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| Advances on molecular mechanism of hepatitis B virus-induced hepatocellular carcinoma |
SHAO Yiming1,2( ),SU Lide1,2,HAO Rui1,2,WANG Qianqian2,NARANMANDURA Hua1,2,*() |
| 1. College of Pharmaceutical Sciences，Inner Mongolia Medical University，Hohhot 010000，China; 2. School of Medicine，Zhejiang University，Hangzhou 310058，China |
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Abstract The pathogenesis of hepatitis B virus （HBV）-associated hepatocellular carcinoma （HCC） is complicated with the crosstalk of multiple factors and the multi-step processes. The main mechanisms underlying the HBV-induced HCC include:①integration of HBV DNA into the host hepatocyte genome to alter gene function at the insertion site，resulting in host genome instability and expression of carcinogenic truncated proteins;②HBV gene mutations at S，C，and X coding regions in the genome;③HBV X gene-encoded HBx protein activates proto-oncogenes and inhibits tumor suppressor genes，leading to the HCC occurrence. In this article，the recent research progress on the molecular mechanism of HBV-induced HCC is comprehensively reviewed，so as to provide insights into the prevention，early prediction and postoperative adjuvant therapy of HCC.
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Received: 23 September 2020
Published: 14 May 2021
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Corresponding Authors:
NARANMANDURA Hua
E-mail: 2018120006@stu.immu.edu.cn;narenman@zju.edu.cn
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乙型肝炎病毒诱发肝细胞癌分子机制研究进展
乙型肝炎病毒（HBV）诱导肝细胞癌（HCC）的发生是一个多阶段、多因素相互作用的复杂过程。HBV促进HCC发生、发展的途径主要包括HBV DNA整合至宿主肝细胞基因组从而影响整合位点的基因功能、形成致癌作用的截短蛋白、造成宿主基因组的不稳定，HBV基因组S、C、X区基因突变，HBV X基因编码的HBx蛋白激活原癌基因、抑制抑癌基因等。本文综述了近年来HBV诱发HCC分子机制的研究进展，以期为HCC预防、早期预测及术后辅助治疗提供理论指导。
关键词：
乙型肝炎病毒,
肝细胞癌,
基因突变,
基因整合,
乙型肝炎病毒X蛋白,
综述
|
|
| [1] |
THOMAS D L . Global elimination of chronic hepatitis[J]. N Engl J Med, 2019, 380(21): 2041-2050.
doi: 10.1056/NEJMra1810477
|
|
|
| [2] |
WANG M, WANG Y, FENG X, et al. Contribution of hepatitis B virus and hepatitis C virus to liver cancer in China north areas:experience of the Chinese National Cancer Center[J]. Int J Infect Dis, 2017, 15-21.
doi: 10.1016/j.ijid.2017.09.003
|
|
|
| [3] |
LARSSON S B, TRIPODI G, RAIMONDO G, et al. Integration of hepatitis B virus DNA in chronically infected patients assessed by Alu-PCR[J]. J Med Virol, 2018, 90(10): 1568-1575.
doi: 10.1002/jmv.25227
|
|
|
| [4] |
SUNG W K, ZHENG H, LI S, et al. Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma[J]. Nat Genet, 2012, 44(7): 765-769.
doi: 10.1038/ng.2295
|
|
|
| [5] |
KWA W T, EFFENDI K, YAMAZAKI K, et al. Telomerase reverse transcriptase （ TERT） promoter mutation correlated with intratumoral heterogeneity in hepatocellular carcinoma[J] . Pathol Int, 2020, 70(9): 624-632.
doi: 10.1111/pin.12974
|
|
|
| [6] |
PEZZUTO F, BUONAGURO L, BUONAGURO F M, et al. Frequency and geographic distribution of TERT promoter mutations in primary hepatocellular carcinoma[J]. Infect Agent Cancer, 2017, 27.
