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ISSN 2097-3497 (Online)
CN 22-1108/R

Role of the JAK/STAT/SOCS signaling pathway in hepatitis B virus-related liver diseases

DOI: 10.3969/j.issn.1001-5256.2021.06.045
  • Received Date: 2020-10-29
  • Accepted Date: 2020-11-25
  • Published Date: 2021-06-20
  • The JAK/STAT/SOCS signaling pathway can mediate a variety of cytokines involved in inflammation, tumor, and autoimmune diseases and it also plays an important role in hepatitis B virus (HBV) infection-related liver diseases. This article briefly reviews the structure and signal pathway regulation of JAK-STAT and SOCS and elaborates on their role in the development and progression of HBV-related chronic hepatitis B, liver cirrhosis, liver failure, and hepatocellular carcinoma. The final analysis shows that the JAK/STAT/SOCS signaling pathway is dysregulated in HBV-related liver disease and is involved in the development and progression of the disease, and it may even influence the treatment and prognosis of the disease.

     

  • [1]
    WHO. Global hepatitis report, 2017[EB/OL].[2019-11-06]. https://www.who.int/hepatitis/publications/global-hepatitis-report2017/en/.
    [2]
    LIU J, LIANG W, JING W, et al. Countdown to 2030: Eliminating hepatitis B disease, China[J]. Bull World Health Organ, 2019, 97(3): 230-238. DOI: 10.2471/BLT.18.219469.
    [3]
    SEIF F, KHOSHMIRSAFA M, AAZAMI H, et al. The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells[J]. Cell Commun Signal, 2017, 15(1): 23. DOI: 10.1186/s12964-017-0177-y.
    [4]
    BOUSOIK E, MONTAZERI ALIABADI H. "Do We Know Jack" About JAK? A closer look at JAK/STAT signaling pathway[J]. Front Oncol, 2018, 8: 287. DOI: 10.3389/fonc.2018.00287.
    [5]
    NABAVI SM, AHMED T, NAWAZ M, et al. Targeting STATs in neuroinflammation: The road less traveled![J]. Pharmacol Res, 2019, 141: 73-84. DOI: 10.1016/j.phrs.2018.12.004.
    [6]
    LIM CP, CAO X. Structure, function, and regulation of STAT proteins[J]. Mol Biosyst, 2006, 2(11): 536-550. DOI: 10.1039/b606246f.
    [7]
    DURHAM GA, WILLIAMS J, NASIM MT, et al. Targeting SOCS proteins to control JAK-STAT signalling in disease[J]. Trends Pharmacol Sci, 2019, 40(5): 298-308. DOI: 10.1016/j.tips.2019.03.001.
    [8]
    MORRIS R, KERSHAW NJ, BABON JJ. The molecular details of cytokine signaling via the JAK/STAT pathway[J]. Protein Sci, 2018, 27(12): 1984-2009. DOI: 10.1002/pro.3519.
    [9]
    YIN Y, LIU W, DAI Y. SOCS3 and its role in associated diseases[J]. Hum Immunol, 2015, 76(10): 775-780. DOI: 10.1016/j.humimm.2015.09.037.
    [10]
    DEES C, PÖTTER S, ZHANG Y, et al. TGF-β-induced epigenetic deregulation of SOCS3 facilitates STAT3 signaling to promote fibrosis[J]. J Clin Invest, 2020, 130(5): 2347-2363. DOI: 10.1172/JCI122462.
    [11]
    SADLER AJ, WILLIAMS BR. Interferon-inducible antiviral effectors[J]. Nat Rev Immunol, 2008, 8(7): 559-568. DOI: 10.1038/nri2314.
    [12]
    YU Y, WAN P, CAO Y, et al. Hepatitis B virus e antigen activates the suppressor of cytokine signaling 2 to repress interferon action[J]. Sci Rep, 2017, 7(1): 1729. DOI: 10.1038/s41598-017-01773-6.
    [13]
    MITRA B, WANG J, KIM ES, et al. Hepatitis B virus precore protein p22 inhibits alpha interferon signaling by blocking STAT nuclear translocation[J]. J Virol, 2019, 93(13): e00196-19. DOI: 10.1128/JVI.00196-19.
    [14]
    CHANG Z, WANG Y, ZHOU X, et al. STAT3 roles in viral infection: Antiviral or proviral?[J]. Future Virol, 2018, 13(8): 557-574. DOI: 10.2217/fvl-2018-0033.
    [15]
    ZANG M, LI Y, HE H, et al. IL-23 production of liver inflammatory macrophages to damaged hepatocytes promotes hepatocellular carcinoma development after chronic hepatitis B virus infection[J]. Biochim Biophys Acta Mol Basis Dis, 2018, 1864(12): 3759-3770. DOI: 10.1016/j.bbadis.2018.10.004.
    [16]
    ZHAO X, SUN L, MU T, et al. An HBV-encoded miRNA activates innate immunity to restrict HBV replication[J]. J Mol Cell Biol, 2020, 12(4): 263-276. DOI: 10.1093/jmcb/mjz104.
    [17]
