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Volume 40 Issue 5
May  2024
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Article Navigation >  Journal of Clinical Hepatology  > 2024  >  40(5): 1050-1056

The relationship between the Wnt signaling pathway and liver regeneration and its role in liver diseases

DOI: 10.12449/JCH240529
  • 1.

    Graduate School of Guangxi University of Chinese Medicine，Nanning 530001，China

  • 2a..

    Key Laboratory of Traditional Chinese Medicine Clinical Research

  • 2b..

    Guangxi Key Laboratory of Molecular Biology in Traditional Chinese Medicine Prevention and Treatment，The First Affiliated Hospital of Guangxi University of Chinese Medicine，Nanning 530023，China

Research funding:

Natioanal Natural Science Foundation Project (81960841);

Natioanal Natural Science Foundation Project (82274434);

Guangxi Natural Science Foundation Project (2020GXNSFBA297115);

Guangxi Natural Science Foundation Project (2023GXNSFAA026176);

Guangxi Natual Science Foundation Innovation Research Team Project (2020GXNSFAA297070);

Guangxi University Young and Middle School Teachers’ Basic Research Ability Enhancement Project (2022KY0299);

Innovation Project of General Post graduates in Guangxi University of Traditional Chinese Medicine (YCSY2022024)

More Information
  • Corresponding author: LAN Yanmei， lanyanmeixueshu@163.com （ORCID： 0000-0001-9304-0594）
  • Received Date: 2023-08-28
  • Accepted Date: 2023-10-12
  • Published Date: 2024-05-25
    Abstract
  • The Wnt signaling pathway plays an important role in maintaining liver homeostasis and liver regeneration. In healthy livers， the Wnt signaling pathway is mostly inactive， but it is continuously overactivated during cell renewal or regeneration processes， as well as in certain pathological conditions， diseases， precancerous states， and cancers. Persistent liver cell injury often leads to chronic liver diseases such as liver fibrosis， liver cirrhosis， and liver cancer. This article summarizes the basic structural features of the Wnt signaling pathway and analyzes its important role in the pathological progression of various liver diseases， so as to provide new ideas for the prevention and treatment of liver diseases in clinical practice.

     

