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. 2021 Mar 28;46(3):300–308. [Article in Chinese] doi: 10.11817/j.issn.1672-7347.2021.190744

EB病毒编码的microRNAs参与肿瘤的发生和发展

Epstein-Barr virus-encoded microRNAs involve in tumorigenesis and development

LI Weiming 1,2,2, YI Weihong 1, YANG Dazhi 1, LI Guiyuan 2,✉
Editor: 彭 敏宁
PMCID: PMC10929937  PMID: 33927078

Abstract

Epstein-Barr virus (EBV), a definite tumorigenic virus, is closely related to the development of nasopharyngeal cancer, gastric cancer, lymphoma and other tumors. EBV encodes a total of 44 mature microRNAs, which can regulate the expression of virus and host genes. EBV-encoded microRNAs and their regulated target molecules participate in the biological functions of tumor apoptosis, proliferation, invasion, and metastasis during tumorigenesis and development, and play an important role in the development of tumor.

Keywords: Epstein-Barr virus-encoded microRNAs, latent infection, tumor, epithelial-mesenchymal transition

EB病毒(Epstein-Barr virus，EBV)为人类疱疹病毒IV型，属人类疱疹病毒属γ亚科，1964年首次被Epstein等[1]在非洲儿童的伯基特淋巴瘤组织中发现。EBV是一种有害病原体，不仅与鼻咽癌、胃癌、伯基特淋巴瘤的发生密切相关，还是霍奇金淋巴瘤、非霍奇金淋巴瘤、NK/T细胞淋巴瘤的诱因[2-5]。目前EBV导致每年至少新增20万例癌症患者。

EBV在人群中的感染携带率高达90%[6]，且在绝大多数被感染宿主中，EBV会建立终生性的潜伏感染。根据EBV在宿主体内所表达潜伏基因的不同，可以将EBV潜伏感染分为0、I、II和III 4种类型：被EBV感染的处于休眠期的记忆B细胞为0型潜伏感染，只表达EBV编码的RNAs(EBV encoded RNAs，EBERs)这一种潜伏基因；EBV阳性的伯基特淋巴瘤属于I型潜伏感染，宿主体内只表达EBV核抗原1(EBV-determined nuclear antigen 1，EBNA1)、EBERs、Bam HI-A右向转录产物(Bam HI-A rightward transcripts，BARTs)这3种潜伏基因；在霍奇金淋巴瘤、鼻咽癌、NK/T细胞白血病、淋巴上皮样淋巴瘤和EBV相关性胃癌等中，EBV感染为II型潜伏感染，EBV在这几种宿主内均表达EBNA1、EBERs、BARTs、潜伏膜蛋白(latent membrane proteins，LPMs)这4种EBV潜伏基因；淋巴母细胞瘤中的EBV感染为III型潜伏感染，其表达的潜伏基因有EBERs、EBNA1、EBNA2、EBNA3A、EBNA3B、EBNA3C、EBNA-LP(EBNA-leader protein)、LPMs[7-9]。

EBV在不同的宿主中潜伏感染类型不同，表达的潜伏基因不同，而且其编码的微RNA(microRNAs，miRNAs)在不同的潜伏期、不同的宿主组织中表达也有差异。研究[10-11]发现：EBV-miR-BARTs几乎在上述4种潜伏感染类型和裂解性复制的宿主细胞中广泛表达，而EBV-miR-BHRF1s主要在III型潜伏感染类型和裂解性复制阶段的宿主细胞中表达，在其他潜伏感染类型中表达很低，甚至是缺失的。此外，还发现EBV-miR-BARTs在上皮性肿瘤(鼻咽癌和胃癌)组织中的表达水平很高，而在淋巴瘤组织中几乎检测不到[12]；EBV-miR-BHRF1s在淋巴瘤中的表达水平很高，而在鼻咽和上皮性肿瘤中的表达是缺失的。这提示EBV-miR-BARTs可能主要在上皮性肿瘤细胞中发挥调节功能，而EBV-miR-BHRF1s可能更多的是参与淋巴瘤的发生和发展[13-14]。

