Mechanism of hepatitis B virus X inducing hepatocellular carcinoma through Notch signaling pathway in a normal immune mouse model

Mengyao ZHOU; Bin DU; Nan WU; Xin HUANG; Siyao ZHANG; Qin KUANG; Yong WU; Tao FENG

doi:10.16016/j.1000-5404.202011152

您当前的位置：

首页 >

文章列表页 >

Mechanism of hepatitis B virus X inducing hepatocellular carcinoma through Notch signaling pathway in a normal immune mouse model

更新时间：2026-01-09

- Mechanism of hepatitis B virus X inducing hepatocellular carcinoma through Notch signaling pathway in a normal immune mouse model
- Journal of Third Military Medical University Vol. 43, Issue 10, Pages: 883-891(2021)
- 作者机构：
- 作者简介：
- 基金信息：
  
  the General Program of National Natural Science Foundation of China(81071770)
- DOI：10.16016/j.1000-5404.202011152
  CLC：
- Received：17 November 2020，
  
  Published：30 May 2021
- 稿件说明：
移动端阅览
Mengyao ZHOU, Bin DU, Nan WU, et al. Mechanism of hepatitis B virus X inducing hepatocellular carcinoma through Notch signaling pathway in a normal immune mouse model[J]. Journal of Third Military Medical University, 2021, 43(10): 883-891.
DOI：

Mengyao ZHOU, Bin DU, Nan WU, et al. Mechanism of hepatitis B virus X inducing hepatocellular carcinoma through Notch signaling pathway in a normal immune mouse model[J]. Journal of Third Military Medical University, 2021, 43(10): 883-891. DOI： 10.16016/j.1000-5404.202011152.

摘要

Abstract

Objective

To construct a normal immune mouse model carrying hepatitis B virus X (HBx) for long term so as to explore the possible mechanism of HBx causing hepatocellular carcinoma (HCC).

Methods

Hepatic progenitor cells transfected with HBx were injected into Kunming mice

via

hepatic portal vein to construct the animal model. The liver tissues were harvested at 30

180 and 360 d after injection

respectively. The expression of HBx as well as that of Notch1

Notch4 and Hes1 at protein and mRNA levels was detected by Western blotting and RT-qPCR

respectively

and the histopathological changes were observed by HE staining. In addition

a novel γ-secretase inhibitor

DAPT

was intraperitoneally injected at 180 d

and then Western blotting and RT-qPCR were adopted to determine the changes in the expression of apoptosis and cell-cycle-related factors.

Results

The animal model was successfully constructed

and liver cancer occurred at 360 d. Compared with the control group

the mRNA and protein levels of Notch1

Notch4 and Hes1 were all significantly increased in the HBx group at 30 d (

0.05

0.001)

and continued to 360 d (

0.05

0.01); the protein and mRNA levels of Bcl-2

CDK4

CyclinE and CyclinD1 were also up-regulated (protein:

0.001

0.01

0.001

0.01; mRNA:

0.05

0.001

0.01)

while those of Bax down-regulated in the HBx group (

0.001;

0.001). However

the inhibitor DAPT significantly reversed the above trends.

Conclusion

HBx causes anti-apoptosis and abnormal cell cycle changes in mice through persistent activation of the Notch pathway

and then ultimately leads to HCC.

关键词

Keywords

references

SONG P TOBE R G INAGAKI Y The management of hepatocellular carcinoma around the world: a comparison of guidelines from 2001 to 2011 Liver Int 2012 32 7 1053 1063 10.1111/j.1478-3231.2012.02792.x SONG P, TOBE R G, INAGAKI Y, et al . The management of hepatocellular carcinoma around the world: a comparison of guidelines from 2001 to 2011[J ] . Liver Int, 2012, 32(7): 1053-1063. DOI: 10.1111/j.1478-3231.2012.02792.x.

SARTORIUS K SWADLING L AN P The multiple roles of hepatitis B virus X protein (HBx) dysregulated MicroRNA in hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) and immune pathways Viruses 2020 12 7 E746 10.3390/v12070746 SARTORIUS K, SWADLING L, AN P, et al . The multiple roles of hepatitis B virus X protein (HBx) dysregulated MicroRNA in hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) and immune pathways[J ] . Viruses, 2020, 12(7): E746. DOI: 10.3390/v12070746.