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  • [1]
    TREFTS E, GANNON M, WASSERMAN DH. The liver[J]. Curr Biol, 2017, 27( 21): R1147- R1151. DOI: 10.1016/j.cub.2017.09.019.
    [2]
    BAJAJ JS. Alcohol, liver disease and the gut microbiota[J]. Nat Rev Gastroenterol Hepatol, 2019, 16( 4): 235- 246. DOI: 10.1038/s41575-018-0099-1.
    [3]
    MANDATO C, di NUZZI A, VAJRO P. Nutrition and liver disease[J]. Nutrients, 2017, 10( 1): 9. DOI: 10.3390/nu10010009.
    [4]
    XIAO J, WANG F, WONG NK, et al. Global liver disease burdens and research trends: Analysis from a Chinese perspective[J]. J Hepatol, 2019, 71( 1): 212- 221. DOI: 10.1016/j.jhep.2019.03.004.
    [5]
    ASRANI SK, DEVARBHAVI H, EATON J, et al. Burden of liver diseases in the world[J]. J Hepatol, 2019, 70( 1): 151- 171. DOI: 10.1016/j.jhep.2018.09.014.
    [6]
    NUSSE R, CLEVERS H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities[J]. Cell, 2017, 169( 6): 985- 999. DOI: 10.1016/j.cell.2017.05.016.
    [7]
    LOH KM, van AMERONGEN R, NUSSE R. Generating cellular diversity and spatial form: Wnt signaling and the evolution of multicellular animals[J]. Dev Cell, 2016, 38( 6): 643- 655. DOI: 10.1016/j.devcel.2016.08.011.
    [8]
    NAPOLITANO T, SILVANO S, AYACHI C, et al. Wnt pathway in pancreatic development and pathophysiology[J]. Cells, 2023, 12( 4): 565. DOI: 10.3390/cells12040565.
    [9]
    RASLAN AA, YOON JK. WNT signaling in lung repair and regeneration[J]. Mol Cells, 2020, 43( 9): 774- 783. DOI: 10.14348/molcells.2020.0059.
    [10]
    STEINHART Z, ANGERS S. Wnt signaling in development and tissue homeostasis[J]. Development, 2018, 145( 11): dev146589. DOI: 10.1242/dev.146589.
    [11]
    ZHAN T, RINDTORFF N, BOUTROS M. Wnt signaling in cancer[J]. Oncogene, 2017, 36( 11): 1461- 1473. DOI: 10.1038/onc.2016.304.
    [12]
    CLEVERS H, NUSSE R. Wnt/β-catenin signaling and disease[J]. Cell, 2012, 149( 6): 1192- 1205. DOI: 10.1016/j.cell.2012.05.012.
    [13]
    MONGA SP, PEDIADITAKIS P, MULE K, et al. Changes in WNT/beta-catenin pathway during regulated growth in rat liver regeneration[J]. Hepatology, 2001, 33( 5): 1098- 1109. DOI: 10.1053/jhep.2001.23786.
    [14]
    CHEN TY, OH S, GREGORY S, et al. Single-cell omics analysis reveals functional diversification of hepatocytes during liver regeneration[J]. JCI Insight, 2020, 5( 22): e141024. DOI: 10.1172/jci.insight.141024.
    [15]
    APTE U, THOMPSON MD, CUI SS, et al. Wnt/beta-catenin signaling mediates oval cell response in rodents[J]. Hepatology, 2008, 47( 1): 288- 295. DOI: 10.1002/hep.21973.
    [16]
    NELSEN CJ, RICKHEIM DG, TIMCHENKO NA, et al. Transient expression of cyclin D1 is sufficient to promote hepatocyte replication and liver growth invivo[J]. Cancer Res, 2001, 61( 23): 8564- 8568.
    [17]
    TAN XP, BEHARI J, CIEPLY B, et al. Conditional deletion of beta-catenin reveals its role in liver growth and regeneration[J]. Gastroenterology, 2006, 131( 5): 1561- 1572. DOI: 10.1053/j.gastro.2006.08.042.
    [18]
    PLANAS-PAZ L, ORSINI V, BOULTER L, et al. The RSPO-LGR4/5-ZNRF3/RNF43 module controls liver zonation and size[J]. Nat Cell Biol, 2016, 18( 5): 467- 479. DOI: 10.1038/ncb3337.
    [19]
    SUN TL, PIKIOLEK M, ORSINI V, et al. AXIN2+ pericentral hepatocytes have limited contributions to liver homeostasis and regeneration[J]. Cell Stem Cell, 2020, 26( 1): 97- 107. e 6. DOI: 10.1016/j.stem.2019.10.011.
    [20]
    JHO EH, ZHANG T, DOMON C, et al. Wnt/beta-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway[J]. Mol Cell Biol, 2002, 22( 4): 1172- 1183. DOI: 10.1128/MCB.22.4.1172-1183.2002.
    [21]