目前共发现40种EBV-miR-BARTs和4种EBV-miR-BHRF1s，共来源于25种EBV miRNAs前体，可加工形成44种成熟的EBV miRNAs。其中4种EBV-miR-BHRF1s由来自EBV基因组上BHRF1区域(Bam HI fragment H rightward open reading frame)转录的3种EBV-miR-BHRF1s前体加工形成，40种EBV-miR-BARTs由来自BART区域的两个miRNAs簇区(即miRNAs簇区1转录8种EBV-miR-BARTs前体、miRNAs簇区2转录13种EBV-miR-BARTs前体)和单独的BART2区域(转录1种EBV-miR-BARTs前体)所共同转录的22种EBV-miR-BARTs前体加工形成(图1)。这44种成熟的EBV miRNAs是根据所在基因组转录区域、被发现的顺序、miRNAs前体剪切加工后保留片段的位置(-3p/-5p)命名的[15]。

图1.

图1

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25种EBV miRNAs前体与潜伏基因在基因组上的相对位置

Figure 1 Relative position of 25 EBV miRNA precursors and EBV latent genes on the genome

EBV感染宿主细胞后，这些EBV miRNAs通过与病毒自身基因和宿主基因mRNAs的3'端非编码区(3'-untranslated region，3'-UTR)形成非完全互补配对，导致转录下调或者mRNAs降解，从而发挥生物学功能。近年来，许多研究[16-19]表明：EBV miRNAs可以通过调节病毒基因和宿主细胞基因的表达，实现病毒长期潜伏感染、抑制凋亡、促增殖，使得宿主细胞向永生化和肿瘤的方向发生和发展，并且在这个过程中促进肿瘤的侵袭、转移和恶性转化。EBV miRNAs主要通过调控宿主细胞周期进程与潜伏感染、细胞凋亡、细胞迁移和侵袭3个方面调节肿瘤的发生和发展。

1. 调控细胞周期进程与潜伏感染

大约有20%的人类肿瘤的发生和发展与病毒的潜伏感染相关，而病毒的潜伏感染是由病毒对自身和宿主的各种表观遗传机制进行调控而维持的。EBV感染宿主后，可通过EBV miRNAs调节EBV自身和宿主的基因表达，使宿主细胞处于类细胞周期物质合成期，为病毒自身的复制源源不断地提供原料，以维持EBV的生存和繁殖；减少宿主细胞的凋亡，为EBV持续性繁殖争夺时间；抑制EBV的裂解性复制，防止暴发性增殖。这3个方面动态平衡、协作，从而达到持续潜伏感染的目的，为宿主细胞永生化和肿瘤发生和发展提供条件[20]。

在EBV潜伏感染阶段，宿主类细胞周期物质合成的维持和EBV潜伏感染类型的转换受多条信号通路的调控。在这个过程中，EBV miRNAs可以通过调节宿主细胞相关信号分子来调控病毒潜伏感染类型和周期进程。例如，Dicer酶是一种RNA内切酶，是miRNA加工成熟所必需的，它能调节宿主自身和外源性病毒miRNAs的表达，调控EBV感染类型，影响EBV的感染进程[21]。Iizasa等[22-23]研究发现在EBV+鼻咽癌细胞株中，抑制内源性EBV-miR-BART6-5p表达能上调Dicer酶、EBV转录活化因子(Zta和Rta)、潜伏基因(EBNA2和LMP1)的表达，进一步研究发现EBV-miR-BART6-5p靶向宿主Dicer基因mRNA的3'-UTR，抑制Dicer酶的表达，进而调控宿主I/II/III型潜伏感染之间的转换。此外，促分裂原活化的蛋白激酶激酶激酶2(mitogen-activated protein kinase kinase kinase 2，MAP3K2)是多个信号通路的中心分子，其下游有许多转录因子，如转录激活因子1-2(activated transcription factors 1-2，ATF1-2)和原癌基因c-jun，均能与立即早期基因BZLF1(BamH I Z left fragment 1)的启动子区结合，启动BZLF1的表达，激活EBV裂解性复制。通过该过程，宿主MAP3K2基因能激活EBV裂解性复制程序[24-25]，而在B淋巴细胞中，EBV-miR-BART18-5p通过靶向MAP3K2 mRNA的3'-UTR，抑制MAP3K2的表达，在裂解复制的早期抑制病毒的裂解性复制，避免宿主细胞裂解性复制和病毒充分暴露，为实现EBV长期潜伏感染创造条件[26]。