SARTORIUS K MAKAROVA J SARTORIUS B The regulatory role of MicroRNA in hepatitis-B virus-associated hepatocellular carcinoma (HBV-HCC) pathogenesis Cells 2019 8 12 E1504 10.3390/cells8121504 SARTORIUS K, MAKAROVA J, SARTORIUS B, et al . The regulatory role of MicroRNA in hepatitis-B virus-associated hepatocellular carcinoma (HBV-HCC) pathogenesis[J ] . Cells, 2019, 8(12): E1504. DOI: 10.3390/cells8121504.

LAMONTAGNE R J BAGGA S BOUCHARD M J Hepatitis B virus molecular biology and pathogenesis Hepatoma Res 2016 2 163 186 10.20517/2394-5079.2016.05 LAMONTAGNE R J, BAGGA S, BOUCHARD M J. Hepatitis B virus molecular biology and pathogenesis[J]. Hepatoma Res, 2016, 2: 163-186. DOI: 10.20517/2394-5079.2016.05.

LU J XIA Y J CHEN K Oncogenic role of the Notch pathway in primary liver cancer Oncol Lett 2016 12 1 3 10 10.3892/ol.2016.4609 LU J, XIA Y J, CHEN K, et al . Oncogenic role of the Notch pathway in primary liver cancer[J ] . O ncol Lett, 2016, 12(1): 3-10. DOI: 10.3892/ol.2016.4609.

HUANG Q F LI J H ZHENG J H The carcinogenic role of the notch signaling pathway in the development of hepatocellularcarcinoma J Cancer 2019 10 6 1570 1579 10.7150/jca.26847 HUANG Q F, LI J H, ZHENG J H, et al . The carcinogenic role of the notch signaling pathway in the development of hepatocellularcarcinoma[J ] . J Cancer, 2019, 10(6): 1570-1579. DOI: 10.7150/jca.26847.

WANG X Q ZHANG W LUI E L H Notch1-Snail1-E-cadherin pathway in metastatic hepatocellular carcinoma Int J Cancer 2012 131 3 E163 E172 10.1002/ijc.27336 WANG X Q, ZHANG W, LUI E L H, et al . Notch1-Snail1-E-cadherin pathway in metastatic hepatocellular carcinoma[J ] . Int J Cancer, 2012, 131(3): E163-E172. DOI: 10.1002/ijc.27336.

GIOVANNINI C MINGUZZI M GENOVESE F Molecular and proteomic insight into Notch1 characterization in hepatocellular carcinoma Oncotarget 2016 7 26 39609 39626 10.18632/oncotarget.9203 GIOVANNINI C, MINGUZZI M, GENOVESE F, et al . Molecular and proteomic insight into Notch1 characterization in hepatocellular carcinoma[J ] . Oncotarget, 2016, 7(26): 39609-39626. DOI: 10.18632/oncotarget.9203.

GAO J XIONG Y M WANG Y Hepatitis B virus X protein activates Notch signaling by its effects on Notch1 and Notch4 in human hepatocellularcarcinoma Int J Oncol 2016 48 1 329 337 10.3892/ijo.2015.3221 GAO J, XIONG Y M, WANG Y, et al . Hepatitis B virus X protein activates Notch signaling by its effects on Notch1 and Notch4 in human hepatocellularcarcinoma[J ] . Int J Oncol, 2016, 48(1): 329-337. DOI: 10.3892/ijo.2015.3221.

王薛霍本念刘洁 HBx基因激活Akt/mTOR信号通路抑制肝脏细胞凋亡第三军医大学学报 2019 41 10 931 938 10.16016/j.1000-5404.201811185 王薛, 霍本念, 刘洁, 等. HBx基因激活Akt/mTOR信号通路抑制肝脏细胞凋亡[J]. 第三军医大学学报, 2019, 41(10): 931-938. DOI: 10.16016/j.1000-5404.201811185.

WANG X HUO B N LIU J Hepatitis B virus X gene inhibits hepatocyteapoptosis in mice via Akt/mTOR pathway J Third Mil Med Univ 2019 41 10 931 938 10.16016/j.1000-5404.201811185 WANG X, HUO B N, LIU J, et al . Hepatitis B virus X gene inhibits hepatocyteapoptosis in mice via Akt/mTOR pathway[J ] . J Third Mil Med Univ, 2019, 41(10): 931-938. DOI: 10.16016/j.1000-5404.201811185.

