从病毒性肝炎到肝细胞癌：外泌体microRNA的作用

毛元鹏; 于哲; 宋阿倩; 魏红山

doi:10.3969/j.issn.1001-5256.2023.02.030

从病毒性肝炎到肝细胞癌：外泌体microRNA的作用

DOI: 10.3969/j.issn.1001-5256.2023.02.030

毛元鹏¹,
于哲¹,
宋阿倩²,
魏红山^{1, 2, , ,}

1.
北京大学地坛医院教学医院消化科，北京 100015
2.
首都医科大学附属北京地坛医院消化科，北京 100015

基金项目:

国家自然科学基金 (82170541);

北京市自然科学基金 (7202071)

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：毛元鹏负责拟定写作思路，撰写论文；于哲、宋阿倩参与收集文献，分析资料；魏红山负责课题设计，指导撰写论文并最终定稿。

详细信息

通信作者:
魏红山，drwei@ccmu.edu.cn(ORCID: 0000-0001-8893-653X)

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出版历程
- 收稿日期: 2022-06-28
- 录用日期: 2022-07-27
- 出版日期: 2023-02-20

From viral hepatitis to hepatocellular carcinoma: The role of exosomal microRNAs

Yuanpeng MAO¹,
Zhe YU¹,
Aqian SONG²,
Hongshan WEI^{1, 2
, ,
,}

1.
Department of Gastroenterology, Peking University Ditan Teaching Hospital, Beijing 100015, China
2.
Department of Gastroenterology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China

Research funding:

National Natural Science Foundation of China (82170541);

Natural Science Foundation of Beijing (7202071)

More Information

Corresponding author: WEI Hongshan, drwei@ccmu.edu.cn (ORCID: 0000-0001-8893-653X)

摘要

摘要: 外泌体是一种纳米级的磷脂双分子层小囊泡，内含丰富而复杂的生物分子，如DNA、mRNA、microRNA(miRNA)、脂质和蛋白质。外泌体可由大多数种类细胞分泌和摄取，通过细胞间运输的方式完成信息传递。外泌体被受体细胞摄取后，释放其中所含生物活性物质，用以调节受体细胞生物过程，如促进肿瘤的生长和转移。外泌体及其内容物的变化与多种疾病有着重要联系。近年来，关于外泌体miRNA在病毒性肝炎所致肝细胞癌(HCC)发生发展中的作用已经受到广泛关注，并且不同来源的外泌体miRNA在此过程中发挥的作用也有所不同。本文简要回顾了外泌体miRNA在病毒性肝炎相关HCC发生发展中的作用研究，并提出外泌体miRNA可能是针对HCC微环境的免疫治疗靶点。
- 肝炎病毒 /
- 肝硬化 /
- 癌, 肝细胞 /
- 外泌体 /
- 微RNAs
Abstract: Exosomes are nano-sized phospholipid bilayer vesicles containing abundant and complex biomolecules, such as DNA, mRNAs, microRNAs (miRNAs), lipids, and proteins. Exosomes can be secreted and ingested by most types of cells to transfer information through intercellular transport. After uptake by recipient cells, exosomes release bioactive substances to regulate the biological processes of recipient cells, such as promoting tumor growth and metastasis. Changes of exosomes and their contents are associated with a variety of diseases. In recent years, the role of exosomal miRNAs in the development and progression of hepatocellular carcinoma (HCC) caused by viral hepatitis has attracted wide attention, and exosomal miRNAs from different sources play different roles in this process. This article briefly reviews the research on the role of exosomal miRNAs in the development and progression of viral hepatitis-related HCC and proposes that exosomal miRNAs may be the targets for immunotherapy for HCC microenvironment.
- Hepatitis Viruses /
- Liver Cirrhosis /
- Carcinoma, Hepatocellular /
- Exosomes /
- MicroRNAs

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图 1 外泌体miRNA与病毒性肝炎相关HCC的关系

Figure 1. Relationship between exosomal miRNAs and viral hepatitis-related HCC

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表 1 部分外泌体miRNA对HCC的影响

Table 1. Effects of some exosomal miRNAs on HCC

miRNA	影响	参考文献
miR-148a-3p	抑制HCC细胞生长	[27]
miR-155	诱导致癌相关炎症进展	[28]
miR-21	促进HCC肿瘤进展	[30]
miR-1247-3p	促进HCC细胞肺转移	[31]
miR-320a	抑制肿瘤增殖和转移	[35]
miR-374a-5p	抑制肿瘤增殖和转移	[36]
miR-210	促进肿瘤组织血管生成	[37]
miR-103	增加肿瘤组织血管通透性	[38]

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参考文献(38)

