中文English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R

留言板

尊敬的读者、作者、审稿人, 关于本刊的投稿、审稿、编辑和出版的任何问题, 您可以本页添加留言。我们将尽快给您答复。谢谢您的支持!

姓名
邮箱
手机号码
标题
留言内容
验证码

Wnt信号通路与肝再生的关系及其在肝脏疾病中的作用

林玉培 刘晓萍 罗银冰 李飞燕 廖莹莹 莫世聪 毛德文 蓝艳梅

引用本文:
Citation:

Wnt信号通路与肝再生的关系及其在肝脏疾病中的作用

DOI: 10.12449/JCH240529
基金项目: 

国家自然科学基金 (81960841);

国家自然科学基金 (82274434);

广西自然科学基金 (2020GXNSFBA297115);

广西自然科学基金 (2023GXNSFAA026176);

广西自然科学基金创新研究团队项目 (2020GXNSFAA297070);

广西高校中青年教师科研基础能力提升项目 (2022KY0299);

广西中医药大学校级一般硕士研究生创新项目 (YCSY2022024)

利益冲突声明:本文不存在任何利益冲突。
作者贡献声明:毛德文负责研究选题并拟定写作思路;廖莹莹、刘晓萍负责设计论文框架;莫世聪、罗银冰、李飞燕负责收集、整理文献材料;林玉培负责文章撰写;蓝艳梅负责审校。
详细信息
    通信作者:

    蓝艳梅, lanyanmeixueshu@163.com (ORCID: 0000-0001-9304-0594)

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

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
  • 摘要: Wnt信号通路在维持肝脏内稳态和肝脏再生过程中扮演重要角色,在成熟的健康肝脏中,Wnt信号通路大多是不活跃的,但在细胞更新或再生过程中,以及在某些病理条件、疾病、癌前状态和癌症中,Wnt信号通路被持续过度激活。持续的肝细胞损伤常常会导致慢性肝病,如肝纤维化、肝硬化及肝癌等。本文概述了Wnt信号通路的基本结构特点,详细分析了其在多种肝脏疾病病理进展所扮演的重要角色,希望为临床防治肝脏疾病提供新思路。

     

  • 图  1  Wnt信号传导通路

    Figure  1.  Wnt signaling pathway

    表  1  针对Wnt/β-catenin信号传导的药物临床试验

    Table  1.   Clinical trials of agents targeting Wnt/β-catenin signalling

    药物 类型 靶点 作用 阶段 临床试验记录
    LGK974(WNT974) 融合蛋白 Wnt配体 FZD8融合蛋白与FZD8竞争结合Wnt配体 Ⅰ期 NCT01608867,NCT02050178, NCT02069145,NCT02092363
    OMP-131R10 单抗 R-spondin 3 抑制 RSPO-LGR-ZNRF3/RNF43复合体 Ⅰ期 NCT02482441
    OTSA101 单抗 FZD10 抗FZD10型单抗 Ⅰ期 NCT01469975
    OMP-18R5 单抗 FZD受体 抗FZD受体型单抗 Ⅰ期 NCT01345201,NCT01957007, NCT01973309,NCT02005315
    DKN-01 单抗 DKK1 抗DKK1型单抗,抑制非典型β-catenin传导途径 Ⅰ期, Ⅱ期 NCT01457417,NCT01711671, NCT02013154,NCT02375880
    BHQ880 单抗 DKK1 抗DKK1型单抗,抑制非典型β-catenin传导途径 Ⅰ期, Ⅱ期 NCT00741377,NCT01302886, NCT01337752
    Foxy-5 小肽 FZD受体 Wnt 5a类似物 Ⅰ期 NCT02020291,NCT02655952
    PRI 724 小分子 β-catenin, CREB结合蛋白 下调β-catenin反应基因 Ⅰ期, Ⅱ期 NCT01302405,NCT01606579, NCT01764477,NCT02195440
    SM08502 小分子 未知 抑制β-catenin传导途径 Ⅰ期 NCT03355066
    下载: 导出CSV
  • [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.
  • 加载中
图(1) / 表(1)
计量
  • 文章访问数:  597
  • HTML全文浏览量:  175
  • PDF下载量:  51
  • 被引次数: 0
出版历程
  • 收稿日期:  2023-08-28
  • 录用日期:  2023-10-12
  • 出版日期:  2024-05-25
  • 分享
  • 用微信扫码二维码

    分享至好友和朋友圈

目录

    /

    返回文章
    返回