周煜薛淑一李明春 Notch信号通路及其与肝癌相关性的研究进展实用医药杂志 2018 35 9 842 846 10.14172/j.issn1671-4008.2018.09.027 周煜, 薛淑一, 李明春. Notch信号通路及其与肝癌相关性的研究进展[J]. 实用医药杂志, 2018, 35(9): 842-846. DOI: 10.14172/j.issn1671-4008.2018.09.027.

ZHOU Y XUE S Y LI M C Research progress on Notch signaling pathway and its relationship with liver carcinoma Pract J Med Pharm 2018 35 9 842 846 10.14172/j.issn1671-4008.2018.09.027 ZHOU Y, XUE S Y, LI M C. Research progress on Notch signaling pathway and its relationship with liver carcinoma[J]. Pract J Med Pharm, 2018, 35(9): 842-846. DOI: 10.14172/j.issn1671-4008.2018.09.027.

SEKIBA K OTSUKA M OHNO M Inhibition of HBV transcription from cccDNA with nitazoxanide by targeting the HBx-DDB1 interaction Cell Mol Gastroenterol Hepatol 2019 7 2 297 312 10.1016/j.jcmgh.2018.10.010 SEKIBA K, OTSUKA M, OHNO M, et al . Inhibition of HBV transcription from cccDNA with nitazoxanide by targeting the HBx-DDB1 interaction[J ] . Cell Mol Gastroenterol Hepatol, 2019, 7(2): 297 -312. DOI: 10.1016/j.jcmgh.2018.10.010.

LUCIFORA J ARZBERGER S DURANTEL D Hepatitis B virus X protein is essential to initiate and maintain virus replication after infection J Hepatol 2011 55 5 996 1003 10.1016/j.jhep.2011.02.015 LUCIFORA J, ARZBERGER S, DURANTEL D, et al . Hepatitis B virus X protein is essential to initiate and maintain virus replication after infection[J ] . J Hepatol, 2011, 55(5): 996-1003. DOI: 10.1016/j.jhep.2011.02.015.

VAN BREUGEL P C ROBERT E I MUELLER H Hepatitis B virus X protein stimulates gene expression selectively from extrachromosomal DNA templates Hepatology 2012 56 6 2116 2124 10.1002/hep.25928 VAN BREUGEL P C, ROBERT E I, MUELLER H, et al . Hepatitis B virus X protein stimulates gene expression selectively from extrachromosomal DNA templates[J ] . Hepatology, 2012, 56(6): 2116-2124. DOI: 10.1002/hep.25928.

CHENG S T REN J H CAI X F HBx-elevated SIRT2 promotes HBV replication and hepatocarcinogenesis Biochem Biophys Res Commun 2018 496 3 904 910 10.1016/j.bbrc.2018.01.127 CHENG S T, REN J H, CAI X F, et al . HBx-elevated SIRT2 promotes HBV replication and hepatocarcinogenesis[J ] . Biochem Biophys Res Commun, 2018, 496(3): 904-910. DOI: 10.1016/j.bbrc.2018.01.127.

TANG L S Y COVERT E WILSON E Chronic hepatitis B infection: a review JAMA 2018 319 17 1802 1813 10.1001/jama.2018.3795 TANG L S Y, COVERT E, WILSON E, et al . Chronic hepatitis B infection: a review[J ] . JAMA, 2018, 319(17): 1802-1813. DOI: 10.1001/jama.2018.3795.

LI Y FU Y HU X TheHBx-CTTN interaction promotes cell proliferation and migration of hepatocellular carcinoma via CREB1 Cell Death Dis 2019 10 6 405 10.1038/s41419-019-1650-x LI Y, FU Y, HU X, et al . TheHBx-CTTN interaction promotes cell proliferation and migration of hepatocellular carcinoma via CREB1[J ] . Cell Death Dis, 2019, 10(6): 405. DOI: 10.1038/s41419-019-1650-x.

TAN S Y VISVANATHAN S ABU HASSAN R Autophagic degradation of misfolded nuclear receptor Co-repressor (NCoR) is linked to the growth of tumor cells in HBX positive hepatocellular carcinoma (HCC) Front Oncol 2019 9 1335 10.3389/fonc.2019.01335 TAN S Y, VISVANATHAN S, ABU HASSAN R, et al . Autophagic degradation of misfolded nuclear receptor Co-repressor (NCoR) is linked to the growth of tumor cells in HBX positive hepatocellular carcinoma (HCC)[J ] . Front Oncol, 2019, 9: 1335. DOI: 10.3389/fonc.2019.01335.