病毒持续性的潜伏感染的发生和维持并不单单是对宿主细胞基因调控的结果，而是病毒和宿主基因相互协作的结果。在这个过程中，EBV miRNAs除了靶向调节宿主细胞周期相关基因外，还能调控EBV自身基因的表达。在EBV裂解性复制的前期阶段，病毒裂解性复制相关基因大量表达，其中BALF5(BamH I A left fragment 5)是EBV编码的DNA聚合酶和病毒复制的必要条件。通过在宿主细胞中高表达BALF5，为EBV裂解性复制作准备，而Barth等[27]研究发现EBV-miR-BART2-5p能与BALF5 mRNA的3'-UTR靶向结合，在裂解复制前期外源性高表达EBV-miR-BART2-5p，导致BALF5蛋白的表达水平降低40%~50%，并减少20%的病毒裂解释放。这提示EBV通过EBV-miR-BART2-5p抑制BALF5的表达来延缓病毒的裂解性复制，避免因病毒大量繁殖引起宿主细胞的裂解和病毒的暴露，维持潜伏感染状态。

此外，EBV miRNAs不仅能调控EBV裂解性复制周期，防止自身暴发性增殖，还能调节宿主细胞的周期进程。例如，叉头框转录蛋白1(forkhead box P1，FOXP1)是一种抑癌基因，能下调核因子κB(nuclear factor kappa-B，NF-κB)的表达和转录活性，抑制巨噬细胞分泌炎症因子，阻滞宿主细胞的周期进程；EBV-miR-BART11能直接靶向FOXP1，从而促进局部的炎症反应，并在这种局部炎症的微环境中促进肿瘤细胞的周期进程和增殖[28]。EBV通过抑制宿主细胞裂解性复制，促进宿主细胞增殖来实现病毒的持续繁殖和潜伏感染。

2. 调控宿主细胞凋亡

在病毒感染宿主细胞后，宿主细胞的凋亡过程是充分暴露病毒，激活免疫应答，清除病毒和异常细胞。细胞凋亡途径有死亡受体通路和B细胞淋巴瘤-2(B-cell lymphoma-2，Bcl-2)家族介导的线粒体通路这两条主要途径。这两条途径最后都要通过caspase通路来完成，而caspase-3在caspase通路上作为凋亡最终执行分子，对细胞凋亡的调控至关重要[29]。EBV miRNAs能调节caspase-3及其上游通路多种分子的表达，抑制宿主细胞的凋亡，使得EBV潜伏感染的宿主细胞发生凋亡紊乱，而凋亡紊乱在实现病毒持续性潜伏感染的同时，参与肿瘤的发生和发展。在EBV裂解性复制的前期，宿主会先启动这两条凋亡通路。研究[12, 30]发现EBV-miR-BART16、EBV-miR-BART1-3p、EBV-miR-BART22可直接靶向caspase-3，抑制其表达，从而抑制细胞凋亡。

EBV miRNAs除了能对凋亡通路上caspase-3进行调控外，还能对caspase-3上游通路凋亡相关的分子进行调节，主要参与调节Bcl-2家族介导的线粒体通路。Bcl-2家族成员分为抗凋亡类[Bcl-2、Bcl-XL(Bcl-extra large)、Bcl-2L2(Bcl-2-like-2)、MCL-l(myeloid cell leukemia sequence 1)]和促凋亡类[BAX(Bcl-2-associated X protein)、BAK(Bcl2-antagonist/killer)、BAD(Bcl-2 asociated death promoter)、BID(BH3 interacting domain death agonist)、BIM(Bcl-2 interacting mediator of cell death)、PUMA(p53 up-regulated modulator of apoptosis)][31-32]。EBV miRNAs能靶向抑制Bcl-2家族促凋亡类分子的表达，抑制线粒体介导的宿主细胞凋亡，其中BAD所介导的caspase-3依赖性线粒体凋亡通路是EBV裂解周期发生的前提条件。Kim等[33]研究发现在EBV相关胃癌中EBV的立即早期基因BRLF1和BZLF1的表达水平、宿主细胞内子代病毒合成量、以及BAD的表达水平三者同步高表达或低表达。进一步研究[34-35]发现：EBV-miR-BART20-5p通过靶向BRLF1、BZLF1和宿主BAD，抑制病毒裂解性复制和宿主细胞凋亡的发生。此外，BIM、BID、PUMA也是Bcl-2家族成员中介导线粒体凋亡途径的关键分子，EBV-miR-BART4-5p和EBV-miR-BART15靶向抑制BIM[36-37]，EBV-miR-BART4-5p靶向抑制BID[38]，EBV-miR-BART5靶向抑制PUMA[39]，从而减弱Bax的活性，抑制线粒体介导的细胞凋亡，维持病毒长期的潜伏感染。

