非编码RNA对肝细胞癌肿瘤微环境中免疫细胞的作用

杨超然; 李思柔; 刘源; 侯志远; 王元; 杨季红

doi:10.3969/j.issn.1001-5256.2023.04.033

非编码RNA对肝细胞癌肿瘤微环境中免疫细胞的作用

DOI: 10.3969/j.issn.1001-5256.2023.04.033

河北大学附属医院肝胆外科，河北保定 071000

基金项目:

河北省政府资助临床医学优秀人才培养项目 (361007)

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：杨超然、李思柔负责课题设计，资料分析，撰写论文；刘源、侯志远、王元参与收集数据，修改论文；杨季红负责拟定写作思路，指导撰写文章并最后定稿。杨超然和李思柔对本文贡献等同，同为第一作者。

详细信息

通信作者:
杨季红，doctoryangjh@sina.com(ORCID: 0000-0001-8844-8640)

计量
- 文章访问数: 301
- HTML全文浏览量: 65
- PDF下载量: 49
- 被引次数: 0
出版历程
- 收稿日期: 2022-07-28
- 录用日期: 2022-09-09
- 出版日期: 2023-04-20

Role of non-coding RNA on immune cells in tumor microenvironment of hepatocellular carcinoma

Department of Hepatobiliary Surgery, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, China

Research funding:

Hebei Provincial Government Funded Clinical Medicine Talent Training Program (361007)

More Information

Corresponding author: YANG Jihong, doctoryangjh@sina.com (ORCID: 0000-0001-8844-8640)

摘要

摘要: 肝细胞癌(HCC)是一种常见的肝脏恶性肿瘤，具有发病率高、进展快、预后差等特点。近年来发现，非编码RNA(ncRNA)在肿瘤微环境(TME)中参与肿瘤免疫的调节，进而影响HCC的生物学行为。本文简述了ncRNA对TME中免疫细胞的调控作用，并介绍了ncRNA在HCC诊断和治疗中的潜在价值，以期为HCC提供潜在的诊断和治疗策略。
- 癌，肝细胞 /
- RNA /
- 肿瘤微环境 /
- 免疫，细胞
Abstract: Hepatocellular carcinoma (HCC) is a common malignant tumor of the liver characterized by a high incidence rate, rapid progression, and poor prognosis. In recent years, it has been found that non-coding RNA (ncRNA) participates in the regulation of tumor immunity in tumor microenvironment (TME) and in turn affects the biological behavior of HCC. This article briefly describes the regulatory effect of ncRNA on immune cells in TME and introduces the potential value of ncRNA in the diagnosis and treatment of HCC, in order to provide potential diagnostic and treatment strategies for HCC.
- Carcinoma, Hepatocellular /
- RNA /
- Tumor Microenvironment /
- Immunity, Cellular

HTML全文

表 1 异常表达的ncRNA对免疫细胞的调控和功能

Table 1. Modulation of immune cells by abnormal expression ncRNA and function of ncRNA

ncRNA名称	HCC中表达	可检测位置	免疫相关分子	机制	功能
lncRNA HOMER3-AS1^[6]	高表达	HCC细胞	巨噬细胞、CSF-1	HOMER3/Wnt/β-连环蛋白轴	促进HCC进展
miR-570^[12]	低表达	组织和外周血	CD⁺8 T淋巴细胞、IFNγ ⁺T淋巴细胞	-	抑制HCC增殖
miR-26b-5^[13]	低表达	HCC细胞	CD4⁺和CD8⁺ T淋巴细胞(TNFα、IFNγ、IL-6和IL-2)	-	增强抗肿瘤免疫反应
miR-23a^[14]	低表达	细胞和组织	Treg	p65/miR-23a/CCL22	促进肿瘤生长
miR-206^[16]	高表达	细胞	巨噬细胞M1极化	KLF4/CCL2/CCR2	抑制HCC发展
miR-148b^[17]	低表达	细胞和组织	CSF-1表达和巨噬细胞浸润	-	促进HCC生长和转移
miR-506^[20]	低表达	细胞	NK细胞	-	增强抗肿瘤免疫反应
miR-561-5p^[21]	高表达	细胞和组织	NK细胞	miR-561-5p/CX3CL1/NK细胞	促进肿瘤发生和转移
lncRNA FENDRR^[23]	低表达	细胞和组织	Treg	-	抑制肿瘤的免疫逃逸
lncRNA NEAT1^[24]	低表达	外周血单核细胞	CD8⁺ T淋巴细胞	-	增强HCC细胞溶解
lncNNT-AS1^[25]	高表达	组织	CD4⁺ T淋巴细胞	-	增强肿瘤免疫逃逸
lncRNA00662^[29]	高表达	细胞	巨噬细胞M2极化	Wnt/β-catenin	促进肿瘤生长和转移
lncRNA GAS5^[34]	低表达	细胞	NK细胞	miR-544/RUNX3	增强抗肿瘤免疫反应
circRNA hsa_circ_0110102^[36]	高表达	组织	巨噬细胞	-	促进HCC进展
cricRNA Hsa_circ_0074854^[38]	高表达	细胞和组织	巨噬细胞M2极化	-	抑制HCC迁移和侵袭
注：-，文献未提及。