    LUSTIG B, JERCHOW B, SACHS M, et al. Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors[J]. Mol Cell Biol, 2002, 22( 4): 1184- 1193. DOI: 10.1128/MCB.22.4.1184-1193.2002.
    [22]
    JUNG YS, JUN S, KIM MJ, et al. TMEM9 promotes intestinal tumorigenesis through vacuolar-ATPase-activated Wnt/β-catenin signalling[J]. Nat Cell Biol, 2018, 20( 12): 1421- 1433. DOI: 10.1038/s41556-018-0219-8.
    [23]
    HENDERSON NC, RIEDER F, WYNN TA. Fibrosis: From mechanisms to medicines[J]. Nature, 2020, 587( 7835): 555- 566. DOI: 10.1038/s41586-020-2938-9.
    [24]
    SEKI E, SCHWABE RF. Hepatic inflammation and fibrosis: Functional links and key pathways[J]. Hepatology, 2015, 61( 3): 1066- 1079. DOI: 10.1002/hep.27332.
    [25]
    GE WS, WANG YJ, WU JX, et al. β-catenin is overexpressed in hepatic fibrosis and blockage of Wnt/β-catenin signaling inhibits hepatic stellate cell activation[J]. Mol Med Rep, 2014, 9( 6): 2145- 2151. DOI: 10.3892/mmr.2014.2099.
    [26]
    XIONG WJ, HU LJ, JIAN YC, et al. Wnt5a participates in hepatic stellate cell activation observed by gene expression profile and functional assays[J]. World J Gastroenterol, 2012, 18( 15): 1745- 1752. DOI: 10.3748/wjg.v18.i15.1745.
    [27]
    MYUNG SJ, YOON JH, GWAK GY, et al. Wnt signaling enhances the activation and survival of human hepatic stellate cells[J]. FEBS Lett, 2007, 581( 16): 2954- 2958. DOI: 10.1016/j.febslet.2007.05.050.
    [28]
    TOKUNAGA Y, OSAWA Y, OHTSUKI T, et al. Selective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model[J]. Sci Rep, 2017, 7( 1): 325. DOI: 10.1038/s41598-017-00282-w.
    [29]
    IRVINE KM, CLOUSTON AD, GADD VL, et al. Deletion of Wntless in myeloid cells exacerbates liver fibrosis and the ductular reaction in chronic liver injury[J]. Fibrogenesis Tissue Repair, 2015, 8: 19. DOI: 10.1186/s13069-015-0036-7.
    [30]
    PREZIOSI ME, SINGH S, VALORE EV, et al. Mice lacking liver-specific β‍-catenin develop steatohepatitis and fibrosis after iron overload[J]. J Hepatol, 2017, 67( 2): 360- 369. DOI: 10.1016/j.jhep.2017.03.012.
    [31]
    GEH D, ANSTEE QM, REEVES HL. NAFLD-associated HCC: Progress and opportunities[J]. J Hepatocell Carcinoma, 2021, 8: 223- 239. DOI: 10.2147/JHC.S272213.
    [32]
    MONGA SP. β-catenin signaling and roles in liver homeostasis, injury, and tumorigenesis[J]. Gastroenterology, 2015, 148( 7): 1294- 1310. DOI: 10.1053/j.gastro.2015.02.056.
    [33]
    SEO MH, LEE JM, HONG SW, et al. Exendin-4 inhibits hepatic lipogenesis by increasing β-catenin signaling[J]. PLoS One, 2016, 11( 12): e0166913. DOI: 10.1371/journal.pone.0166913.
    [34]
    DEBEBE A, MEDINA V, CHEN CY, et al. Wnt/β-catenin activation and macrophage induction during liver cancer development following steatosis[J]. Oncogene, 2017, 36( 43): 6020- 6029. DOI: 10.1038/onc.2017.207.
    [35]
    LIU SG, YEH TH, SINGH VP, et al. β-catenin is essential for ethanol metabolism and protection against alcohol-mediated liver steatosis in mice[J]. Hepatology, 2012, 55( 3): 931- 940. DOI: 10.1002/hep.24766.
    [36]
    GO GW, SRIVASTAVA R, HERNANDEZ-ONO A, et al. The combined hyperlipidemia caused by impaired Wnt-LRP6 signaling is reversed by Wnt3a rescue[J]. Cell Metab, 2014, 19( 2): 209- 220. DOI: 10.1016/j.cmet.2013.11.023.
    [37]
    CARPINO G, NOBILI V, RENZI A, et al. Macrophage activation in pediatric nonalcoholic fatty liver disease(NAFLD) correlates with hepatic progenitor cell response via Wnt3a pathway[J]. PLoS One, 2016, 11( 6): e0157246. DOI: 10.1371/journal.pone.0157246.
    [38]
    Chinese Society of Hepatology, Chinese Medical Association. Guideline on the management of cholestasis liver diseases[J]. J Clin Hepatol, 2022, 38( 1): 62- 69. DOI: 10.3760/cma.j.cn112138-20211112-00795.