EBV miRNAs不仅可靶向作用于Bcl-2家族成员，还可以作用于Bcl-2家族相关分子调控宿主细胞线粒体凋亡途径。例如，外线粒体膜转运蛋白22(translocase of outer mitochondrial membrane 22，TOMM22)是促凋亡蛋白Bax的受体，位于线粒体外膜，在凋亡执行阶段，通过与Bax结合，改变线粒体外膜的通透性，释放凋亡因子进入细胞质，诱导细胞凋亡。研究[40]发现：EBV-miR-BART16通过竞争性靶向结合TOMM22，减弱Bax与TOMM22的结合，抑制线粒体介导的凋亡，为病毒的生存繁殖争取时间，促进潜伏感染的宿主细胞永生化和肿瘤的发生和发展。

3. 参与肿瘤细胞侵袭、转移及恶性转化

肿瘤细胞转移是患者复发、预后差和死亡的主要原因。侵袭、转移的发生是肿瘤细胞与肿瘤细胞、肿瘤细胞与细胞外基质以及肿瘤细胞与正常细胞之间相互作用的结果，是一个多因素、多步骤的过程，其中上皮间质转换(epithelial-mesenchymal transition，EMT)是导致肿瘤恶性进展的病理过程，尤其对来源于上皮细胞的肿瘤，通过EMT使上皮细胞向间充质样细胞转换，包括细胞骨架的重排，获得迁移和侵袭能力[41]。在EBV相关肿瘤细胞中，EBV miRNAs能调节肿瘤细胞的EMT过程，增强肿瘤细胞的侵袭、转移能力，促进肿瘤恶性转化。

EMT涉及TGF-β信号通路、Wnt信号通路、Notch信号通路、PI3K-Akt-mTOR信号通路等多条信号通路。这些通路最终作用于EMT表型分子，如表达下调的表型分子[E-钙黏蛋白(E-cadherin)、角蛋白(cytokeratin)、ZO-1(zonula occluden-1)]；表达上调的表型分子[N-钙黏蛋白(N-cadherin)、波形蛋白(vinmentin)、Snail蛋白1、Snail蛋白2、Twist蛋白、基质金属蛋白酶-2(matrix metalloproteinase-2，MMP-2)、基质金属蛋白酶-3(matrix metallo-proteinase-3，MMP-3)、基质金属蛋白酶-9(matrix metalloproteinase-9，MMP-9)、锌指e-box结合蛋白1(zinc finger e-box-binding protein 1，Zeb1)]等，其中E-cadherin是细胞黏附分子，是上皮细胞的重要标志物，在稳定上皮细胞形态、结构和功能上起重要作用，E-cadherin表达的丢失被认为是EMT最显著的特征[42]。Hsu等[43]研究发现EBV-miR-BART9能直接靶向E-cadherin mRNA的3'-UTR，抑制E-cadherin的表达，诱导间充质样表型发生，促进EMT，增强肿瘤细胞的迁移和侵袭能力。

EMT发生不是单一性的标志分子发生改变。在EBV感染宿主后，EBV miRNAs不仅直接作用于EMT的表型分子，还作用于EMT相关信号通路的抑制分子，共同促进EMT和肿瘤的发生和发展。例如人第10染色体同源丢失磷酸酶-张力蛋白基因(phosphate and tension homology deleted on chromsome ten，PTEN)是一种抑癌基因，其不仅能促进细胞的凋亡、延缓细胞的周期进程，还能作用于多条PTEN依赖信号通路(如PI3K/Akt和Akt/GSK-3β信号通路)，最终抑制Snail和N-cadherin等EMT标志性表型分子的表达，阻碍EMT发生[44]。研究[45]发现在鼻咽癌组织中EBV-miR-BART7-3p和EBV-miR-BART1的表达水平与肿瘤恶性程度呈正相关，进一步研究[46]发现EBV-miR-BART7-3p和EBV-miR-BART1均可直接靶向同一个肿瘤抑制因子PTEN，促进EMT的发生。除EBV-miR-BART7-3p和EBV-miR-BART1外，Wong等[47]基于生物信息学分析和预测，发现多种EBV-miR-BARTs可直接靶向PTEN mRNA的3'-UTR，即鼻咽癌细胞中的EBV-miR-BART9和EBV-miR-BART18-5p，胃癌细胞中的EBV-miR-BART2-5p、EBV-miR-BART5、EBV-miR-BART14和EBV-miR-BART21-3p均能向抑制PTEN的表达。