[1]	PAN BT, JOHNSTONE RM. Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor[J]. Cell, 1983, 33(3): 967-978. DOI: 10.1016/0092-8674(83)90040-5.
[2]	SIMONS M, RAPOSO G. Exosomes--vesicular carriers for intercellular communication[J]. Curr Opin Cell Biol, 2009, 21(4): 575-581. DOI: 10.1016/j.ceb.2009.03.007.
[3]	AMBROS V. The functions of animal microRNAs[J]. Nature, 2004, 431(7006): 350-355. DOI: 10.1038/nature02871.
[4]	LIU R, MA X, CHEN L, et al. MicroRNA-15b suppresses Th17 differentiation and is associated with pathogenesis of multiple sclerosis by targeting O-GlcNAc transferase[J]. J Immunol, 2017, 198(7): 2626-2639. DOI: 10.4049/jimmunol.1601727.
[5]	LAKSHMI S, HUGHES TA, PRIYA S. Exosomes and exosomal RNAs in breast cancer: A status update[J]. Eur J Cancer, 2021, 144: 252-268. DOI: 10.1016/j.ejca.2020.11.033.
[6]	HENNING RJ. Cardiovascular exosomes and MicroRNAs in cardiovascular physiology and pathophysiology[J]. J Cardiovasc Transl Res, 2021, 14(2): 195-212. DOI: 10.1007/s12265-020-10040-5.
[7]	THÉRY C, ZITVOGEL L, AMIGORENA S. Exosomes: composition, biogenesis and function[J]. Nat Rev Immunol, 2002, 2(8): 569-579. DOI: 10.1038/nri855.
[8]	KALLURI R, LEBLEU VS. The biology, function, and biomedical applications of exosomes[J]. Science, 2020, 367(6478): eaau6977. DOI: 10.1126/science.aau6977.
[9]	LI X, LI C, ZHANG L, et al. The significance of exosomes in the development and treatment of hepatocellular carcinoma[J]. Mol Cancer, 2020, 19(1): 1. DOI: 10.1186/s12943-019-1085-0.
[10]	LI C, ZHOU T, CHEN J, et al. The role of Exosomal miRNAs in cancer[J]. J Transl Med, 2022, 20(1): 6. DOI: 10.1186/s12967-021-03215-4.
[11]	CHAHAR HS, BAO X, CASOLA A. Exosomes and their role in the life cycle and pathogenesis of RNA viruses[J]. Viruses, 2015, 7(6): 3204-3225. DOI: 10.3390/v7062770.
[12]	JIANG W, MA P, DENG L, et al. Hepatitis A virus structural protein pX interacts with ALIX and promotes the secretion of virions and foreign proteins through exosome-like vesicles[J]. J Extracell Vesicles, 2020, 9(1): 1716513. DOI: 10.1080/20013078.2020.1716513.
[13]	ZHANG GL, LI YX, ZHENG SQ, et al. Suppression of hepatitis B virus replication by microRNA-199a-3p and microRNA-210[J]. Antiviral Res, 2010, 88(2): 169-175. DOI: 10.1016/j.antiviral.2010.08.008.
[14]	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.
[15]	RAMAKRISHNAIAH V, THUMANN C, FOFANA I, et al. Exosome-mediated transmission of hepatitis C virus between human hepatoma Huh7.5 cells[J]. Proc Natl Acad Sci U S A, 2013, 110(32): 13109-13113. DOI: 10.1073/pnas.1221899110.
[16]	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.
[17]	THAKURI B KC, ZHANG J, ZHAO J, et al. HCV-associated exosomes upregulate RUNXOR and RUNX1 expressions to promote MDSC expansion and suppressive functions through STAT3-miR124 axis[J]. Cells, 2020, 9(12): 2715. DOI: 10.3390/cells9122715.
[18]	ZHOU Y, WANG X, SUN L, et al. Toll-like receptor 3-activated macrophages confer anti-HCV activity to hepatocytes through exosomes[J]. FASEB J, 2016, 30(12): 4132-4140. DOI: 10.1096/fj.201600696R.
[19]	CHEN L, CHEN R, KEMPER S, et al. Suppression of fibrogenic signaling in hepatic stellate cells by Twist1-dependent microRNA-214 expression: Role of exosomes in horizontal transfer of Twist1[J]. Am J Physiol Gastrointest Liver Physiol, 2015, 309(6): G491-G499. DOI: 10.1152/ajpgi.00140.2015.
[20]	CHEN L, CHEN R, VELAZQUEZ VM, et al. Fibrogenic signaling is suppressed in hepatic stellate cells through targeting of connective tissue growth factor (CCN2) by cellular or exosomal microRNA-199a-5p[J]. Am J Pathol, 2016, 186(11): 2921-2933. DOI: 10.1016/j.ajpath.2016.07.011.
