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The functional role of exosome in hepatocellular carcinoma

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Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with limited therapeutic options. Exosome is a member of extracellular vesicles that can be released by different cells in liver to communicate with other cells. HCC development has been characterized by a dysfunction of exosome regulation through many molecular mechanisms. The aim of the present review is to summarize the literature on exosomes in HCC, their roles in hepatocarcinogenesis from liver disease, molecules exchange between tumor cells and neighboring cells, metastasis, chemoresistant, immunosuppression, early diagnose and therapy application.


Literatures about HCC and exosomes from PubMed databases were reviewed in this article.


As our review described, exosomes can induce malignant transformation of liver disease via promoting viral diffusion and inflammation, exchange oncogenic factors between tumor cells, sustain tumor growth by neighboring stromal cells, play a important role in metastasis, trigger chemoresistance through transmitting long noncoding RNAs, stimulate immune activation as well as immune evasion, be utilized in biomarkers discovery and therapeutic options.


Available data suggested that exosomes may play an important role in HCC development. More studies on the way that exosomes mediated the HCC progression are needed to promote the clinical utilization of exosomes.

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  1. Basu S, Bhattacharyya SN (2014) Insulin-like growth factor-1 prevents miR-122 production in neighbouring cells to curtail its intercellular transfer to ensure proliferation of human hepatoma cells. Nucleic Acids Res 42:7170–7185. https://doi.org/10.1093/nar/gku346

  2. Becker A, Thakur BK, Weiss JM, Kim HS, Peinado H, Lyden D (2016) Extracellular vesicles in cancer: cell-to-cell mediators of metastasis. Cancer Cell 30:836–848. https://doi.org/10.1016/j.ccell.2016.10.009

  3. Blanc L, Vidal M (2018) New insights into the function of Rab GTPases in the context of exosomal secretion. Small GTPases 9:95–106. https://doi.org/10.1080/21541248.2016.1264352

  4. Brimacombe CL et al (2011) Neutralizing antibody-resistant hepatitis C virus cell-to-cell transmission. J Virol 85:596–605. https://doi.org/10.1128/JVI.01592-10

  5. Bruix J, Gores GJ, Mazzaferro V (2014) Hepatocellular carcinoma: clinical frontiers and perspectives. Gut 63:844–855. https://doi.org/10.1136/gutjnl-2013-306627

  6. Cancer Genome Atlas Research Network, Electronic address wbe (2017) Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell 169:1327–1341. https://doi.org/10.1016/j.cell.2017.05.046

  7. Chaiteerakij R, Addissie BD, Roberts LR (2015) Update on biomarkers of hepatocellular carcinoma. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc 13:237–245. https://doi.org/10.1016/j.cgh.2013.10.038

  8. Chiba M, Kimura M, Asari S (2012) Exosomes secreted from human colorectal cancer cell lines contain mRNAs, microRNAs and natural antisense RNAs, that can transfer into the human hepatoma HepG2 and lung cancer A549 cell lines. Oncol Rep 28:1551–1558. https://doi.org/10.3892/or.2012.1967

  9. Choi JY, Jung SW, Kim HY, Kim M, Kim Y, Kim DG, Oh EJ (2013) Diagnostic value of AFP-L3 and PIVKA-II in hepatocellular carcinoma according to total-AFP. World J Gastroenterol 19:339–346. https://doi.org/10.3748/wjg.v19.i3.339

  10. Cobb DA, Kim OK, Golden-Mason L, Rosen HR, Hahn YS (2018) Hepatocyte-derived exosomes promote T follicular regulatory cell expansion during hepatitis C. Virus Infect Hepatol 67:71–85. https://doi.org/10.1002/hep.29409

  11. Conigliaro A et al (2015) CD90+ liver cancer cells modulate endothelial cell phenotype through the release of exosomes containing H19 lncRNA. Mol Cancer 14:155. https://doi.org/10.1186/s12943-015-0426-x