doi: 10.1186/s13027-017-0138-5
|
|
|
| [7] |
YU J I, CHOI C, HA S Y, et al. Clinical importance of TERT overexpression in hepatocellular carcinoma treated with curative surgical resection in HBV endemic area[J]. Sci Rep, 2017, 7(1): 12258.
doi: 10.1038/s41598-017-12469-2
|
|
|
| [8] |
ZHANG H, WENG X, YE J, et al. Promoter hypermethylation of TERT is associated with hepatocellular carcinoma in the Han Chinese population[J]. Clin Res Hepatol Gastro- enterol, 2015, 39(5): 600-609.
doi: 10.1016/j.clinre.2015.01.002
|
|
|
| [9] |
SZE K M F, HO D W H, CHIU Y T, et al. Hepatitis B virus–telomerase reverse transcriptase promoter integration harnesses host elf4，resulting in telomerase reverse transcriptase gene transcription in hepatocellular carcinoma[J/OL]. Hepatology, 2021, 73(1): 23-40.
doi: 10.1002/hep.31231
|
|
|
| [10] |
GUERRERO R B, ROBERTS L R . The role of hepatitis B virus integrations in the pathogenesis of human hepatocellular carcinoma[J]. J Hepatol, 2005, 42(5): 760-777.
doi: 10.1016/j.jhep.2005.02.005
|
|
|
| [11] |
EHEDEGO H, MOHS A, JANSEN B, et al. Loss of cyclin E1 attenuates hepatitis and hepatocarcinogene sis in a mouse model of chronic liver injury[J]. Oncogene, 2018, 37(25): 3329-3339.
doi: 10.1038/s41388-018-0181-8
|
|
|
| [12] |
SONNTAG R, GIEBELER N, NEVZOROVA Y A, et al. Cyclin E1 and cyclin-dependent kinase 2 are critical for initiation，but not for progression of hepatocellular carcinoma[J]. Proc Natl Acad Sci USA, 2018, 115(37): 9282-9287.
doi: 10.1073/pnas.1807155115
|
|
|
| [13] |
JEGAL M E, JUNG S Y, HAN Y S, et al. C-terminal truncated HBx reduces doxorubicin cytotoxicity via ABCB1 upregulation in Huh-7 hepatocellular carcinoma cells[J] . BMB Rep, 2019, 52(5): 330-335.
doi: 10.5483/BMBRep.2019.52.5.312
|
|
|
| [14] |
LUDGATE L, LIU K, LUCKENBAUGH L, et al. Cell-free hepatitis B virus capsid assembly dependent on the core protein C-terminal domain and regulated by phosphorylation[J]. J Virol, 2016, 90(12): 5830-5844.
doi: 10.1128/JVI.00394-16
|
|
|
| [15] |
LI M, SHEN Y, CHEN Y, et al. Characterization of hepatitis B virus infection and viral DNA integration in non‐Hodgkin lymphoma[J]. Int J Cancer, 2020, 147(8): 2199-2209.
doi: 10.1002/ijc.33027
|
|
|
| [16] |
齐鲁楠，陈圆圆，陈祖舜，等. 广西地区乙肝病毒/黄曲霉毒素B1双暴露相关性肝细胞性肝癌微阵列比较基因组学的研究[J]. 中国癌症防治杂志，2013，5（3）:201–210.DOI:10.3969/j.issn.1674-5671.2013.03.04 .
|
|
|
| [17] |
PANG E, WONG N, LAI P B S, et al. Consistent chromosome 10 rearrangements in four newly established human hepatocellular carcinoma cell lines[J]. Genes Chromosom Cancer, 2002, 33(2): 150-159.
doi: 10.1002/gcc.1220
|
|
|
| [18] |
LI C L, LI C Y, LIN Y Y, et al. Androgen receptor enhances hepatic telomerase reverse transcriptase gene transcription after hepatitis B virus integration or point mutation in promoter region[J]. Hepatology, 2019, 69(2): 498-512.