下载: 导出CSV

参考文献(44)

[1]	SUNG H, FERLAY J, SIEGEL RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249. DOI: 10.3322/caac.21660.
[2]	DING W, TAN YL, QIAN Y, et al. First-line targ veted therapies of advanced hepatocellular carcinoma: A Bayesian network analysis of randomized controlled trials[J]. PLoS One, 2020, 15(3): e0229492. DOI: 10.1371/journal.pone.0229492.
[3]	ANASTASIADOU E, JACOB LS, SLACK FJ. Non-coding RNA networks in cancer[J]. Nat Rev Cancer, 2018, 18(1): 5-18. DOI: 10.1038/nrc.2017.99.
[4]	AKBARI DILMAGHNAI N, SHOOREI H, SHARIFI G, et al. Non-coding RNAs modulate function of extracellular matrix proteins[J]. Biomed Pharmacother, 2021, 136: 111240. DOI: 10.1016/j.biopha.2021.111240.
[5]	SHI TT, MORISHITA A, KOBARA H, et al. The role of long non-coding RNA and microRNA networks in hepatocellular carcinoma and its tumor microenvironment[J]. Int J Mol Sci, 2021, 22(19): 10630. DOI: 10.3390/ijms221910630.
[6]	PU J, LI WC, WANG AM, et al. Long non-coding RNA HOMER3-AS1 drives hepatocellular carcinoma progression via modulating the behaviors of both tumor cells and macrophages[J]. Cell Death Dis, 2021, 12(12): 1103. DOI: 10.1038/s41419-021-04309-z.
[7]	GIRALDO NA, SANCHEZ-SALAS R, PESKE JD, et al. The clinical role of the TME in solid cancer[J]. Br J Cancer, 2019, 120(1): 45-53. DOI: 10.1038/s41416-018-0327-z.
[8]	PASCUT D, PRATAMA MY, VO NVT, et al. The crosstalk between tumor cells and the microenvironment in hepatocellular carcinoma: The role of exosomal microRNAs and their clinical implications[J]. Cancers, 2020, 12(4): 823. DOI: 10.3390/cancers12040823.
[9]	JIA ZM, JIA JL, YAO LH, et al. Crosstalk of exosomal non-coding RNAs in the tumor microenvironment: Novel frontiers[J]. Front Immunol, 2022, 13: 900155. DOI: 10.3389/fimmu.2022.900155.
[10]	XIA HM, HUANG ZY, LIU SQ, et al. Exosomal non-coding RNAs: Regulatory and therapeutic target of hepatocellular carcinoma[J]. Front Oncol, 2021, 11: 653846. DOI: 10.3389/fonc.2021.653846.
[11]	DIENER C, HART M, KEHL T, et al. Quantitative and time-resolved miRNA pattern of early human T cell activation[J]. Nucleic Acids Res, 2020, 48(18): 10164-10183. DOI: 10.1093/nar/gkaa788.
[12]	LIN YX, LIU S, SU L, et al. miR-570 inhibits proliferation, angiogenesis, and immune escape of hepatocellular carcinoma[J]. Cancer Biother Radiopharm, 2018, 33(6): 252-257. DOI: 10.1089/cbr.2017.2389.
[13]	HAN W, LI N, LIU J, et al. microRNA-26b-5p enhances T cell responses by targeting PIM-2 in hepatocellular carcinoma[J]. Cell Signal, 2019, 59: 182-190. DOI: 10.1016/j.cellsig.2018.11.011.
[14]	LI ZQ, WANG HY, ZENG QL, et al. p65/miR-23a/CCL22 axis regulated regulatory T cells recruitment in hepatitis B virus positive hepatocellular carcinoma[J]. Cancer Med, 2020, 9(2): 711-723. DOI: 10.1002/cam4.2611.
[15]	WANG C, MA C, GONG LH, et al. Macrophage polarization and its role in liver disease[J]. Front Immunol, 2021, 12: 803037. DOI: 10.3389/fimmu.2021.803037.
[16]	LIU NN, WANG XM, STEER CJ, et al. microRNA-206 promotes the recruitment of CD8⁺ T cells by driving M1 polarisation of Kupffer cells[J]. Gut, 2022, 71(8): 1642-1655. DOI: 10.1136/gutjnl-2021-324170.