  12. Costa-Silva B et al (2015) Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol 17:816–826. https://doi.org/10.1038/ncb3169

  13. De Toro J, Herschlik L, Waldner C, Mongini C (2015) Emerging roles of exosomes in normal and pathological conditions: new insights for diagnosis and therapeutic applications. Front Immunol 6:203. https://doi.org/10.3389/fimmu.2015.00203

  14. Devhare PB, Sasaki R, Shrivastava S, Di Bisceglie AM, Ray R, Ray RB (2017) Exosome-mediated intercellular communication between hepatitis C virus-infected hepatocytes and hepatic stellate cells. J Virol 91:1–14. https://doi.org/10.1128/JVI.02225-16

  15. Dreux M et al (2012) Short-range exosomal transfer of viral RNA from infected cells to plasmacytoid dendritic cells triggers innate immunity. Cell Host Microbe 12:558–570. https://doi.org/10.1016/j.chom.2012.08.010

  16. Elgner F, Ren H, Medvedev R, Ploen D, Himmelsbach K, Boller K, Hildt E (2016) The intracellular cholesterol transport inhibitor U18666A inhibits the exosome-dependent release of mature hepatitis C virus. J Virol 90:11181–11196. https://doi.org/10.1128/JVI.01053-16

  17. El-Serag HB (2012) Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 142:1264–1273. https://doi.org/10.1053/j.gastro.2011.12.061

  18. El-Serag HB, Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132:2557–2576. https://doi.org/10.1053/j.gastro.2007.04.061

  19. Enomoto Y et al (2017) Identification of the novel 3′ UTR sequences of human IL-21 mRNA as potential targets of miRNAs. Sci Rep 7:7780. https://doi.org/10.1038/s41598-017-07853-x

  20. Fabbri M et al (2012) MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc Natl Acad Sci USA 109:E2110–E2116

  21. Fang JH, Zhang ZJ, Shang LR, Luo YW, Lin Y, Yuan Y, Zhuang SM (2018a) Hepatoma cell-secreted exosomal microRNA-103 increases vascular permeability and promotes metastasis by targeting junction proteins. Hepatology. https://doi.org/10.1002/hep.29920

  22. Fang T et al (2018b) Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer. Nat Commun 9:191. https://doi.org/10.1038/s41467-017-02583-0

  23. Feng D et al (2010) Cellular internalization of exosomes occurs through phagocytosis. Traffic 11:675–687. https://doi.org/10.1111/j.1600-0854.2010.01041.x

  24. Fornari F et al (2015) Circulating microRNAs, miR-939, miR-595, miR-519d and miR-494, Identify Cirrhotic Patients with HCC. PloS One 10:e0141448. https://doi.org/10.1371/journal.pone.0141448

  25. Fu X et al (2018) Exosomal microRNA-32-5p induces multidrug resistance in hepatocellular carcinoma via the PI3K/Akt pathway. J Exp Clin Cancer Res 37:1–18. https://doi.org/10.1186/s13046-018-0677-7

  26. Giannelli G, Koudelkova P, Dituri F, Mikulits W (2016) Role of epithelial to mesenchymal transition in hepatocellular carcinoma. J Hepatol 65:798–808. https://doi.org/10.1016/j.jhep.2016.05.007

  27. Guerrieri F, Belloni L, Pediconi N, Levrero M (2013) Molecular mechanisms of HBV-associated hepatocarcinogenesis. Semin Liver Dis 33:147–156. https://doi.org/10.1055/s-0033-1345721

  28. Hanahan D, Coussens LM (2012) Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21:309–322. https://doi.org/10.1016/j.ccr.2012.02.022

  29. He M et al (2015) Hepatocellular carcinoma-derived exosomes promote motility of immortalized hepatocyte through transfer of oncogenic proteins and RNAs. Carcinogenesis 36:1008–1018. https://doi.org/10.1093/carcin/bgv081