DUAN L WU R ZHANG X Y HBx-induced S100A9 in NF-κB dependent manner promotes growth and metastasis of hepatocellular carcinoma cells Cell Death Dis 2018 9 6 629 10.1038/s41419-018-0512-2 DUAN L, WU R, ZHANG X Y, et al . HBx-induced S100A9 in NF-κB dependent manner promotes growth and metastasis of hepatocellular carcinoma cells[J ] . Cell Death Dis, 2018, 9(6): 629. DOI: 10.1038/s41419-018-0512-2.

CHIU A P TSCHIDA B R SHAM TT HBx-K130M/V131I promotes liver cancer in transgenic mice via AKT/FOXO1 signaling pathway and arachidonic acid metabolism Mol Cancer Res 2019 17 7 1582 1593 10.1158/1541-7786.MCR-18-1127 CHIU A P, TSCHIDA B R, SHAM TT, et al . HBx-K130M/V131I promotes liver cancer in transgenic mice via AKT/FOXO1 signaling pathway and arachidonic acid metabolism[J ] . Mol Cancer Res, 2019, 17(7): 1582-1593. DOI: 10.1158/1541-7786.MCR-18-1127.

BRAY S J Notch signalling in context Nat Rev Mol Cell Biol 2016 17 11 722 735 10.1038/nrm.2016.94 BRAY S J. Notch signalling in context[J]. Nat Rev Mol Cell Biol, 2016, 17(11): 722-735. DOI: 10.1038/nrm.2016.94.

ADAMS J M JAFAR-NEJAD H The roles of notch signaling in liver development and disease Biomolecules 2019 9 10 608 10.3390/biom9100608 ADAMS J M, JAFAR-NEJAD H. The roles of notch signaling in liver development and disease[J]. Biomolecules, 2019, 9(10): 608. DOI: 10.3390/biom9100608.

ZHU B SUN L LUO W Activated Notch signaling augments cell growth in hepatocellular carcinoma via up-regulating the nuclear receptor NR4A2 Oncotarget 2017 8 14 23289 23302 10.18632/oncotarget.15576 ZHU B, SUN L, LUO W, et al . Activated Notch signaling augments cell growth in hepatocellular carcinoma via up-regulating the nuclea r receptor NR4A2[J ] . Oncotarget, 2017, 8(14): 23289-23302. DOI: 10.18632/oncotarget.15576.

BAO S X JIN S WANG C H Androgen receptor suppressesvasculogenic mimicry in hepatocellular carcinoma via circRNA7/miRNA7-5p/VE-cadherin/Notch4 signalling J Cell Mol Med 2020 24 23 14110 14120 10.1111/jcmm.16022 BAO S X, JIN S, WANG C H, et al . Androgen receptor suppressesvasculogenic mimicry in hepatocellular carcinoma via circRNA7/miRNA7-5p/VE-cadherin/Notch4 signalling[J ] . J Cell Mol Med, 2020, 24(23): 14110-14120. DOI: 10.1111/jcmm.16022.

VILLANUEVA A ALSINET C YANGER K Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice Gastroenterology 2012 143 6 1660 1669 10.1053/j.gastro.2012.09.002 VILLANUEVA A, ALSINET C, YANGER K, et al . Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice[J ] . Gastroenterology, 2012, 143(6): 1660-1669. e7. DOI: 10.1053/j.gastro.2012.09.002.

KIM W KHAN S K GVOZDENOVIC-JEREMIC J Hippo signaling interactions withWnt/β-catenin and Notch signaling repress liver tumorigenesis J Clin Invest 2017 127 1 137 152 10.1172/JCI88486 KIM W, KHAN S K, GVOZDENOVIC-JEREMIC J, et al . Hippo signaling interactions withWnt/β-catenin and Notch signaling repress liver tumorigenesis[J ] . J Clin Invest, 2017, 127(1): 137-152. DOI: 10.1172/JCI88486.

JIA S Q REN JJ DONG P D Probing the hepatic progenitor cell in human hepatocellular carcinoma Gastroenterol Res Pract 2013 2013 145253 10.1155/2013/145253 JIA S Q, REN JJ, DONG P D, et al . Probing the hepatic progenitor cell in human hepatocellular carcinoma[J ] . Gastroenterol Res Pract, 2013, 2013: 145253. DOI: 10.1155/2013/145253.