除了经典的抑癌基因PTEN外，β-转运素重复包含蛋白(beta-transducin repeat containing，BTRC)也是一种抑癌基因，能促进EMT标志物N-cadherin和Snail泛素化，抑制EMT。研究[48]发现：在106例鼻咽癌患者的肿瘤标本中，EBV-miR-BART10-3p表达与BTRC表达呈负相关，与鼻咽癌患者不良预后呈正相关，进一步研究发现EBV-miR-BART10-3p通过向靶BTRC，抑制BTRC的表达，促进鼻咽癌细胞的EMT和恶性转化。此外，N-myc下游调节基因1(N-myc downstream regulated gene 1，NDRG1)也是上皮细胞分化的标志物，作为肿瘤抑制因子能与Wnt信号通路的低密度脂蛋白受体相关蛋白6(low density lipoprotein receptor related protein 6，LRP6)受体结合，抑制Wnt信号通路及Wnt信号通路激活的EMT，从而减弱肿瘤细胞的侵袭和转移能力[49]，Kanda等[50]研究发现多种EBV miRNAs协同作用，能抑制NDRG1的表达，激活Wnt信号通路和EMT，促上皮性肿瘤细胞的去分化和肿瘤转移。

4. 结 语

绝大部分EBV miRNAs具有癌基因作用，这与EBV作为一种明确的致瘤病毒是相符的；但是并不是所有的EBV miRNAs都发挥癌基因作用。为了逃避宿主免疫监视，保持持续性的潜伏感染状态，少数的EBV miRNAs还具有抑癌的功能，比如，EBV-miR-BART6-3p能抑制鼻咽癌和胃癌的侵袭、转移与增殖[51]；EBV-miR-BART6-3p和miR-142协同作用于IL-6R和PTEN，促进细胞增殖[52]；EBV-miR-BART15-3p通过靶向BRUCE促进EBV相关胃癌细胞的凋亡[53]；不限于EBV miRNAs，EBV编码的转录因子Rta和Zta也可以抑制鼻咽癌细胞的增殖[54]。EBV这些“抑癌”的生物学功能似乎与其致瘤性相互矛盾，但如果将EBV、携带EBV的宿主和机体免疫系统作为一个整体，从长远角度看，这些“抑癌”功能可能作为EBV潜伏期与裂解期、潜伏感染与宿主免疫监视的平衡枢纽，最终有利于EBV的生存和繁殖，使宿主遭受更严重的EBV感染，那么这种“抑癌”很可能就是一种促癌作用了。

近年来，基于对EBV miRNAs的靶基因及其相关信号通路的深入研究，44种靶基因及其生物学功能得以阐明(表1)，可以明确EBV miRNAs通过调节病毒和宿主细胞基因的表达，实现病毒持续性潜伏感染、促进宿主细胞周期进程和抑制宿主细胞凋亡，并协助被感染的宿主细胞发生免疫逃逸，增强肿瘤细胞的侵袭、转移能力，而这些调节作用使得感染EBV的宿主细胞脱离正常的自我监控，进而向肿瘤发生的方向发展。虽然目前有些EBV miRNAs甚至已明确相关功能的EBV miRNAs可能还存有其他生物学功能和机制尚未被发现，但是随着研究的深入，对EBV miRNAs功能和机制更系统、更全面的揭示，EBV miRNAs可作为潜在标志物，为EBV相关肿瘤的临床诊断、治疗、预后评估等方面提供新的策略。

表1.