  30. Hood JL (2016) Melanoma exosome induction of endothelial cell GM-CSF in pre-metastatic lymph nodes may result in different M1 and M2 macrophage mediated angiogenic processes. Med Hypotheses 94:118–122. https://doi.org/10.1016/j.mehy.2016.07.009

  31. Hoshino A et al (2015) Tumour exosome integrins determine organotropic. Metastasis Nat 527:329–335. https://doi.org/10.1038/nature15756

  32. Huang A et al (2015) Exosomal transfer of vasorin expressed in hepatocellular carcinoma cells promotes migration of human umbilical vein endothelial cells. Int J Biol Sci 11:961–969. https://doi.org/10.7150/ijbs.11943

  33. Imjeti NS et al (2017) Syntenin mediates SRC function in exosomal cell-to-cell communication. Proc Natl Acad Sci USA 114:12495–12500. https://doi.org/10.1073/pnas.1713433114

  34. Jang SY et al (2017) Circulating serum exosomal microRNA-203 as a non-invasive biomarker for predicting prognosis in hepatocellular carcinoma. J Hepatol 66:S672–S673. https://doi.org/10.1016/s0168-8278(17)31815-9

  35. Jia X et al (2017) Label-free proteomic analysis of exosomes derived from inducible hepatitis B virus-replicating HepAD38 cell line. Mol Cell Proteom 16:S144–S160

  36. Kajihara J et al (2016) The Clinical impact of transcatheter arterial chemoembolization (TACE)-induced c-Met upregulation on TACE refractoriness in hepatocellular carcinoma digestive. Dis Sci 61:1572–1581. https://doi.org/10.1007/s10620-015-4018-9

  37. Kapoor NR (2014) Hepatitis B virus X protein modulates tumor micro-environment by means of exosomes. J Hepatol 60:S84. https://doi.org/10.1016/s0168-8278(14)60215-4

  38. Kapoor NR, Chadha R, Kumar S, Choedon T, Reddy VS, Kumar V (2017) The HBx gene of hepatitis B virus can influence hepatic microenvironment via exosomes by transferring its mRNA and protein. Virus Res 240:166–174. https://doi.org/10.1016/j.virusres.2017.08.009

  39. Kew M (2011) Hepatitis B virus x protein in the pathogenesis of hepatitis B virus-induced hepatocellular carcinoma. J Gastroenterol Hepatol 26(Suppl 1):144–152

  40. Klungboonkrong V, Das D, McLennan G (2017) Molecular mechanisms and targets of therapy for hepatocellular carcinoma. J Vasc Interv Radiol 28:949–955. https://doi.org/10.1016/j.jvir.2017.03.002

  41. Ko SF et al (2015) Adipose-derived mesenchymal stem cell exosomes suppress hepatocellular carcinoma growth in a rat model: apparent diffusion coefficient, natural killer T-cell responses, and histopathological features. Stem Cells Int 2015:1–11. https://doi.org/10.1155/2015/853506

  42. Kogure T, Yan IK, Lin WL, Patel T (2013) Extracellular vesicle-mediated transfer of a novel long noncoding RNA TUC339: a mechanism of intercellular signaling in human hepatocellular. Cancer Genes Cancer 4:261–272. https://doi.org/10.1177/1947601913499020

  43. Kourembanas S (2015) Exosomes: vehicles of intercellular signaling, biomarkers, and vectors of cell therapy. Annu Rev Physiol 77:13–27. https://doi.org/10.1146/annurev-physiol-021014-071641

  44. Kouwaki T et al (2016) Extracellular vesicles including exosomes regulate innate immune responses to hepatitis B virus infection. Front Immunol 7:335. https://doi.org/10.3389/fimmu.2016.00335

  45. Kouwaki T, Okamoto M, Tsukamoto H, Fukushima Y, Oshiumi H (2017) Extracellular vesicles deliver host and virus RNA and regulate innate immune. Response Int J Mol Sci 18:1–12. https://doi.org/10.3390/ijms18030666