WARD S C THUNG S N LIM K H Hepatic progenitor cells in liver cancers from Asian children Liver Int 2010 30 1 102 111 10.1111/j.1478-3231.2009.02126.x WARD S C, THUNG S N, LIM K H, et al . Hepatic progenitor cells in liver cancers from Asian children[J ] . Liver Int, 2010, 30(1): 102-111. DOI: 10.1111/j.1478-3231.2009.02126.x.

SOKOLOWSKI K M BALAMURUGAN M KUNNIMALAIYAAN S Role ofAkt inhibition on Notch1 expression in hepatocellular carcinoma: potential role for dual targeted therapy Am J Surg 2016 211 4 755 760 10.1016/j.amjsurg.2015.11.029 SOKOLOWSKI K M, BALAMURUGAN M, KUNNIMALAIYAAN S, et al . Role ofAkt inhibition on Notch1 expression in hepatocellular carcinoma: potential role for dual targeted therapy[J ] . Am J Surg, 2016, 211(4): 755-760. DOI: 10.1016/j.amjsurg.2015.11.029.

ZHOU S J DENG Y L LIANG H F Hepatitis B virus X protein promotes CREB-mediated activation of miR-3188 and Notch signaling in hepatocellular carcinoma Cell Death Differ 2017 24 9 1577 1587 10.1038/cdd.2017.87 ZHOU S J, DENG Y L, LIANG H F, et al . Hepatitis B virus X protein promotes CREB-mediated activation of miR-3188 and Notch signaling in hepatocellular carcinoma[J ] . Cell Death Differ, 2017, 24(9): 1577-1587. DOI: 10.1038/cdd.2017.87.

尹洁王晓娜 IL-35调控恶性肿瘤发生发展机制的研究进展中国肿瘤临床 2018 45 10 529 534 10.3969/j.issn.1000-8179.2018.10.050 尹洁, 王晓娜. IL-35调控恶性肿瘤发生发展机制的研究进展[J]. 中国肿瘤临床, 2018, 45(10): 529-534. DOI: 10.3969/j.issn.1000-8179.2018.10.050.

YIN J WANG Y N Advances in the mechanism of IL-35 regulating the development of malignant tumors Chin J Clin Oncol 2018 45 10 529 534 10.3969/j.issn.1000-8179.2018.10.050 YIN J, WANG Y N. Advances in the mechanism of IL-35 regulating the development of malignant tumors[J]. Chin J Clin Oncol, 2018, 45(10): 529-534. DOI: 10.3969/j.issn.1000-8179.2018.10.050.

SHAO X MA J JIA S Interleukin-35 suppresses antiviral immune response in chronic hepatitis B virus infection Front Cell Infect Microbiol 2017 7 472 10.3389/fcimb.2017.00472 SHAO X, MA J, JIA S, et al . Interleukin-35 suppresses antiviral immune response in chronic hepatitis B virus infection[J ] . Front Cell Infect Microbiol, 2017, 7: 472. DOI: 10.3389/fcimb.2017.00472.

Views

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

Role of Notch signaling in hyperoxia-induced oligodendrocyte maturation disorder of neonatal mice

From population cohort to cellular mechanisms: prenatal estriol exposure induces autism spectrum disorder in offspring via disrupting the Notch signaling pathway and neuronal proliferation

SLC38A1 drives malignant progression of hepatocellular carcinoma by activating PI3K/AKT signaling via enhanced glutamine uptake

Emerging advances in clinical diagnosis and treatment of hepatocellular carcinoma: evolution of comprehensive treatment strategies

PD-L1 promotes hepatocellular carcinoma progression by inhibiting PTP1B and activating FAK

Related Author

刘光建

郭冉

杜敏

刘杨

刘剑霞

徐颖

RAN Guanghui

SONG Anhua

Related Institution

School of Public Health， Guilin Medical University

School of Public Health， Guangxi Medical University

Department of Hepatobiliary， First Affiliated Hospital， Army Medical University （Third Military Medical University）

Digestive Disease Center， Chongqing Hygeia Hospital

Institute of Hepatobiliary Surgery of PLA，First Affiliated Hospital， Army Medical University （Third Military Medical University）

⁰