外泌体在慢性乙型肝炎和HBV相关肝细胞癌发生发展中的作用机制
DOI: 10.3969/j.issn.1001-5256.2022.09.034
利益冲突声明:所有作者均声明不存在利益冲突。
作者贡献声明:郭紫薇、陈贺宁、曹旭负责设计研究,资料分析,撰写论文;郭紫薇、张嘉鑫、张宁怡、靳茜参与检索文献,数据提取,修改论文;李小科、叶永安负责拟定写作思路,指导撰写文章并最后定稿。
Mechanism of action of exosomes in the development and progression of hepatitis B virus-related chronic hepatitis and hepatocellular carcinoma
-
摘要: 外泌体是由细胞内多囊泡体形成,携带脂质、蛋白质、编码和非编码RNA以及线粒体DNA等多种生物大分子,在体内可由包括肝细胞、肝星状细胞和免疫细胞在内的不同细胞类型释放,起着细胞间通讯的作用。越来越多研究表明,外泌体参与了HBV感染导致的慢性乙型肝炎(CHB)及肝细胞癌(HCC)的发生、发展及转归,有望成为HBV感染相关性HCC的早期诊断及预后评估的潜在生物学标志物。本文综述了外泌体在HBV感染宿主过程中的作用及其在CHB和HCC的发生、发展及预后中的重要性,以期为该领域的基础和临床研究提供新思路。Abstract: Exosomes (EXOs) are formed by intracellular multivesicular bodies and carry a variety of biomacromolecules such as lipids, proteins, encoding and non-coding RNAs, and mitochondrial DNA. EXOs can be released in vivo by different cell types, including hepatocytes, hepatic stellate cells, and immune cells and play the role of intercellular communication. More and more studies have shown that EXOs are involved in the development, progression, and prognosis of chronic hepatitis B (CHB) and hepatocellular carcinoma (HCC) caused by hepatitis B virus (HBV) infection and are expected to become potential biomarkers for the early diagnosis and prognostic evaluation of HBV-related HCC. This article reviews the role of EXOs in the host infection process of HBV and the importance of EXOs in the development, progression, and prognosis of CHB and HCC, in order to provide new ideas for the basic and clinical research in this field.
-
Key words:
- Exosomes /
- Hepatitis B Virus /
- Hepatitis B, Chronic /
- Carcinoma, Hepatocellular /
- Pathologic Processes
-
[1] ZHANG L, YU D. Exosomes in cancer development, metastasis, and immunity[J]. Biochim Biophys Acta Rev Cancer, 2019, 1871(2): 455-468. DOI: 10.1016/j.bbcan.2019.04.004. [2] JOHNSTONE RM, ADAM M, HAMMOND JR, et al. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes)[J]. J Biol Chem, 1987, 262(19): 9412-9420. [3] PEGTEL DM, GOULD SJ. Exosomes[J]. Annu Rev Biochem, 2019, 88: 487-514. DOI: 10.1146/annurev-biochem-013118-111902. [4] ZHAO L, WANG Y, ZHANG Y. The potential diagnostic and therapeutic applications of exosomes in drug-induced liver injury[J]. Toxicol Lett, 2021, 337: 68-77. DOI: 10.1016/j.toxlet.2020.11.021. [5] ZHANG Y, BI J, HUANG J, et al. Exosome: a review of its classification, isolation techniques, storage, diagnostic and targeted therapy applications[J]. Int J Nanomedicine, 2020, 15: 6917-6934. DOI: 10.2147/IJN.S264498. [6] KALLURI R, LEBLEU VS. The biology, function, and biomedical applications of exosomes[J]. Science, 2020, 367(6478): eaau6977. DOI: 10.1126/science.aau6977. [7] BANG C, THUM T. Exosomes: new players in cell-cell communication[J]. Int J Biochem Cell Biol, 2012, 44(11): 2060-2064. DOI: 10.1016/j.biocel.2012.08.007. [8] MASYUK AI, HUANG BQ, WARD CJ, et al. Biliary exosomes influence cholangiocyte regulatory mechanisms and proliferation through interaction with primary cilia[J]. Am J Physiol Gastrointest Liver Physiol, 2010, 299(4): G990-G999. DOI: 10.1152/ajpgi.00093.2010. [9] RAPOSO