, precancerous lesions, hepatocyte loss
MeSH terms
Humans, Liver Cirrhosis, Liver Neoplasms, Liver Regeneration, beta Catenin, Wnt Signaling Pathway

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