  46. Kubes P, Jenne C (2018) Immune responses in the liver. Annu Rev Immunol 36:9.1–9.31. https://doi.org/10.1146/annurev-immunol-051116-052415

  47. Lambert AW, Pattabiraman DR, Weinberg RA (2017) Emerging biological principles of metastasis. Cell 168:670–691. https://doi.org/10.1016/j.cell.2016.11.037

  48. Lau EY et al (2016) Cancer-associated fibroblasts regulate tumor-initiating cell plasticity in hepatocellular carcinoma through c-Met/FRA1/HEY1. Signal Cell Rep 15:1175–1189. https://doi.org/10.1016/j.celrep.2016.04.019

  49. Li Y, Masaki T, Lemon SM (2013a) miR-122 and the hepatitis C RNA genome: more than just stability. RNA Biol 10:919–923. https://doi.org/10.4161/rna.25137

  50. Li Y, Masaki T, Yamane D, McGivern DR, Lemon SM (2013b) Competing and noncompeting activities of miR-122 and the 5′ exonuclease Xrn1 in regulation of hepatitis C virus replication. Proc Natl Acad Sci USA 110:1881–1886. https://doi.org/10.1073/pnas.1213515110

  51. Li B, Mao R, Liu C, Zhang W, Tang Y, Guo Z (2018) LncRNA FAL1 promotes cell proliferation and migration by acting as a CeRNA of miR-1236 in hepatocellular carcinoma cells. Life Sci 197:122–129. https://doi.org/10.1016/j.lfs.2018.02.006

  52. Lin XJ, Fang JH, Yang XJ, Zhang C, Yuan Y, Zheng L, Zhuang SM (2018) Hepatocellular carcinoma cell-secreted exosomal microRNA-210 promotes angiogenesis in vitro and in vivo. Mol Ther Nucleic Acids 11:243–252. https://doi.org/10.1016/j.omtn.2018.02.014

  53. Liu WH et al (2015) Combination of exosomes and circulating microRNAs may serve as a promising tumor marker complementary to alpha-fetoprotein for early-stage hepatocellular carcinoma diagnosis in rats. J Cancer Res Clin Oncol 141:1767–1778. https://doi.org/10.1007/s00432-015-1943-0

  54. Liu Y et al (2016) Tumor exosomal RNAs promote lung pre-metastatic niche formation by activating alveolar epithelial TLR3 to recruit neutrophils. Cancer Cell 30:243–256. https://doi.org/10.1016/j.ccell.2016.06.021

  55. Liu W et al (2017) Serum exosomal miR-125b is a novel prognostic marker for hepatocellular carcinoma. OncoTargets Ther 10:3843–3851. https://doi.org/10.2147/OTT.S140062

  56. Liu H et al (2018) Tumor-derived exosomes promote tumor self-seeding in hepatocellular carcinoma by transferring miRNA-25-5p to enhance cell motility. Oncogene. https://doi.org/10.1038/s41388-018-0309-x

  57. Longatti A, Boyd B, Chisari FV (2015) Virion-independent transfer of replication-competent hepatitis C virus RNA between permissive cells. J Virol 89:2956–2961. https://doi.org/10.1128/JVI.02721-14

  58. Lou G, Chen Z, Zheng M, Liu Y (2017) Mesenchymal stem cell-derived exosomes as a new therapeutic strategy for liver diseases. Exp Mol Med 49:e346. https://doi.org/10.1038/emm.2017.63

  59. Lu Z et al (2017) Dendritic cell-derived exosomes elicit tumor regression in autochthonous hepatocellular carcinoma mouse models. J Hepatol 67:739–748. https://doi.org/10.1016/j.jhep.2017.05.019

  60. Luo F, Sun Z, Han Q, Xue C, Bai C (2017) Effect of human hepatocellular carcinoma HepG2 cell-derived exosome on the differentiation of mesenchymal stem cells and Their interaction. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 39:312–317. https://doi.org/10.3881/j.issn.1000-503X.2017.03.003