[17]	KE M, ZHANG Z, CONG L, et al. microRNA-148b-colony-stimulating factor-1 signaling-induced tumor-associated macrophage infiltration promotes hepatocellular carcinoma metastasis[J]. Biomed Pharmacother, 2019, 120: 109523. DOI: 10.1016/j.biopha.2019.109523.
[18]	PIÑEIRO FERNÁNDEZ J, LUDDY KA, HARMON C, et al. Hepatic tumor microenvironments and effects on NK cell phenotype and function[J]. Int J Mol Sci, 2019, 20(17): 4131. DOI: 10.3390/ijms20174131.
[19]	ZHANG QF, YIN WW, XIA Y, et al. Liver-infiltrating CD11b-CD27- NK subsets account for NK-cell dysfunction in patients with hepatocellular carcinoma and are associated with tumor progression[J]. Cell Mol Immunol, 2017, 14(10): 819-829. DOI: 10.1038/cmi.2016.28.
[20]	SU ZX, YE XP, SHANG LM. miR-506 promotes natural killer cell cytotoxicity against human hepatocellular carcinoma cells by targeting STAT3[J]. Yonsei Med J, 2019, 60(1): 22-29. DOI: 10.3349/ymj.2019.60.1.22.
[21]	CHEN EB, ZHOU ZJ, XIAO K, et al. The miR-561-5p/CX3CL1 signaling axis regulates pulmonary metastasis in hepatocellular carcinoma involving CX3CR1⁺ natural killer cells infiltration[J]. Theranostics, 2019, 9(16): 4779-4794. DOI: 10.7150/thno.32543.
[22]	ZOU H, SHAO CX, ZHOU QY, et al. The role of lncRNAs in hepatocellular carcinoma: Opportunities as novel targets for pharmacological intervention[J]. Expert Rev Gastroenterol Hepatol, 2016, 10(3): 331-340. DOI: 10.1586/17474124.2016.1116382.
[23]	YU Z, ZHAO H, FENG X, et al. Long non-coding RNA FENDRR acts as a miR-423-5p sponge to suppress the treg-mediated immune escape of hepatocellular carcinoma cells[J]. Mol Ther Nucleic Acids, 2019, 17: 516-529. DOI: 10.1016/j.omtn.2019.05.027.
[24]	YAN K, FU Y, ZHU N, et al. Repression of lncRNA NEAT1 enhances the antitumor activity of CD8⁺T cells against hepatocellular carcinoma via regulating miR-155/Tim-3[J]. Int J Biochem Cell Biol, 2019, 110: 1-8. DOI: 10.1016/j.biocel.2019.01.019.
[25]	WANG YK, YANG L, DONG XC, et al. Overexpression of NNT-AS1 activates TGF- β signaling to decrease tumor CD4 lymphocyte infiltration in hepatocellular carcinoma[J]. Biomed Res Int, 2020, 2020: 8216541. DOI: 10.1155/2020/8216541.
[26]	WAN S, ZHAO E, KRYCZEK I, et al. Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells[J]. Gastroenterology, 2014, 147(6): 1393-1404. DOI: 10.1053/j.gastro.2014.08.039.
[27]	BAIG MS, ROY A, RAJPOOT S, et al. Tumor-derived exosomes in the regulation of macrophage polarization[J]. Inflamm Res, 2020, 69(5): 435-451. DOI: 10.1007/s00011-020-01318-0.
[28]	LUO HL, LUO T, LIU JJ, et al. Macrophage polarization-associated lnc-Ma301 interacts with caprin-1 to inhibit hepatocellular carcinoma metastasis through the Akt/Erk1 pathway[J]. Cancer Cell Int, 2021, 21(1): 422. DOI: 10.1186/s12935-021-02133-1.
[29]	TIAN XH, WU YY, YANG YT, et al. Long noncoding RNA LINC00662 promotes M2 macrophage polarization and hepatocellular carcinoma progression via activating Wnt/β-catenin signaling[J]. Mol Oncol, 2020, 14(2): 462-483. DOI: 10.1002/1878-0261.12606.
[30]	YE YB, XU Y, LAI Y, et al. Long non-coding RNA cox-2 prevents immune evasion and metastasis of hepatocellular carcinoma by altering M1/M2 macrophage polarization[J]. J Cell Biochem, 2018, 119(3): 2951-2963. DOI: 10.1002/jcb.26509.