doi: 10.1002/hep.30201
|
|
|
| [19] |
HOSSAIN M G, MAHMUD M M, NAZIR K, et al. PreS1 mutations alter the large HBsAg antigenicity of a hepatitis B virus strain isolated in Bangladesh[J]. Int J Mol Sci, 2020, 21(2): 546.
doi: 10.3390/ijms21020546
|
|
|
| [20] |
CHEVALIEZ S, RODRIGUEZ C, POITEAU L, et al. Primary resistance of hepatitis B virus to nucleoside and nucleotide analogues[J]. J Viral Hepat, 2019, 26(2): 278-286.
doi: 10.1111/jvh.13025
|
|
|
| [21] |
金子铮，金方方，文凤，等.血清HBV DNA前S/S区基因突变检测的回顾性临床应用研究[J]. 标记免疫分析与临床，2019，155（9）:26–30，49.DOI:CNKI:SUN:BJMY.0.2019-09-004 .
|
|
|
| [22] |
LIN C M, WANG G M, JOW G M, et al. Functional analysis of hepatitis B virus pre-s deletion variants associated with hepatocellular carcinoma[J]. J Biomed Sci, 2012, 19(1): 17.
doi: 10.1186/1423-0127-19-17
|
|
|
| [23] |
郑羽飘，钱宝鑫，覃琴，等.乙肝病毒S基因Pre-S区突变的人肝癌细胞HepG2稳定株构建及其生物学行为变化[J]. 山东医药，2019，59（2）:36–39. DOI:10.3969/j.issn.1002-266X.2019.02.009 .
|
|
|
| [24] |
束毅，王伟，代鹏，等.肝癌患者体内乙型肝炎病毒基因组BCP/Pre C区基因突变多样性分析[J]. 病毒学报，2017，33（1）:36–43.DOI：10.13242j. cnki.bingduxuebao.003087 .
|
|
|
| [25] |
PODLAHA O, GANE E, BRUNETTO M, et al. Large-scale viral genome analysis identifies novel clinical associations between hepatitis B virus and chronically infected patients[J]. Sci Rep, 2019, 9(1): 10529.
doi: 10.1038/s41598-019-46609-7
|
|
|
| [26] |
徐丹丹，张曼，吴黎黎.乙型肝炎病毒基本核心启动子区A1762T/G1764A突变检测的意义[J]. 检验医学与临床，2017，14（1）:32–34.DOI:10.3969/j.issn.1672-9455.2017.01.011 .
|
|
|
| [27] |
MU?OZ A, CHEN J G, EGNER P A, et al. Predictive power of hepatitis B 1762T/1764A mutations in plasma for hepatocellular carcinoma risk in Qidong，China [J]. Carcinogenesis, 2011, 32(6): 860-865.
doi: 10.1093/carcin/bgr055
|
|
|
| [28] |
HUANG Y, TAI A W, TONG S, et al. HBV core promoter mutations promote cellular proliferation through E2F1-mediated upregulation of S-phase kinase-associated protein 2 transcription[J]. J Hepatol, 2013, 58(6): 1068-1073.
doi: 10.1016/j.jhep.2013.01.014
|
|
|
| [29] |
GONZáLEZ C, TABERNERO D, CORTESE M F, et al. Detection of hyper-conserved regions in hepatitis B virus X gene potentially useful for gene therapy[J]. World J Gastroenterol, 2018, 24(19): 2095-2107.
doi: 10.3748/wjg.v24.i19.2095
|
|
|
| [30] |
SALPINI R, SURDO M, CORTESE M F, et al. SAT-195-The novel HBx mutation F30V correlates with HCC in vivo，hampers HBV replicative efficiency and enhances anti-apoptotic activity of HBx N-terminus in vitro[J/OL] . J Hepatol, 2019, 70(1): e716.