  61. Lv LH et al (2012) Anticancer drugs cause release of exosomes with heat shock proteins from human hepatocellular carcinoma cells that elicit effective natural killer cell antitumor responses in vitro. J Biol Chem 287:15874–15885. https://doi.org/10.1074/jbc.M112.340588

  62. Ma C, Zhang Q, Greten TF (2017) Nonalcoholic fatty liver disease promotes hepatocellular carcinoma through direct and indirect effects on hepatocytes. FEBS J 285:752–762. https://doi.org/10.1111/febs.14209

  63. Malfettone A et al (2017) Transforming growth factor-β-induced plasticity causes a migratory stemness phenotype in hepatocellular carcinoma. Cancer Lett 392:39–50. https://doi.org/10.1016/j.canlet.2017.01.037

  64. Medvedev R, Hildt E, Ploen D (2017) Look who’s talking-the crosstalk between oxidative stress and autophagy supports exosomal-dependent release of HCV particles. Cell Biol Toxicol 33:211–231

  65. Mohrmann L et al (2018) Liquid biopsies using plasma exosomal nucleic acids and plasma cell-free DNA compared with clinical outcomes of patients with advanced cancers. Clin Cancer Res Off J Am Assoc Cancer Res 24:181–188. https://doi.org/10.1158/1078-0432.CCR-17-2007

  66. Pascual S, Herrera I, Irurzun J (2016) New advances in hepatocellular carcinoma. World J Hepatol 8:421–438. https://doi.org/10.4254/wjh.v8.i9.421

  67. Peinado H et al (2012) Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through. MET Nat Med 18:883–891. https://doi.org/10.1038/nm.2753

  68. Pi F et al (2018) Nanoparticle orientation to control RNA loading and ligand display on extracellular vesicles for cancer regression. Nat Nanotechnol 13:82–89. https://doi.org/10.1038/s41565-017-0012-z

  69. Qin X, Wang J, Wang X, Liu F, Jiang B, Zhang Y (2017) Targeting Rabs as a novel therapeutic strategy for cancer therapy. Drug Discov Today 22:1139–1147. https://doi.org/10.1016/j.drudis.2017.03.012

  70. Qu Z, Wu J, Wu J, Luo D, Jiang C, Ding Y (2016) Exosomes derived from HCC cells induce sorafenib resistance in hepatocellular carcinoma both in vivo and in vitro. J Exp Clin Cancer Res 35:1–12. https://doi.org/10.1186/s13046-016-0430-z

  71. Qu Z et al (2017) Exosomal miR-665 as a novel minimally invasive biomarker for hepatocellular carcinoma diagnosis and prognosis. Oncotarget 8:80666–80678

  72. Raab-Traub N, Dittmer DP (2017) Viral effects on the content and function of extracellular vesicles. Nat Rev Microbiol 15:559–572. https://doi.org/10.1038/nrmicro.2017.60

  73. Rao Q et al (2016) Tumor-derived exosomes elicit tumor suppression in murine hepatocellular carcinoma models and humans in vitro. Hepatology 64:456–472

  74. Raposo G, Stoorvogel W (2013) Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol 200:373–383. https://doi.org/10.1083/jcb.201211138

  75. Record M, Subra C, Silvente-Poirot S, Poirot M (2011) Exosomes as intercellular signalosomes and pharmacological effectors. Biochem Pharmacol 81:1171–1182. https://doi.org/10.1016/j.bcp.2011.02.011

  76. Ridder K et al (2014) Extracellular vesicle-mediated transfer of genetic information between the hematopoietic system and the brain in response to inflammation. PLoS Biol 12:e1001874. https://doi.org/10.1371/journal.pbio.1001874

  77. Robbins PD, Morelli AE (2014) Regulation of immune responses by extracellular vesicles. Nat Rev Immunol 14:195–208. https://doi.org/10.1038/nri3622