[31]	SASAKI R, KANDA T, YOKOSUKA O, et al. Exosomes and hepatocellular carcinoma: From bench to bedside[J]. Int J Mol Sci, 2019, 20(6): 1406. DOI: 10.3390/ijms20061406.
[32]	QI F, DU XJ, ZHAO ZY, et al. Tumor mutation burden-associated LINC00638/miR-4732-3p/ULBP1 axis promotes immune escape via PD-L1 in hepatocellular carcinoma[J]. Front Oncol, 2021, 11: 729340. DOI: 10.3389/fonc.2021.729340.
[33]	ZHANG L, HU SS, CHEN JS, et al. Comprehensive analysis of the MIR4435-2HG/miR-1-3p/MMP9/miR-29-3p/DUXAP8 ceRNA network axis in hepatocellular carcinoma[J]. Discov Oncol, 2021, 12(1): 38. DOI: 10.1007/s12672-021-00436-3.
[34]	FANG PP, XIANG LX, CHEN WL, et al. LncRNA GAS5 enhanced the killing effect of NK cell on liver cancer through regulating miR-544/RUNX3[J]. Innate Immun, 2019, 25(2): 99-109. DOI: 10.1177/1753425919827632.
[35]	CHEN W, QUAN Y, FAN S, et al. Exosome-transmitted circular RNA hsa_circ_0051443 suppresses hepatocellular carcinoma progression[J]. Cancer Lett, 2020, 475: 119-128. DOI: 10.1016/j.canlet.2020.01.022.
[36]	WANG XX, SHENG W, XU T, et al. CircRNA hsa_circ_0110102 inhibited macrophage activation and hepatocellular carcinoma progression via miR-580-5p/PPARα/CCL2 pathway[J]. Aging, 2021, 13(8): 11969-11987. DOI: 10.18632/aging.202900.
[37]	ZHANG PF, GAO C, HUANG XY, et al. Cancer cell-derived exosomal circUHRF1 induces natural killer cell exhaustion and may cause resistance to anti-PD1 therapy in hepatocellular carcinoma[J]. Mol Cancer, 2020, 19(1): 110. DOI: 10.1186/s12943-020-01222-5.
[38]	WANG Y, GAO RF, LI JP, et al. Downregulation of hsa_circ_0074854 suppresses the migration and invasion in hepatocellular carcinoma via interacting with HuR and via suppressing exosomes-mediated macrophage M2 polarization[J]. Int J Nanomedicine, 2021, 16: 2803-2818. DOI: 10.2147/IJN.S284560.
[39]	TANG X, REN H, GUO M, et al. Review on circular RNAs and new insights into their roles in cancer[J]. Comput Struct Biotechnol J, 2021, 19: 910-928. DOI: 10.1016/j.csbj.2021.01.018.
[40]	SHI Y, LIU JB, DENG J, et al. The role of ceRNA-mediated diagnosis and therapy in hepatocellular carcinoma[J]. Hereditas, 2021, 158(1): 44. DOI: 10.1186/s41065-021-00208-7.
[41]	CHEN WL, XU XM. New progress in the study of markers for the early diagnosis of liver cancer[J]. China Med Herald, 2023, 20(1): 40-44. DOI: 10.20047/j.issn1673-7210.2023.01.08. 陈文亮, 徐细明. 肝癌早期诊断标志物的研究新进展[J]. 中国医药导报, 2023, 20(1): 40-44. DOI: 10.20047/j.issn1673-7210.2023.01.08.
[42]	HUANG FX, LI HY, LI ZK, et al. Regulation of thymosinα1 resistance to hepatocellular carcinoma by long chain non-coding RNA LINC0110[J]. Chin J Immunol, 2022, 38(10): 1207-1211. DOI: 10.3969/j.issn.1000-484X.2022.10.010.5 黄凤霞, 李海燕, 李正堃, 等. 长链非编码RNA LINC01105调控肝癌对胸腺素α1耐药[J]. 中国免疫学杂志, 2022, 38(10): 1207-1211. DOI: 10.3969/j.issn.1000-484X.2022.10.010.5
[43]	SUN QY, LI J, JIN BX, et al. Evaluation of miR-331-3p and miR-23b-3p as serum biomarkers for hepatitis C virus-related hepatocellular carcinoma at early stage[J]. Clin Res Hepatol Gastroenterol, 2020, 44(1): 21-28. DOI: 10.1016/j.clinre.2019.03.011.
[44]	HUANG WJ, TIAN XP, BI SX, et al. The β-catenin/TCF-4-LINC01278-miR-1258-Smad2/3 axis promotes hepatocellular carcinoma metastasis[J]. Oncogene, 2020, 39(23): 4538-4550. DOI: 10.1038/s41388-020-1307-3.