EBV miRNAs的靶基因及其相关生物学功能

Table 1 Target genes of EBV miRNAs and their related biological functions

基因组转录区域 EBV-miRNAs前体 成熟EBV miRNAs 靶基因 相关功能
BART簇区1 EBV-miR-BART1 EBV-miR-BART1-3p Caspase-3 细胞凋亡[12]
IL-12β 免疫应答[55]
EBV-miR-BART1-5p LY75 免疫应答[56]
SP100 抗病毒[37]
EBV-miR-BART3 EBV-miR-BART3-3p IPO7 免疫应答[57]
DAZAP2 侵袭、转移[12]
EBV-miR-BART3-5p DICE 细胞凋亡[12]
EBV-miR-BART4 EBV-miR-BART4-3p Unknown
EBV-miR-BART4-5p Caspase-3 细胞凋亡[58]
BID 细胞凋亡[38]
基因组转录区域 EBV-miRNAs前体 成熟EBV miRNAs 靶基因 相关功能
BART簇区1 EBV-miR-BART5 EBV-miR-BART5-3p PUMA 细胞凋亡[39]
p53 侵袭、转移[59]
EBV-miR-BART5-5p PUMA 细胞凋亡[39]
ATM 侵袭、转移[17]
EBV-miR-BART6 EBV-miR-BART6-3p LOC553103 侵袭、转移[51]
PTEN 侵袭、转移[52]
RIG-I 免疫应答[60]
EBV-miR-BART6-5p DICER1 潜伏感染[22]
EBNA2、Zta、Rta 潜伏感染[22]
EBV-miR-BART15 EBV-miR-BART15 NLRP3 免疫应答[61]
BRUCE 细胞凋亡[53]
EBV-miR-BART16 EBV-miR-BART16 TOMM22 细胞凋亡[40]
Caspase-3 细胞凋亡[30]
EBV-miR-BART17 EBV-miR-BART17-3p BNRF2 潜伏感染[37]
EBV-miR-BART17-5p LMP1 免疫应答[62]
BART簇区2 EBV-miR-BART7 EBV-miR-BART7-3p PTEN 侵袭、转移[46]
EBV-miR-BART7-5p Unknown
EBV-miR-BART8 EBV-miR-BART8-3p Unknown
EBV-miR-BART8-5p Caspase-3 细胞凋亡[58]
EBV-miR-BART9 EBV-miR-BART9-3p E-cadherin 侵袭、转移[43]
EBV-miR-BART9-5p E-cadherin 侵袭、转移[43]
EBV-miR-BART10 EBV-miR-BART10-3p DKK1 侵袭、转移[63]
BTRC 侵袭、转移[48]
EBV-miR-BART10-5p Unknown
EBV-miR-BART11 EBV-miR-BART11-3p FOXP1 细胞增殖[28]
EBV-miR-BART11-5p EBF1 侵袭、转移[64]
EBV-miR-BART12 EBV-miR-BART12 Unknown
EBV-miR-BART13 EBV-miR-BART13-3p CAPRIN2 侵袭、转移[65]
EBV-miR-BART13-5p Unknown
EBV-miR-BART14 EBV-miR-BART14-3p Unknown
EBV-miR-BART14-5p Unknown
EBV-miR-BART18 EBV-miR-BART18-3p Unknown
EBV-miR-BART18-5p MAP3K2 细胞增殖[26]
EBV-miR-BART19 EBV-miR-BART19-3p WIFI 侵袭、转移[47]
EBV-miR-BART19-5p Unknown
EBV-miR-BART20 EBV-miR-BART20-3p Unknown
EBV-miR-BART20-5p T-bet 免疫应答[66]
BAD 细胞凋亡[35]
EBV-miR-BART21 EBV-miR-BART21-3p Unknown
EBV-miR-BART21-5p Unknown
EBV-miR-BART22 EBV-miR-BART22 MAP2K4 细胞增殖[67]
BART2区 EBV-miR-BART2 EBV-miR-BART2-3p Unknown
EBV-miR-BART2-5p BALF5 潜伏感染[27]
BHRF1区 EBV-miR-BHRF1-1 EBV-miR-BHRF1-1 SCRN1 细胞分泌[37]
EBV-miR-BHRF1-2 EBV-miR-BHRF1-2-3p PRDM1 免疫应答[68]
EBV-miR-BHRF1-2-5p IL-1 receptor 免疫应答[69]
EBV-miR-BHRF1-3 EBV-miR-BHRF1-3 TAP2 免疫应答[70]
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基金资助

深圳市南山区科技创新局教育(卫生)科技资助项目(2018005)。

This work was supported by Education (Health) Science and Technology Fund from Shenzhen Nanshan District Science and Technology Innovation Bureau, China (2018005).

利益冲突声明

作者声称无任何利益冲突。

原文网址

http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/202103300.pdf

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