  78. Shirvani-Dastgerdi E, Schwartz R, Ploss A (2016a) Hepatocarcinogenesis associated with hepatitis B, delta and C viruses. Curr Opin Virol 20:1–10

  79. Shirvani-Dastgerdi E, Schwartz RE, Ploss A (2016b) Hepatocarcinogenesis associated with hepatitis B, delta and C viruses. Curr Opin Virol 20:1–10. https://doi.org/10.1016/j.coviro.2016.07.009

  80. Shrivastava S, Devhare P, Sujijantarat N, Steele R, Kwon YC, Ray R, Ray RB (2015) Knockdown of autophagy inhibits infectious hepatitis C virus release by the exosomal pathway. J Virol 90:1387–1396. https://doi.org/10.1128/JVI.02383-15

  81. Simonsen JB (2017) What are we looking at? Extracellular vesicles, lipoproteins, or both? Circ Res 121:920–922. https://doi.org/10.1161/CIRCRESAHA.117.311767

  82. Sohn W et al (2015) Serum exosomal microRNAs as novel biomarkers for hepatocellular carcinoma. Exp Mol Med 47:e184. https://doi.org/10.1038/emm.2015.68

  83. Steinbichler TB, Dudas J, Riechelmann H, Skvortsova II (2017) The role of exosomes in cancer metastasis. Semin Cancer Biol 44:170–181. https://doi.org/10.1016/j.semcancer.2017.02.006

  84. Stetler JL, Canup BS, Puckett RP, Meng X, Qiang M, Laroui H (2015) The characterization, addressing, and effects of CaCo2BBe and HEPG2 cells secreted exosomes on in vitro cellular inflammation. Gastroenterology 148:S–S938. https://doi.org/10.1016/s0016-5085(15)33200-5

  85. Sugimachi K et al (2015) Identification of a bona fide microRNA biomarker in serum exosomes that predicts hepatocellular carcinoma recurrence after liver transplantation. Br J Cancer 112:532–538. https://doi.org/10.1038/bjc.2014.621

  86. Sun C, Fu B, Gao Y, Liao X, Sun R, Tian Z, Wei H (2012) TGF-beta1 down-regulation of NKG2D/DAP10 and 2B4/SAP expression on human NK cells contributes to HBV persistence. PLoS Pathog 8:e1002594. https://doi.org/10.1371/journal.ppat.1002594

  87. Syn N, Wang L, Sethi G, Thiery JP, Goh BC (2016) Exosome-mediated metastasis: from epithelial–mesenchymal transition to escape from immunosurveillance. Trends Pharmacol Sci 37:606–617. https://doi.org/10.1016/j.tips.2016.04.006

  88. Takahashi K, Yan IK, Haga H, Patel T (2014a) Modulation of hypoxia-signaling pathways by extracellular linc-RoR. J Cell Sci 127:1585–1594. https://doi.org/10.1242/jcs.141069

  89. Takahashi K, Yan IK, Kogure T, Haga H, Patel T (2014b) Extracellular vesicle-mediated transfer of long non-coding RNA ROR modulates chemosensitivity in human hepatocellular cancer. FEBS Open Bio 4:458–467. https://doi.org/10.1016/j.fob.2014.04.007

  90. Takahashi K, Yan IK, Wood J, Haga H, Patel T (2014c) Involvement of extracellular vesicle long noncoding RNA (linc-VLDLR) in tumor cell responses to chemotherapy. Mol Cancer Res 12:1377–1387. https://doi.org/10.1158/1541-7786.MCR-13-0636

  91. Tang J, Li Y, Liu K, Zhu Q, Yang W, Xiong L, Guo D (2018) Exosomal miR-9-3p suppresses HBGF-5 expression and is a functional biomarker in hepatocellular carcinoma. Minerva Med 109:15–23

  92. Tey SK, Mao X, Yam JWP (2016) Role of nuclear Met-derived exosomes in hepatocellular carcinoma metastasis and lung premetastatic niche formation. Eur J Cancer 61:S63. https://doi.org/10.1016/s0959-8049(16)61217-0