    WU S, CHEN X, TANG Y, et al. Delivery of Tapasin-modified CTL epitope peptide via cytoplasmic transduction peptide induces CTLs by JAK/STAT signaling pathway in vivo[J]. Acta Biochim Biophys Sin (Shanghai), 2018, 50(2): 181-190. DOI: 10.1093/abbs/gmx133.
    [18]
    HOAN NX, van TONG H, GIANG DP, et al. SOCS3 genetic variants and promoter hypermethylation in patients with chronic hepatitis B[J]. Oncotarget, 2017, 8(10): 17127-17139. DOI: 10.18632/oncotarget.15083.
    [19]
    ZHANG P, LI F, LI N, et al. Genetic variations of SOCS1 are associated with chronic hepatitis B virus infection[J]. Hum Immunol, 2014, 75(8): 709-714. DOI: 10.1016/j.humimm.2014.04.010.
    [20]
    TANG LY, HELLER M, MENG Z, et al. Transforming growth factor-β (TGF-β) directly activates the JAK1-STAT3 axis to induce hepatic fibrosis in coordination with the SMAD pathway[J]. J Biol Chem, 2017, 292(10): 4302-4312. DOI: 10.1074/jbc.M116.773085.
    [21]
    GU YJ, SUN WY, ZHANG S, et al. Targeted blockade of JAK/STAT3 signaling inhibits proliferation, migration and collagen production as well as inducing the apoptosis of hepatic stellate cells[J]. Int J Mol Med, 2016, 38(3): 903-911. DOI: 10.3892/ijmm.2016.2692.
    [22]
    ZHAO J, QI YF, YU YR. STAT3: A key regulator in liver fibrosis[J]. Ann Hepatol, 2021, 21: 100224. DOI: 10.1016/j.aohep.2020.06.010.
    [23]
    MAIR M, BLAAS L, ÖSTERREICHER CH, et al. JAK-STAT signaling in hepatic fibrosis[J]. Front Biosci (Landmark Ed), 2011, 16: 2794-2811. DOI: 10.2741/3886.
    [24]
    ZHANG W, NIU M, YAN K, et al. Stat3 pathway correlates with the roles of leptin in mouse liver fibrosis and sterol regulatory element binding protein-1c expression of rat hepatic stellate cells[J]. Int J Biochem Cell Biol, 2013, 45(3): 736-744. DOI: 10.1016/j.biocel.2012.12.019.
    [25]
    MARTÍ-RODRIGO A, ALEGRE F, MORAGREGA ÁB, et al. Rilpivirine attenuates liver fibrosis through selective STAT1-mediated apoptosis in hepatic stellate cells[J]. Gut, 2020, 69(5): 920-932. DOI: 10.1136/gutjnl-2019-318372.
    [26]
    CHENG C, HUANG C, MA TT, et al. New surprises of suppressor of cytokine signalling in liver fibrosis[J]. Expert Opin Ther Targets, 2014, 18(4): 415-426. DOI: 10.1517/14728222.2014.885953.
    [27]
    YOSHIDA T, OGATA H, KAMIO M, et al. SOCS1 is a suppressor of liver fibrosis and hepatitis-induced carcinogenesis[J]. J Exp Med, 2004, 199(12): 1701-1707. DOI: 10.1084/jem.20031675.
    [28]
    JAMHIRI I, SHAHIN K, KHODABANDEH Z, et al. Recombinant NS3 protein induced expression of immune modulatory elements in hepatic stellate cells during its fibrotic activity[J]. Viral Immunol, 2018, 31(8): 575-582. DOI: 10.1089/vim.2018.0018.
    [29]
    KIM HY, JHUN JY, CHO ML, et al. Interleukin-6 upregulates Th17 response via mTOR/STAT3 pathway in acute-on-chronic hepatitis B liver failure[J]. J Gastroenterol, 2014, 49(8): 1264-1273. DOI: 10.1007/s00535-013-0891-1.
    [30]
    LI Y, HAN MF, LI WN, et al. SOCS3 expression correlates with severity of inflammation in mouse hepatitis virus strain 3-induced acute liver failure and HBV-ACLF[J]. J Huazhong Univ Sci Technolog Med Sci, 2014, 34(3): 348-353. DOI: 10.1007/s11596-014-1281-5.
    [31]
    LI SS, YANG M, CHEN YP, et al. Dendritic cells with increased expression of suppressor of cytokine signaling 1(SOCS1) gene ameliorate lipopolysaccharide/d-galactosamine-induced acute liver failure[J]. Mol Immunol, 2018, 101: 10-18. DOI: 10.1016/j.molimm.2018.05.016.
    [32]
    ZHANG JJ, FAN YC, ZHAO ZH, et al. Prognoses of patients with acute-on-chronic hepatitis B liver failure are closely associated with altered SOCS1 mRNA expression and cytokine production following glucocorticoid treatment[J]. Cell Mol Immunol, 2014, 11(4): 396-404. DOI: 10.1038/cmi.2014.23.
    [33]
    MA HC, WANG X, WU MN, et al. Interleukin-10 contributes to therapeutic effect of mesenchymal stem cells for acute liver failure via signal transducer and activator of transcription 3 signaling pathway[J]. Chin Med J (Engl), 2016, 129(8): 967-975. DOI: 10.4103/0366-6999.179794.
    [34]
    YIN JP, YUE ZC, ZHUO SY. STAT3: A key molecule in the progression of liver cancer mediated by chronic inflammation[J]. J Clin Hepatol, 2020, 36(4): 948-952. DOI: 10.3969/j.issn.1001-5256.2020.04.054.