doi: 10.1016/S0618-8278（19）31430-6
|
|
|
| [31] |
SZE K M F, CHU G K Y, LEE J M F, et al. C-terminal truncated hepatitis B virus x protein is associated with metastasis and enhances invasiveness by C-Jun/matrix metalloproteinase protein 10 activation in hepatocellular carcinoma[J]. Hepatology, 2013, 57(1): 131-139.
doi: 10.1002/hep.25979
|
|
|
| [32] |
QU L S, ZHU J, LIU T T, et al. Effect of combined mutations in the enhancer II and basal core promoter of hepatitis B virus on development of hepatocellular carcinoma in Qidong，China[J]. Hepatol Res, 2014, 44(12): 1186-1195.
doi: 10.1111/hepr.12291
|
|
|
| [33] |
王玉凤. HBX蛋白与TGF-β致HBV相关性肝病的研究进展[J]. 重庆医学，2017，46（28）: 4011–4012.DOI:10.3969/j.issn.1671-8348.2017.28. 044 .
|
|
|
| [34] |
YUASA R，TAKAHASHI K，DIEN B V，et al. Properties of hepatitis B virus genome recovered from Vietnamese patients with fulminant hepatitis in comparison with those of acute hepatitis[J]. J Med Virol，2000，61（1）:23–28. DOI:10.1002/（SICI）1096-9071（200005）61:13.3.CO .
|
|
|
| [35] |
RANG K Y, RAN B M, WOO C J . Integrin α6 as an invasiveness marker for hepatitis B viral X-driven hepatocellular carcinoma[J]. Cancer Biomark, 2018, 23(1): 135-144.
doi: 10.3233/CBM-181498
|
|
|
| [36] |
SALERNO D, CHIODO L, ALFANO V, et al. Hepatitis B protein HBx binds the DLEU2 lncRNA to sustain cccDNA and host cancer-related gene transcription[J]. Gut, 2020, 69(11): 2016-2024.
doi: 10.1136/gutjnl-2019-319637
|
|
|
| [37] |
HEUKERS R, ALTINTAS I, RAGHOENATH S, et al. Targeting hepatocyte growth factor receptor （Met） positive tumor cells using internalizing nanobody-decorated albumin nanoparticles[J]. Biomaterials, 2014, 35(1): 601-610.
doi: 10.1016/j.biomaterials.2013.10.001
|
|
|
| [38] |
CHEN L, HU L, LI L, et al. Dysregulation of β-catenin by hepatitis B virus X protein in HBV-infected human hepatocellular carcinomas[J]. Front Med China, 2010, 4(4): 399-411.
doi: 10.1007/s11684-010-0170-y
|
|
|
| [39] |
LIU N, WANG D N, LIU H Y, et al. Potential dynamic analysis of tumor suppressor p53 regulated by Wip1 protein[J/OL]. Chin Phys B, 2020, 29(6): 068704.
doi: 10.1088/1674-1056/ab84d1
|
|
|
| [40] |
YANG W Y, RAO P S, LUO Y C, et al. Omics-based investigation of diet-induced obesity synergized with HBx， Src，and p53 mutation accelerating hepato- carcinogenesis in zebrafish model[J] . Cancers, 2019, 11(12): 1899.
doi: 10.3390/cancers11121899
|
|
|
| [41] |
LIU N, LIU Q, YANG X, et al. Hepatitis B virus-upregulated LNC-HUR1 promotes cell proliferation and tumorigenesis by blocking p53 activity[J]. Hepatology, 2018, 68(6): 2130-2144.
doi: 10.1002/hep.30098
|
|
|
| [42] |
CHOI J H, JEONG H, JANG K L . Hepatitis B virus X protein suppresses all-trans retinoic acid-induced apoptosis in human hepatocytes by repressing p14 expression via DNA methylation[J]. J Gen Virol, 2017, 98(11): 2786-2798.
doi: 10.1099/jgv.0.000958
|
|
|
| [43] |
DU W, HU H, ZHANG J, et al. The mechanism of MAPK signal transduction pathway involved with electroacupuncture treatment for different diseases[J]. Evid Based Complement Alternat Med, 2019, 1-10.