  93. Thery C, Zitvogel L, Amigorena S (2002) Exosomes: composition, biogenesis and function. Nat Rev Immunol 2:569–579. https://doi.org/10.1038/nri855

  94. Tkach M, Thery C (2016) Communication by extracellular vesicles: where we are and where we need to go. Cell 164:1226–1232. https://doi.org/10.1016/j.cell.2016.01.043

  95. Todorova D, Simoncini S, Lacroix R, Sabatier F, Dignat-George F (2017) Extracellular vesicles in angiogenesis. Circ Res 120:1658–1673. https://doi.org/10.1161/CIRCRESAHA.117.309681

  96. Trehanpati N, Vyas AK (2017) Immune regulation by T regulatory cells in hepatitis B virus-related inflammation and cancer. Scand J Immunol 85:175–181. https://doi.org/10.1111/sji.12524

  97. Vescovo T, Refolo G, Vitagliano G, Fimia GM, Piacentini M (2016) Molecular mechanisms of hepatitis C virus-induced hepatocellular carcinoma. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis 22:853–861. https://doi.org/10.1016/j.cmi.2016.07.019

  98. Wang H, Hou L, Li A, Duan Y, Gao H, Song X (2014) Expression of serum exosomal microRNA-21 in human hepatocellular carcinoma. BioMed Res Int 2014:1–5. https://doi.org/10.1155/2014/864894

  99. Wang X et al (2015) Investigation of the roles of exosomes in colorectal cancer liver metastasis. Oncol Rep 33:2445–2453. https://doi.org/10.3892/or.2015.3843

  100. Wang F, Li L, Piontek K, Sakaguchi M, Selaru FM (2017a) Exosome miR-335 as a novel therapeutic strategy in hepatocellular carcinoma. Hepatology. https://doi.org/10.1002/hep.29586

  101. Wang M, Tian F, Ying W, Qian X (2017b) Quantitative proteomics reveal the anti-tumour mechanism of the carbohydrate recognition domain of Galectin-3 in hepatocellular carcinoma. Sci Rep 7:5189. https://doi.org/10.1038/s41598-017-05419-5

  102. Wang S, Xu M, Li X, Su X, Xiao X, Keating A, Zhao RC (2018a) Exosomes released by hepatocarcinoma cells endow adipocytes with tumor-promoting properties. J Hematol Oncol 11:82. https://doi.org/10.1186/s13045-018-0625-1

  103. Wang X et al (2018b) 14-3-3ζ delivered by hepatocellular carcinoma-derived exosomes impaired anti-tumor function of tumor-infiltrating T lymphocytes. Cell Death Dis 9:159

  104. Wei J et al (2015) Vps4A functions as a tumor suppressor by regulating the secretion and uptake of exosomal microRNAs in human hepatoma cells. Hepatology 61:1284–1294

  105. Wendler F, Stamp GW, Giamas G (2016) Tumor-stromal cell communication: small vesicles signal big changes. Trends Cancer 2:326–329. https://doi.org/10.1016/j.trecan.2016.05.007

  106. Wieckowski EU, Visus C, Szajnik M, Szczepanski MJ, Storkus WJ, Whiteside TL (2009) Tumor-derived microvesicles promote regulatory T cell expansion and induce apoptosis in tumor-reactive activated CD8+ T lymphocytes. J Immunol 183:3720–3730. https://doi.org/10.4049/jimmunol.0900970

  107. Wiklander OP et al (2015) Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J Extracell Vesicles 4:26316. https://doi.org/10.3402/jev.v4.26316

  108. Xiao W-H (2010) Effect of 5-aza-2′-deoxycytidine on immune-associated proteins in exosomes from hepatoma. World J Gastroenterol 16:2371. https://doi.org/10.3748/wjg.v16.i19.2371