[21]	LEE YS, KIM SY, KO E, et al. Exosomes derived from palmitic acid-treated hepatocytes induce fibrotic activation of hepatic stellate cells[J]. Sci Rep, 2017, 7(1): 3710. DOI: 10.1038/s41598-017-03389-2.
[22]	QU Y, ZHANG Q, CAI X, et al. Exosomes derived from miR-181-5p-modified adipose-derived mesenchymal stem cells prevent liver fibrosis via autophagy activation[J]. J Cell Mol Med, 2017, 21(10): 2491-2502. DOI: 10.1111/jcmm.13170.
[23]	SUN C, SHI C, DUAN X, et al. Exosomal microRNA-618 derived from mesenchymal stem cells attenuate the progression of hepatic fibrosis by targeting Smad4[J]. Bioengineered, 2022, 13(3): 5915-5927. DOI: 10.1080/21655979.2021.2023799.
[24]	KIM JH, LEE CH, LEE SW. Exosomal transmission of MicroRNA from HCV replicating cells stimulates transdifferentiation in hepatic stellate cells[J]. Mol Ther Nucleic Acids, 2019, 14: 483-497. DOI: 10.1016/j.omtn.2019.01.006.
[25]	CHALLAGUNDLA KB, WISE PM, Neviani P, et al. Exosome-mediated transfer of microRNAs within the tumor microenvironment and neuroblastoma resistance to chemotherapy[J]. J Natl Cancer Inst, 2015, 107(7): djv135. DOI: 10.1093/jnci/djv135.
[26]	BOVY N, BLOMME B, FRÈRES P, et al. Endothelial exosomes contribute to the antitumor response during breast cancer neoadjuvant chemotherapy via microRNA transfer[J]. Oncotarget, 2015, 6(12): 10253-10266. DOI: 10.18632/oncotarget.3520.
[27]	ZHANG X, CHEN F, HUANG P, et al. Exosome-depleted MiR-148a-3p derived from hepatic stellate cells promotes tumor progression via ITGA5/PI3K/Akt axis in hepatocellular carcinoma[J]. Int J Biol Sci, 2022, 18(6): 2249-2260. DOI: 10.7150/ijbs.66184.
[28]	CHEN C, LUO F, LIU X, et al. NF-kB-regulated exosomal miR-155 promotes the inflammation associated with arsenite carcinogenesis[J]. Cancer Lett, 2017, 388: 21-33. DOI: 10.1016/j.canlet.2016.11.027.
[29]	AFFO S, YU LX, SCHWABE RF. The role of cancer-associated fibroblasts and fibrosis in liver cancer[J]. Annu Rev Pathol, 2017, 12: 153-186. DOI: 10.1146/annurev-pathol-052016-100322.
[30]	ZHOU Y, REN H, DAI B, et al. Hepatocellular carcinoma-derived exosomal miRNA-21 contributes to tumor progression by converting hepatocyte stellate cells to cancer-associated fibroblasts[J]. J Exp Clin Cancer Res, 2018, 37(1): 324. DOI: 10.1186/s13046-018-0965-2.
[31]	FANG T, LV H, LV G, et al. Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer[J]. Nat Commun, 2018, 9(1): 191. DOI: 10.1038/s41467-017-02583-0.
[32]	YANG F, NING Z, MA L, et al. Exosomal miRNAs and miRNA dysregulation in cancer-associated fibroblasts[J]. Mol Cancer, 2017, 16(1): 148. DOI: 10.1186/s12943-017-0718-4.
[33]	YUGAWA K, YOSHIZUMI T, MANO Y, et al. Cancer-associated fibroblasts promote hepatocellular carcinoma progression through downregulation of exosomal miR-150-3p[J]. Eur J Surg Oncol, 2021, 47(2): 384-393. DOI: 10.1016/j.ejso.2020.08.002.
[34]	XIE F, YUAN Y, XIE L, et al. miRNA-320a inhibits tumor proliferation and invasion by targeting c-Myc in human hepatocellular carcinoma[J]. Onco Targets Ther, 2017, 10: 885-894. DOI: 10.2147/OTT.S122992.
[35]	ZHANG Z, LI X, SUN W, et al. Loss of exosomal miR-320a from cancer-associated fibroblasts contributes to HCC proliferation and metastasis[J]. Cancer Lett, 2017, 397: 33-42. DOI: 10.1016/j.canlet.2017.03.004.
[36]	LIN Q, ZHOU CR, BAI MJ, et al. Exosome-mediated miRNA delivery promotes liver cancer EMT and metastasis[J]. Am J Transl Res, 2020, 12(3): 1080-1095.
[37]	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.
[38]	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.