doi: 10.1155/2019/8138017
|
|
|
| [44] |
TU W, GONG J, TIAN D, et al. Hepatitis B virus X protein induces SATB1 expression through activation of ERK and p38MAPK pathways to suppress anoikis[J]. Dig Dis Sci, 2019, 64(11): 3203-3214.
doi: 10.1007/s10620-019-05681-9
|
|
|
| [45] |
蒲长宇，周后龙，彭亮，等.乙型肝炎病毒X蛋白对肝癌细胞MKK3，p38MAPK表达的影响[J]. 现代肿瘤医学，2011，（4）:640–644.DOI:10.3969/j.issn.1672-4992.2011.04.06 .
|
|
|
| [46] |
SOHEL M . Circulating microRNAs as biomarkers in cancer diagnosis[J]. Life Sci, 2020, 117473.
doi: 10.1016/j.lfs.2020.117473
|
|
|
| [47] |
姚国栋，连源，陈鹏，等. MicroRNA在肿瘤中的研究进展[J]. 河北医药，2019，41（5）:771–775.DOI:10.3969/j.issn.1002-7386.2019.05.035 .
|
|
|
| [48] |
UNNIKRISHNAN A, FREEMAN W M, JACKSON J, et al. The role of DNA methylation in epigenetics of aging[J]. Pharmacol Ther, 2019, 172-185.
doi: 10.1016/j.pharmthera.2018.11.001
|
|
|
| [49] |
WEI X, XIANG T, REN G, et al. miR-101 is down-regulated by the hepatitis B virus x protein and induces aberrant DNA methylation by targeting DNA methyltransferase 3A[J]. Cell Signal, 2013, 25(2): 439-446.
doi: 10.1016/j.cellsig.2012.10.013
|
|
|
| [50] |
伍刚，郑波，黄锐，等.HBx 下调 miR-16 家族表达促进肝癌细胞恶性转化[J]. 中国普外基础与临床杂志，2017，24（4）: 412–419.DOI:10.7507/1007-9424.201611043 .
|
|
|
| [51] |
WU G, YU F, XIAO Z, et al. Hepatitis B virus X protein downregulates expression of the miR-16 family in malignant hepatocytes in vitro[J] . Br J Cancer, 2011, 105(1): 146-153.
doi: 10.1038/bjc.2011.190
|
|
|
| [52] |
ZHANG X, LIU S, HU T, et al. Up-regulated microRNA-143 transcribed by nuclear factor kappa B enhances hepatocarcinoma metastasis by repressing fibronectin expression[J]. Hepatology, 2009, 50(2): 490-499.
doi: 10.1002/hep.23008
|
|
|
| [53] |
KONG G, ZHANG J, ZHANG S, et al. Upregulated microRNA-29a by hepatitis B virus X protein enhances hepatoma cell migration by targeting PTEN in cell culture model[J/OL]. PLoS One, 2011, 6(5): e19518.
doi: 10.1371/journal.pone.0019518
|
|
|
| [54] |
LAN T, CHANG L, WU L, et al. IL-6 plays a crucial role in HBV infection[J]. J Clin Transl Hepatol, 2015, 3(4): 271-276.
doi: 10.14218/JCTH.2015.00024
|
|
|
| [55] |
HU Z, LUO D, WANG D, et al. IL-17 activates the IL-6/STAT3 signal pathway in the proliferation of hepatitis B virus-related hepatocellular carcinoma[J]. Cell Physiol Biochem, 2017, 43(6): 2379-2390.
doi: 10.1159/000484390
|
|
|
| [56] |
QUETIER I, BREZILLON N, REVAUD J, et al. C-terminal-truncated hepatitis B virus X protein enhances the development of diethylnitrosamine-induced hepatocellular carcinogenesis[J]. J Gen Virol, 2015, 96(3): 614-625.