G, STOORVOGEL W. Extracellular vesicles: exosomes, microvesicles, and friends[J]. J Cell Biol, 2013, 200(4): 373-383. DOI: 10.1083/jcb.201211138. [10] VALADI H, EKSTRÖM K, BOSSIOS A, et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells[J]. Nat Cell Biol, 2007, 9(6): 654-659. DOI: 10.1038/ncb1596. [11] KOSAKA N, IGUCHI H, YOSHIOKA Y, et al. Secretory mechanisms and intercellular transfer of microRNAs in living cells[J]. J Biol Chem, 2010, 285(23): 17442-17452. DOI: 10.1074/jbc.M110.107821. [12] ISAAC R, REIS F, YING W, et al. Exosomes as mediators of intercellular crosstalk in metabolism[J]. Cell Metab, 2021, 33(9): 1744-1762. DOI: 10.1016/j.cmet.2021.08.006. [13] BUKONG TN, MOMEN-HERAVI F, KODYS K, et al. Exosomes from hepatitis C infected patients transmit HCV infection and contain replication competent viral RNA in complex with Ago2-miR122-HSP90[J]. PLoS Pathog, 2014, 10(10): e1004424. DOI: 10.1371/journal.ppat.1004424. [14] DREUX M, GARAIGORTA U, BOYD B, et al. Short-range exosomal transfer of viral RNA from infected cells to plasmacytoid dendritic cells triggers innate immunity[J]. Cell Host Microbe, 2012, 12(4): 558-570. DOI: 10.1016/j.chom.2012.08.010. [15] DARGAN DJ, SUBAK-SHARPE JH. The effect of herpes simplex virus type 1 L-particles on virus entry, replication, and the infectivity of naked herpesvirus DNA[J]. Virology, 1997, 239(2): 378-388. DOI: 10.1006/viro.1997.8893. [16] TERRAULT NA, LOK A, MCMAHON BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance[J]. Hepatology, 2018, 67(4): 1560-1599. DOI: 10.1002/hep.29800. [17] NI M, ZENG L. Reasearch progress in relationships between miRNA single nucleotide polymorphisms and HBV infection-related diseases[J]. J Jilin Univ (Med Edit), 2021, 47(6): 1588-1593. DOI: 10.13481/j.1671-587X.20210633.倪盟, 曾雷. miRNA单核苷酸多态性与HBV感染相关疾病关系的研究进展[J]. 吉林大学学报(医学版), 2021, 47(6): 1588-1593. DOI: 10.13481/j.1671-587X.20210633. [18] MASYUK AI, MASYUK TV, LARUSSO NF. Exosomes in the pathogenesis, diagnostics and therapeutics of liver diseases[J]. J Hepatol, 2013, 59(3): 621-625. DOI: 10.1016/j.jhep.2013.03.028. [19] ZHU YF, YU SX, QIU HJ, et al. Exosomes: another arena for the game between viruses and hosts[J]. Chin J Biotech, 2020, 36(9): 1732-1740. DOI: 10.13345/j.cjb.200039.朱依凡, 于少雄, 仇华吉, 等. 外泌体: 病毒与宿主博弈的另一"角斗场"[J]. 生物工程学报, 2020, 36(9): 1732-1740. DOI: 10.13345/j.cjb.200039. [20] MECKES DG Jr. Exosomal communication goes viral[J]. J Virol, 2015, 89(10): 5200-5203. DOI: 10.1128/JVI.02470-14. [21] ANDERSON MR, KASHANCHI F, JACOBSON S. Exosomes in viral disease[J]. Neurotherapeutics, 2016, 13(3): 535-546. DOI: 10.1007/s13311-016-0450-6. [22] LIU J, LIU Q, WANG DM, et al. Correlation between serum exosomal miR-122 and miR-146a expression and HBV-DNA load in patients with chronic hepatitis B[J]. Chin J Difficult Comp Cases, 2020, 19(10): 976-979, 984. DOI: 10.3969/j.issn.1671-6450.2020.10.002.刘娇, 刘青, 王大明, 等. 慢性乙型肝炎患者血清外泌体miR-122、miR-146a表达与HBV-DNA载量的相关性[J]. 