    音金萍, 岳紫晨, 卓少元. STAT3: 慢性炎症介导肝癌进程的关键分子[J]. 临床肝胆病杂志, 2020, 36(4): 948-952. DOI: 10.3969/j.issn.1001-5256.2020.04.054.
    [35]
    LI TF, SU CY, HUANG G, et al. IL-6 suppresses CCR7 expression in human monocyte-derived dendritic cells via STAT3 pathway[J]. J Third Mil Med Univ, 2015, 37(8): 751-756.
    [36]
    XIONG S, WANG R, CHEN Q, et al. Cancer-associated fibroblasts promote stem cell-like properties of hepatocellular carcinoma cells through IL-6/STAT3/Notch signaling[J]. Am J Cancer Res, 2018, 8(2): 302-316.
    [37]
    YIN Z, MA T, LIN Y, et al. IL-6/STAT3 pathway intermediates M1/M2 macrophage polarization during the development of hepatocellular carcinoma[J]. J Cell Biochem, 2018, 119(11): 9419-9432. DOI: 10.1002/jcb.27259.
    [38]
    WANG B, LIU T, WU JC, et al. STAT3 aggravates TGF-β1-induced hepatic epithelial-to-mesenchymal transition and migration[J]. Biomed Pharmacother, 2018, 98: 214-221. DOI: 10.1016/j.biopha.2017.12.035.
    [39]
    CHEN G, WANG H, XIE S, et al. STAT1 negatively regulates hepatocellular carcinoma cell proliferation[J]. Oncol Rep, 2013, 29(6): 2303-2310. DOI: 10.3892/or.2013.2398.
    [40]
    JIN Y, SUN Z, GENG J, et al. IL-21 reinvigorates exhausted natural killer cells in patients with HBV-associated hepatocellular carcinoma in STAT1-depedent pathway[J]. Int Immunopharmacol, 2019, 70: 1-8. DOI: 10.1016/j.intimp.2019.02.007.
    [41]
    GAO MD, ZHANG YH, ZHAO Y. Role of signal transduction and transcription factors STAT1 and STAT3 in the pathogen-esis of hepatocellular carcinoma and liver failure[J]. J Clin Hepatol, 2018, 34(9): 2017-2020. DOI: 10.3969/j.issn.1001-5256.2018.09.040

    高梦丹, 张永宏, 赵艳. STAT1与STAT3在肝细胞癌及肝衰竭发病机制中的作用[J]. 临床肝胆病杂志, 2018, 34(9): 2017-2020. DOI: 10.3969/j.issn.1001-5256.2018.09.040.
    [42]
    KALTENECKER D, THEMANNS M, MUELLER KM, et al. Hepatic growth hormone - JAK2 - STAT5 signalling: Metabolic function, non-alcoholic fatty liver disease and hepatocellular carcinoma progression[J]. Cytokine, 2019, 124: 154569. DOI: 10.1016/j.cyto.2018.10.010.
    [43]
    WANG X, LIAO X, YU T, et al. Analysis of clinical significance and prospective molecular mechanism of main elements of the JAK/STAT pathway in hepatocellular carcinoma[J]. Int J Oncol, 2019, 55(4): 805-822. DOI: 10.3892/ijo.2019.4862.
    [44]
    ZHANG X, WANG J, CHENG J, et al. An integrated analysis of SOCS1 down-regulation in HBV infection-related hepatocellular carcinoma[J]. J Viral Hepat, 2014, 21(4): 264-271. DOI: 10.1111/jvh.12137.
    [45]
    KHAN M, GHOSH A, VARIYA B, et al. Hepatocyte growth control by SOCS1 and SOCS3[J]. Cytokine, 2019, 121: 154733. DOI: 10.1016/j.cyto.2019.154733.
    [46]
    YANG Z, ZHU H, ZHANG L, et al. DNA methylation of SOCS1/2/3 predicts hepatocellular carcinoma recurrence after liver transplantation[J]. Mol Biol Rep, 2020, 47(3): 1773-1782. DOI: 10.1007/s11033-020-05271-3.
    [47]
    CUI M, SUN J, HOU J, et al. The suppressor of cytokine signaling 2 (SOCS2) inhibits tumor metastasis in hepatocellular carcinoma[J]. Tumour Biol, 2016, 37(10): 13521-13531. DOI: 10.1007/s13277-016-5215-7.
    [48]
    ZHANG M, LIU S, CHUA MS, et al. SOCS5 inhibition induces autophagy to impair metastasis in hepatocellular carcinoma cells via the PI3K/Akt/mTOR pathway[J]. Cell Death Dis, 2019, 10(8): 612. DOI: 10.1038/s41419-019-1856-y.
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