doi: 10.1099/vir.0.070680-0
|
|
|
| [57] |
吴胜斌，王应灯.人参皂苷Rg1对肾间质纤维化大鼠肾组织肝细胞生长因子及转化生长因子-β1的影响[J]. 中华实用诊断与治疗杂志，2019，33（5）: 422–425.DOI:10.13507/j.issn.1674-3474.2019. 05.002 .
|
|
|
| [58] |
JI L, LIN Z, WAN Z, et al. miR-486-3p mediates hepatocellular carcinoma sorafenib resistance by targeting FGFR4 and EGFR[J]. Cell Death Dis, 2020, 11(4): 250.
doi: 10.1038/s41419-020-2413-4
|
|
|
| [59] |
YOU N, LIU W, TANG L, et al. Tg737 signaling is required for hypoxia-enhanced invasion and migration of hepatoma cells[J]. J Exp Clin Cancer Res, 2012, 31(1): 75.
doi: 10.1186/1756-9966-31-75
|
|
|
| [60] |
刘婷，吴俊成，陆伦根，等. STAT3加重TGF-β1诱导的肝癌细胞上皮-间质转化的发生[J]. 肝脏，2018，（2）:128–132.DOI:10.3969/j.issn.1008-1704.2018.02.010 .
|
|
|
| [61] |
ZHANG Q, SONG G, YAO L, et al. miR-3928v is induced by HBx via NF-κB/EGR1 and contributes to hepatocellular carcinoma malignancy by down-regulating VDAC3[J]. J Exp Clin Cancer Res, 2018, 37(1): 14.
doi: 10.1186/s13046-018-0681-y
|
|
|
| [62] |
KUO C Y, CHIU V, HSIEH P C, et al. Chrysophanol attenuates hepatitis B virus X protein-induced hepatic stellate cell fibrosis by regulating endoplasmic reticulum stress and ferroptosis[J]. J Pharmacol Sci, 2020, 144(3): 172-182.
doi: 10.1016/j.jphs.2020.07.014
|
|
|
| [63] |
ZHOU L, YANG Y, TIAN D, et al. Oxidative stress-induced 1，N6-ethenodeoxyadenosine adduct formation contributes to hepatocarcinogenesis [J]. Oncol Rep, 2013, 29(3): 875-884.
doi: 10.3892/or.2013.2227
|
|
|
| [64] |
REN F L, LI W N, XIANG A, et al. Distribution and difference of APOBEC‐induced mutations in the TpCpW context of HBV DNA between HCC and non‐HCC[J]. J Med Virol, 2020, 92(1): 53-61.
doi: 10.1002/jmv.25572
|
|
|
| [65] |
LIU W, WU J, YANG F, et al. Genetic polymorphisms predisposing the interleukin 6–induced APOBEC3B-UNG imbalance increase HCC risk via promoting the generation of APOBEC-signature HBV mutations [J]. Clin Cancer Res, 2019, 25(18): 5525-5536.
doi: 10.1158/1078-0432.CCR-18-3083
|
|
|
| [66] |
LIU Y, FENG J, SUN M, et al. Long non-coding RNA HULC activates HBV by modulating HBx/STAT3/miR-539/APOBEC3B signaling in HBV-related hepatocellular carcinoma[J]. Cancer Lett, 2019, 158-170.
doi: 10.1016/j.canlet.2019.04.008
|
|
|
| [67] |
NIK-ZAINAL S, WEDGE D C, ALEXANDROV L B, et al. Association of a germline copy number polymorphism of APOBEC3A and APOBEC3B with burden of putative APOBEC-dependent mutations in breast cancer[J]. Nat Genet, 2014, 46(5): 487-491.
doi: 10.1038/ng.2955
|
|
|
| [68] |
XU R, ZHANG X, ZHANG W, et al. Association of human APOBEC3 cytidine deaminases with the generation of hepatitis virus B x antigen mutants and hepatocellular carcinoma[J]. Hepatology, 2007, 46(6): 1810-1820.
doi: 10.1002/hep.21893
|
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