  109. Xiao W et al (2013) Effects of the epigenetic drug MS-275 on the release and function of exosome-related immune molecules in hepatocellular carcinoma cells. Eur J Med Res 18:61

  110. Xiao F et al (2014) Hepatitis C virus cell-cell transmission and resistance to direct-acting antiviral agents. PLoS Pathog 10:e1004128. https://doi.org/10.1371/journal.ppat.1004128

  111. Xiong L, Zhen S, Yu Q, Gong Z (2017) HCV-E2 inhibits hepatocellular carcinoma metastasis by stimulating mast cells to secrete exosomal shuttle microRNAs. Oncol Lett 14:2141–2146. https://doi.org/10.3892/ol.2017.6433

  112. Xu H et al (2018a) Serum exosomal hnRNPH1 mRNA as a novel marker for hepatocellular carcinoma. Clin Chem Lab Med. https://doi.org/10.1515/cclm-2017-0327

  113. Xu H et al (2018b) Serum exosomal long noncoding RNAs ENSG00000258332.1 and LINC00635 for the diagnosis and prognosis of hepatocellular carcinoma. Cancer Epidemiol Biomark Prev. https://doi.org/10.1158/1055-9965.EPI-17-0770

  114. Yang Y, Han Q, Hou Z, Zhang C, Tian Z, Zhang J (2017) Exosomes mediate hepatitis B virus (HBV) transmission and NK-cell dysfunction. Cell Mol Immunol 14:465–475. https://doi.org/10.1038/cmi.2016.24

  115. Yao H, Liu N, Lin MC, Zheng J (2016) Positive feedback loop between cancer stem cells and angiogenesis in hepatocellular carcinoma. Cancer Lett 379:213–219. https://doi.org/10.1016/j.canlet.2016.03.014

  116. Yu S et al (2007) Tumor exosomes inhibit differentiation of bone marrow dendritic cells. J Immunol 178:6867–6875. https://doi.org/10.4049/jimmunol.178.11.6867

  117. Zeng C et al (2010) A novel GSK-3 beta-C/EBP alpha–miR-122–insulin-like growth factor 1 receptor regulatory circuitry in human. Hepatocell Carcinoma Hepatol 52:1702–1712. https://doi.org/10.1002/hep.23875

  118. Zhang H et al (2017a) Exosome-delivered EGFR regulates liver microenvironment to promote gastric cancer liver metastasis. Nat Commun 8:15016. https://doi.org/10.1038/ncomms15016

  119. Zhang J et al (2017b) Motile hepatocellular carcinoma cells preferentially secret sugar metabolism regulatory proteins via exosomes. Proteomics 17:1–13. https://doi.org/10.1002/pmic.201700103

  120. Zhang QF et al (2017c) Tumor derived exsomes mediate tumor infiltrating NK-cell dysfunction in patients with hepatocellular carcinoma via TGF-β/SMAD pathway. J Hepatol 66:S77. https://doi.org/10.1016/s0168-8278(17)30416-6

  121. Zhang Z et al (2017d) Loss of exosomal miR-320a from cancer-associated fibroblasts contributes to HCC proliferation and metastasis. Cancer Lett 397:33–42. https://doi.org/10.1016/j.canlet.2017.03.004

  122. Zhang C et al (2018) lncRNA-HEIH in serum and exosomes as a potential biomarker in the HCV-related hepatocellular carcinoma. Cancer Biomark 21:1–9. https://doi.org/10.3233/CBM-170727

  123. Zheng X et al (2015) Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527:525–530. https://doi.org/10.1038/nature16064

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Thanks to my colleagues in our laboratory for the support in this work.

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Correspondence to Baoguo Li.

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Liu, H., Li, B. The functional role of exosome in hepatocellular carcinoma. J Cancer Res Clin Oncol 144, 2085–2095 (2018). https://doi.org/10.1007/s00432-018-2712-7

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  • Hepatocellular carcinoma
  • Exosome
  • MiRNA
  • Metastasis
  • Biomarker