疑难病杂志, 2020, 19(10): 976-979, 984. DOI: 10.3969/j.issn.1671-6450.2020.10.002. [23] SHI Y, DU L, LV D, et al. Exosomal interferon-induced transmembrane protein 2 transmitted to dendritic cells inhibits interferon alpha pathway activation and blocks anti-hepatitis B virus efficacy of exogenous interferon alpha[J]. Hepatology, 2019, 69(6): 2396-2413. DOI: 10.1002/hep.30548. [24] YANG Y, HAN Q, HOU Z, et al. Exosomes mediate hepatitis B virus (HBV) transmission and NK-cell dysfunction[J]. Cell Mol Immunol, 2017, 14(5): 465-475. DOI: 10.1038/cmi.2016.24. [25] WU W, WU D, YAN W, et al. Interferon-induced macrophage-derived exosomes mediate antiviral activity against hepatitis b virus through miR-574-5p[J]. J Infect Dis, 2021, 223(4): 686-698. DOI: 10.1093/infdis/jiaa399. [26] CHEN H, WANG LW, HUANG YQ, et al. Interferon-alpha induces high expression of APOBEC3G and STAT-1 in vitro and in vivo[J]. Int J Mol Sci, 2010, 11(9): 3501-3512. DOI: 10.3390/ijms11093501. [27] LI J, LIU K, LIU Y, et al. Exosomes mediate the cell-to-cell transmission of IFN-α-induced antiviral activity[J]. Nat Immunol, 2013, 14(8): 793-803. DOI: 10.1038/ni.2647. [28] YAO Z, QIAO Y, LI X, et al. Exosomes exploit the virus entry machinery and pathway to transmit alpha interferon-induced antiviral activity[J]. J Virol, 2018, 92(24): e01578-18. DOI: 10.1128/JVI.01578-18. [29] DU KL, SUN XD, XU HX, et al. Research progress of SSS exosomes in virus infection[J]. Int J Virol, 2021, 1(1): 86-88. DOI: 10.3760/cma.j.issn.1673-4092.2021.01.020.杜凯丽, 孙晓东, 徐红霞, 等. sss外泌体在病毒感染中的研究进展[J]. 国际病毒学杂志, 2021, 1(1): 86-88. DOI: 10.3760/cma.j.issn.1673-4092.2021.01.020. [30] YANG JD, HAINAUT P, GORES GJ, et al. A global view of hepatocellular carcinoma: trends, risk, prevention and management[J]. Nat Rev Gastroenterol Hepatol, 2019, 16(10): 589-604. DOI: 10.1038/s41575-019-0186-y. [31] GUO W, GAO Y, LI N, et al. Exosomes: New players in cancer (Review)[J]. Oncol Rep, 2017, 38(2): 665-675. DOI: 10.3892/or.2017.5714. [32] CHEN R, XU X, TAO Y, et al. Exosomes in hepatocellular carcinoma: a new horizon[J]. Cell Commun Signal, 2019, 17(1): 1. DOI: 10.1186/s12964-018-0315-1. [33] LIU J, REN L, LI S, et al. The biology, function, and applications of exosomes in cancer[J]. Acta Pharm Sin B, 2021, 11(9): 2783-2797. DOI: 10.1016/j.apsb.2021.01.001. [34] WANG H, LU Z, ZHAO X. Tumorigenesis, diagnosis, and therapeutic potential of exosomes in liver cancer[J]. J Hematol Oncol, 2019, 12(1): 133. DOI: 10.1186/s13045-019-0806-6. [35] YANG X, LI H, SUN H, et al. Hepatitis B virus-encoded microRNA controls viral replication[J]. J Virol, 2017, 91(10): e01919-16. DOI: 10.1128/JVI.01919-16. [36] KOGURE T, LIN WL, YAN IK, et al. Intercellular nanovesicle-mediated microRNA transfer: a mechanism of environmental modulation of hepatocellular cancer cell growth[J]. Hepatology, 2011, 54(4): 1237-1248. DOI: 10.1002/hep.24504. [37] WANG S, XU M, LI X, et al. Exosomes released by hepatocarcinoma cells endow adipocytes with tumor-promoting properties[J]. J Hematol Oncol, 2018, 11(1): 82. DOI: 10.1186/s13045-018-0625-1. [38] HE M, QIN H, POON TC, et al. Hepatocellular carcinoma-derived exosomes promote motility of immortalized hepatocyte through transfer of oncogenic