    中华医学会肝病学分会. 胆汁淤积性肝病管理指南(2021年)[J]. 临床肝胆病杂志, 2022, 38( 1): 62- 69. DOI: 10.3760/cma.j.cn112138-20211112-00795.
    [39]
    YEH TH, KRAULAND L, SINGH V, et al. Liver-specific β‍-catenin knockout mice have bile canalicular abnormalities, bile secretory defect, and intrahepatic cholestasis[J]. Hepatology, 2010, 52( 4): 1410- 1419. DOI: 10.1002/hep.23801.
    [40]
    LEMBERGER UJ, FUCHS CD, KARER M, et al. Hepatocyte specific expression of an oncogenic variant of β-catenin results in cholestatic liver disease[J]. Oncotarget, 2016, 7( 52): 86985- 86998. DOI: 10.18632/oncotarget.13521.
    [41]
    SHACKEL NA, MCGUINNESS PH, ABBOTT CA, et al. Identification of novel molecules and pathogenic pathways in primary biliary cirrhosis: CDNA array analysis of intrahepatic differential gene expression[J]. Gut, 2001, 49( 4): 565- 576. DOI: 10.1136/gut.49.4.565.
    [42]
    TANAKA A, LEUNG PS, KENNY TP, et al. Genomic analysis of differentially expressed genes in liver and biliary epithelial cells of patients with primary biliary cirrhosis[J]. J Autoimmun, 2001, 17( 1): 89- 98. DOI: 10.1006/jaut.2001.0522.
    [43]
    THOMPSON MD, AWUAH P, SINGH S, et al. Disparate cellular basis of improved liver repair in beta-catenin-overexpressing mice after long-term exposure to 3, 5-diethoxycarbonyl-1, 4-dihydrocollidine[J]. Am J Pathol, 2010, 177( 4): 1812- 1822. DOI: 10.2353/ajpath.2010.100173.
    [44]
    OKABE H, YANG J, SYLAKOWSKI K, et al. Wnt signaling regulates hepatobiliary repair following cholestatic liver injury in mice[J]. Hepatology, 2016, 64( 5): 1652- 1666. DOI: 10.1002/hep.28774.
    [45]
    SACKETT SD, GAO Y, SHIN S, et al. Foxl1 promotes liver repair following cholestatic injury in mice[J]. Lab Invest, 2009, 89( 12): 1387- 1396. DOI: 10.1038/labinvest.2009.103.
    [46]
    BRAY F, FERLAY J, SOERJOMATARAM I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2018, 68( 6): 394- 424. DOI: 10.3322/caac.21492.
    [47]
    GILES RH, van ES JH, CLEVERS H. Caught up in a Wnt storm: Wnt signaling in cancer[J]. Biochim Biophys Acta, 2003, 1653( 1): 1- 24. DOI: 10.1016/s0304-419x(03)00005-2.
    [48]
    WANG Z, SHENG YY, GAO XM, et al. β-catenin mutation is correlated with a favorable prognosis in patients with hepatocellular carcinoma[J]. Mol Clin Oncol, 2015, 3( 4): 936- 940. DOI: 10.3892/mco.2015.569.
    [49]
    DING X, YANG Y, HAN BD, et al. Transcriptomic characterization of hepatocellular carcinoma with CTNNB1 mutation[J]. PLoS One, 2014, 9( 5): e95307. DOI: 10.1371/journal.pone.0095307.
    [50]
    LIAO X, SONG G, XU ZH, et al. Oxaliplatin resistance is enhanced by saracatinib via upregulation Wnt-ABCG1 signaling in hepatocellular carcinoma[J]. BMC Cancer, 2020, 20( 1): 31. DOI: 10.1186/s12885-019-6480-9.
    [51]
    LEUNG HW, LEUNG CON, LAU EY, et al. EPHB2 activates β-catenin to enhance cancer stem cell properties and drive sorafenib resistance in hepatocellular carcinoma[J]. Cancer Res, 2021, 81( 12): 3229- 3240. DOI: 10.1158/0008-5472.CAN-21-0184.
    [52]
    KARABICICI M, AZBAZDAR Y, OZHAN G, et al. Changes in Wnt and TGF-β signaling mediate the development of regorafenib resistance in hepatocellular carcinoma cell line HuH7[J]. Front Cell Dev Biol, 2021, 9: 639779. DOI: 10.3389/fcell.2021.639779.
    [53]
    CADORET A, OVEJERO C, SAADI-KHEDDOUCI S, et al. Hepatomegaly in transgenic mice expressing an oncogenic form of beta-catenin[J]. Cancer Res, 2001, 61( 8): 3245- 3249.
