EGF受体抑制剂通过下调STAT3磷酸化来全面抑制乙型肝炎病毒。

StephenW

Biochem Biophys Rep. 2020 Apr 18;22:100763. doi: 10.1016/j.bbrep.2020.100763. eCollection 2020 Jul.
EGF receptor inhibitors comprehensively suppress hepatitis B virus by downregulation of STAT3 phosphorylation.
Gan CJ1, Li WF1, Li CN1, Li LL2, Zhou WY2, Peng XM1.
Author information

1
    Center of Infectious Diseases, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong, 519000, China.
2
    Central Laboratory, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong, 519000, China.

Abstract

Current antiviral therapy can not cure chronic hepatitis B virus (HBV) infection or eliminate the risk of hepatocellular carcinoma. The licensed epidermal growth factor receptor (EGFR) inhibitors have found to inhibit hepatitis C virus replication via downregulation of signal transducers and activators of transcription 3 (STAT3) phosphorylation. Since STAT3 is also involved in HBV replication, we further studied the anti-HBV efficacy of the EGFR inhibitors in this study. HBV-transfected HepG2.2.15 cells and HBV-infected HepG2-NTCP cells were used as cell models, and HBV replication, the syntheses of viral antigens and the magnitude of the covalently closed circular DNA (cccDNA) reservoir were used as indictors to test the anti-HBV effects of EGFR inhibitors erlotinib and gefitinib. Erlotinib inhibited HBV replication with a half-maximal inhibitory concentration of 1.05 μM. It also reduced the syntheses of viral antigens at concentrations of 2.5 μM or higher. The underlying mechanism was possibly correlated with its inhibition on STAT3 phosphorylation via up-regulation of suppressor of cytokine signaling 3. Gefitinib also inhibited HBV replication and antigen syntheses. Compared with the commonest antiviral drug entecavir, these EGFR inhibitors additionally reduced hepatitis B e antigen and erlotinib also marginally affected the cccDNA reservoir in HBV-infected HepG2-NTCP cells. Interestingly, these promising anti-HBV effects were significantly enhanced by extension of treatment duration. In conclusion, EGFR inhibitors demonstrated a comprehensive anti-HBV potential, highlighting a new strategy to cure HBV infection and suggesting animal model-related studies or clinical try in the future.

© 2020 The Authors.
KEYWORDS:

Antiviral therapy; Covalently closed circular DNA; EGF, epidermal growth factor; EGFR, epidermal growth factor inhibitor; Epidermal growth factor receptor inhibitor; GEq, genome equivalent; HBV, hepatitis B virus; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma; HNF3, hepatocyte nuclear factor 3; Hepatitis B virus; IFN, interferon; MTT, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide; NAs, nucleotide/nucleoside analogues; NTCP, sodium taurocholate cotransporting polypeptide; PCR, polymerase chain reaction; SOCS3, suppressor of cytokine signaling 3; STAT3; STAT3, signal transduction and activators of transcription 3; cccDNA, covalently closed circular DNA

PMID:
    32322693
PMCID:
    PMC7170955
DOI:
    10.1016/j.bbrep.2020.100763

StephenW

Biochem Biophys Rep.2020 Apr 18; 22：100763。 doi：10.1016 / j.bbrep.2020.100763。 eCollection 2020年7月
EGF受体抑制剂通过下调STAT3磷酸化来全面抑制乙型肝炎病毒。
甘CJ1，李WF1，李CN1，李LL2，周WY2，彭XM1。
作者信息

1个
    中山大学附属第五医院传染病中心，广东珠海519000
2
    中山大学附属第五医院中心实验室，广东珠海519000

抽象

当前的抗病毒治疗不能治愈慢性乙型肝炎病毒（HBV）感染或消除肝细胞癌的风险。已发现获得许可的表皮生长因子受体（EGFR）抑制剂可通过下调信号转导子和转录激活因子3（STAT3）的磷酸化来抑制丙型肝炎病毒的复制。由于STAT3也参与HBV复制，因此我们在此研究中进一步研究了EGFR抑制剂的抗HBV功效。使用HBV转染的HepG2.2.15细胞和HBV感染的HepG2-NTCP细胞作为细胞模型，并用HBV复制，病毒抗原的合成和共价闭合环状DNA（cccDNA）储库的大小作为指标来测试EGFR抑制剂厄洛替尼和吉非替尼的抗HBV作用。厄洛替尼以最大抑制浓度1.05μM抑制HBV复制。它还以2.5μM或更高的浓度减少了病毒抗原的合成。潜在的机制可能与其通过上调细胞因子信号传导抑制剂3对STAT3磷酸化的抑制有关。吉非替尼还抑制HBV复制和抗原合成。与最常用的抗病毒药物恩替卡韦相比，这些EGFR抑制剂还减少了乙型肝炎e抗原，厄洛替尼也对HBV感染的HepG2-NTCP细胞中的cccDNA储库有轻微的影响。有趣的是，延长治疗时间显着增强了这些有希望的抗乙肝病毒作用。总之，EGFR抑制剂具有全面的抗HBV潜力，突出了治疗HBV感染的新策略，并建议将来进行动物模型相关研究或临床尝试。

©2020作者。
关键字：

抗病毒治疗；共价封闭的环状DNA； EGF，表皮生长因子； EGFR，表皮生长因子抑制剂；表皮生长因子受体抑制剂； GEq，基因组当量； HBV，乙肝病毒； HBeAg，乙型肝炎e抗原； HBsAg，乙肝表面抗原； HCC，肝细胞癌； HNF3，肝细胞核因子3；乙型肝炎病毒;干扰素，干扰素； MTT，3-（4,5-二甲基-2-噻唑基）-2,5-二苯基-2-H-溴化四唑; NAs，核苷酸/核苷类似物； NTCP，牛磺胆酸钠共转运多肽； PCR，聚合酶链反应； SOCS3，细胞因子信号传导抑制剂3； STAT3; STAT3，信号转导和转录激活因子3； cccDNA，共价闭合的环状DNA

PMID：
    32322693
PMCID：
    PMC7170955
DOI：
    10.1016 / j.bbrep.2020.100763

StephenW

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