proteins and RNAs[J]. Carcinogenesis, 2015, 36(9): 1008-1018. DOI: 10.1093/carcin/bgv081. [39] ZHANG H, DENG T, GE S, et al. Exosome circRNA secreted from adipocytes promotes the growth of hepatocellular carcinoma by targeting deubiquitination-related USP7[J]. Oncogene, 2019, 38(15): 2844-2859. DOI: 10.1038/s41388-018-0619-z. [40] LIN XJ, FANG JH, YANG XJ, et al. Hepatocellular carcinoma cell-secreted exosomal MicroRNA-210 promotes angiogenesis in vitro and in vivo[J]. Mol Ther Nucleic Acids, 2018, 11: 243-252. DOI: 10.1016/j.omtn.2018.02.014. [41] YUKAWA H, SUZUKI K, AOKI K, et al. Imaging of angiogenesis of human umbilical vein endothelial cells by uptake of exosomes secreted from hepatocellular carcinoma cells[J]. Sci Rep, 2018, 8(1): 6765. DOI: 10.1038/s41598-018-24563-0. [42] FANG JH, ZHANG ZJ, SHANG LR, et al. Hepatoma cell-secreted exosomal microRNA-103 increases vascular permeability and promotes metastasis by targeting junction proteins[J]. Hepatology, 2018, 68(4): 1459-1475. DOI: 10.1002/hep.29920. [43] LI R, WANG Y, ZHANG X, et al. Exosome-mediated secretion of LOXL4 promotes hepatocellular carcinoma cell invasion and metastasis[J]. Mol Cancer, 2019, 18(1): 18. DOI: 10.1186/s12943-019-0948-8. [44] FORNER A, REIG M, BRUIX J. Hepatocellular carcinoma[J]. Lancet, 2018, 391(10127): 1301-1314. DOI: 10.1016/S0140-6736(18)30010-2. [45] MA F, VAYALIL J, LEE G, et al. Emerging role of tumor-derived extracellular vesicles in T cell suppression and dysfunction in the tumor microenvironment[J]. J Immunother Cancer, 2021, 9(10): e003217. DOI: 10.1136/jitc-2021-003217. [46] PATHANIA AS, PRATHIPATI P, CHALLAGUNDLA KB. New insights into exosome mediated tumor-immune escape: Clinical perspectives and therapeutic strategies[J]. Biochim Biophys Acta Rev Cancer, 2021, 1876(2): 188624. DOI: 10.1016/j.bbcan.2021.188624. [47] YE L, ZHANG Q, CHENG Y, et al. Tumor-derived exosomal HMGB1 fosters hepatocellular carcinoma immune evasion by promoting TIM-1+ regulatory B cell expansion[J]. J Immunother Cancer, 2018, 6(1): 145. DOI: 10.1186/s40425-018-0451-6. [48] MAO X, XU J, WANG W, et al. Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives[J]. Mol Cancer, 2021, 20(1): 131. DOI: 10.1186/s12943-021-01428-1. [49] XI L, PENG M, LIU S, et al. Hypoxia-stimulated ATM activation regulates autophagy-associated exosome release from cancer-associated fibroblasts to promote cancer cell invasion[J]. J Extracell Vesicles, 2021, 10(11): e12146. DOI: 10.1002/jev2.12146. [50] CHEN Y, MCANDREWS KM, KALLURI R. Clinical and therapeutic relevance of cancer-associated fibroblasts[J]. Nat Rev Clin Oncol, 2021, 18(12): 792-804. DOI: 10.1038/s41571-021-00546-5. [51] LIU Z, YOU Y, CHEN Q, et al. Extracellular vesicle-mediated communication between hepatocytes and natural killer cells promotes hepatocellular tumorigenesis[J]. Mol Ther, 2022, 30(2): 606-620. DOI: 10.1016/j.ymthe.2021.07.015. [52] KOUWAKI T, OKAMOTO M, TSUKAMOTO H, et al. Extracellular vesicles deliver host and virus RNA and regulate innate immune response[J]. Int J Mol Sci, 2017, 18(3): 666. DOI: 10.3390/ijms18030666.