    [54]
    ZHAN N, MICHAEL AA, WU KY, et al. The effect of selective c-MET inhibitor on hepatocellular carcinoma in the MET-active, β‍-catenin-mutated mouse model[J]. Gene Expr, 2018, 18( 2): 135- 147. DOI: 10.3727/105221618X15174108894682.
    [55]
    PATIL MA, LEE SA, MACIAS E, et al. Role of cyclin D1 as a mediator of c-met- and beta-catenin-induced hepatocarcinogenesis[J]. Cancer Res, 2009, 69( 1): 253- 261. DOI: 10.1158/0008-5472.CAN-08-2514.
    [56]
    BANALES JM, CARDINALE V, CARPINO G, et al. Expert consensus document: Cholangiocarcinoma: Current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma(ENS-CCA)[J]. Nat Rev Gastroenterol Hepatol, 2016, 13( 5): 261- 280. DOI: 10.1038/nrgastro.2016.51.
    [57]
    TOKUMOTO N, IKEDA S, ISHIZAKI Y, et al. Immunohistochemical and mutational analyses of Wnt signaling components and target genes in intrahepatic cholangiocarcinomas[J]. Int J Oncol, 2005, 27( 4): 973- 980.
    [58]
    ZHANG KS, ZHOU Q, WANG YF, et al. Inhibition of Wnt signaling induces cell apoptosis and suppresses cell proliferation in cholangiocarcinoma cells[J]. Oncol Rep, 2013, 30( 3): 1430- 1438. DOI: 10.3892/or.2013.2560.
    [59]
    SUGIMACHI K, TAGUCHI K, AISHIMA S, et al. Altered expression of beta-catenin without genetic mutation in intrahepatic cholangiocarcinoma[J]. Mod Pathol, 2001, 14( 9): 900- 905. DOI: 10.1038/modpathol.3880409.
    [60]
    LOILOME W, BUNGKANJANA P, TECHASEN A, et al. Activated macrophages promote Wnt/β-catenin signaling in cholangiocarcinoma cells[J]. Tumour Biol, 2014, 35( 6): 5357- 5367. DOI: 10.1007/s13277-014-1698-2.
    [61]
    BOULTER L, GUEST RV, KENDALL TJ, et al. WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited[J]. J Clin Invest, 2015, 125( 3): 1269- 1285. DOI: 10.1172/JCI76452.
    [62]
    SHEN DY, ZHANG W, ZENG X, et al. Inhibition of Wnt/β-catenin signaling downregulates P-glycoprotein and reverses multi-drug resistance of cholangiocarcinoma[J]. Cancer Sci, 2013, 104( 10): 1303- 1308. DOI: 10.1111/cas.12223.
    [63]
    HUANG GL, LUO Q, RUI G, et al. Oncogenic activity of retinoic acid receptor γ is exhibited through activation of the Akt/NF-κB and Wnt/β-catenin pathways in cholangiocarcinoma[J]. Mol Cell Biol, 2013, 33( 17): 3416- 3425. DOI: 10.1128/MCB.00384-13.
    [64]
    KOCH A, DENKHAUS D, ALBRECHT S, et al. Childhood hepatoblastomas frequently carry a mutated degradation targeting box of the beta-catenin gene[J]. Cancer Res, 1999, 59( 2): 269- 273.
    [65]
    FORBES SA, BEARE D, BOUTSELAKIS H, et al. COSMIC: Somatic cancer genetics at high-resolution[J]. Nucleic Acids Res, 2017, 45( D1): D777- D783. DOI: 10.1093/nar/gkw1121.
    [66]
    ARMENGOL C, CAIRO S, FABRE M, et al. Wnt signaling and hepatocarcinogenesis: The hepatoblastoma model[J]. Int J Biochem Cell Biol, 2011, 43( 2): 265- 270. DOI: 10.1016/j.biocel.2009.07.012.
    [67]
    CAIRO S, ARMENGOL C, DE REYNIÈS A, et al. Hepatic stem-like phenotype and interplay of Wnt/beta-catenin and Myc signaling in aggressive childhood liver cancer[J]. Cancer Cell, 2008, 14( 6): 471- 484. DOI: 10.1016/j.ccr.2008.11.002.
    [68]
    TAO JY, CALVISI DF, RANGANATHAN S, et al. Activation of β-catenin and Yap1 in human hepatoblastoma and induction of hepatocarcinogenesis in mice[J]. Gastroenterology, 2014, 147( 3): 690- 701. DOI: 10.1053/j.gastro.2014.05.004.
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