WJCR  >> Vol. 8 No. 1 (January 2018)

    外泌体生物学特性及其在肝癌中的作用研究
    Biological Characteristics of Exosomes and Their Role in Hepatocellular Carcinoma

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作者:  

张腾飞:上海交通大学附属第六人民医院普外科,上海;安徽医科大学附属巢湖医院普外科,安徽 合肥;
黄修燕:上海交通大学附属第六人民医院普外科,上海

关键词:
肝细胞肝癌外泌体miRNA生物标记分子Hepatocellular Carcinoma Exosomes miRNA Biomarker

摘要:

肝细胞癌(HCC)发生发展的分子机制尚未完全清楚,可能涉及病毒致癌作用、癌基因和抑癌基因失活、癌细胞凋亡等。外泌体能介导细胞间物质传递和信息交流,在多种癌症发生发展中起着重要作用。本文旨在总结外泌体生物学特性及其在肝癌发生发展、诊断和治疗中的作用。

The mechanism of hepatocellular carcinoma (HCC) development is not yet fully understood, which may be related to the carcinogenesis of the virus, the inactivation of oncogenes and tumor sup-pressor genes, cancer cell apoptosis. Exosomes, which can mediate the material transfer between cells and the exchange of information, play significant roles in the occurrence and development of a variety of cancers. This article aims to summarize the biological characteristics of exosomes and their roles in the development, diagnosis and treatment of HCC.

1. 引言

近年来,我国及世界范围内肝细胞癌(Hepatocellular Carcinoma,HCC)的发生率和死亡率仍居高不下,给国民经济带来沉重负担。外泌体作为细胞外囊泡的一种,通过传递功能活性物质(如蛋白质、RNA)介导细胞间的信息交流。越来越多的研究证明,外泌体在肿瘤细胞信号通路调控、早期诊断、分子治疗等方面有着重要作用,为肝癌等恶性肿瘤的诊疗提供新的思路和方向 [1] 。本文旨在总结外泌体的生物学特性及其在肝癌发生发展、诊断和治疗中的作用。

2. 外泌体的简介

2.1. 外泌体的生物学特性、形成和释放

外泌体直径在30~120 nm间,具有双层膜结构,由细胞以胞吐方式分泌到细胞外。多种细胞如肝细胞 [2] 、神经细胞 [3] 、B细胞、T细胞、干细胞 [4] 等可以分泌外泌体。外泌体广泛存在人体的血、尿、腹腔积液等体液中,因而较易获得 [5] [6] [7] 。外泌体的形成涉及多种机制,最经典的是内吞体运输排序复合物(Endosomal Sorting Complexs Required for transport, ESCRT)途径,该复合物包含ESCRT-0、ESCRT-1、ESCRT-2、ESCRT-3及多种辅助蛋白如VPS4A (Vacuolar protein sortin 4 homolog A)、IGF-1 (Insulin-like growth factor-1)、Alix等,上述蛋白共同参与着多囊体(Multivesicular Body,MVB)的形成。此外,跨膜蛋白的介导和神经酰胺合成过程中也可诱发膜泡的出胞而形成外泌体 [8] 。MVB与细胞膜的融合及胞膜的胞吐与外泌体的释放密切相关,另外,MVB还可以通过多种途径参与胞内多囊泡的分选和多种细胞器形态的发生相关 [9] [10] 。最近研究发现,小的GTPase醛在线虫和哺乳动物的肿瘤细胞中释放出体外释放。更具体地说,c.elegans ral-1是MVBs生物起源的必要条件,之后由MVB与质膜融合。故研究者提出模型来解释体外分泌的二尖瓣功能,它在动物体内的保护及其在肿瘤进展中的可能作用 [11] 。

2.2. 外泌体生物学作用

外泌体最早被认为是细胞内“废物”运输载体,此后,有人发现外泌体有免疫调控和抗原呈递作用 [12] 。但最新研究显示,通过向DU145KD细胞添加纯化的外源DU145外泌体,增强T细胞的反应,表明肿瘤外体的显性效应是免疫抑制,而不是抗原呈递 [13] 。外泌体之所以可以介导细胞–细胞间的交流与其含有大量核苷酸(mRNA、microRNA、lncRNA、核糖体RNA等)、蛋白(膜转运蛋白、融合蛋白、热休克蛋白等)、脂质(胆固醇、磷脂、甘油二脂等)密切相关。其中,CD81、CD63等蛋白是外泌体特有的,可作为外泌体的鉴定标志 [14] 。细胞间信息交流的异常调节和异常交互导致了肿瘤的发生。在肿瘤细胞的进展中,肿瘤细胞分泌的外泌体通过自身膜蛋白与靶细胞识别并融合,将体内物质(尤其是miRNAs)释放到靶细胞,从而调节受体细胞的转录 [15] [16] 。外泌体促进肿瘤发展、侵袭和转移,促进肿瘤的血管新生,在肝癌、胃癌等多种肿瘤的发生发展中起着关键作用 [17] 。

3. 外泌体在肝癌中的作用

HCC源性外泌体可能在肿瘤的局部转移、肝内转移和多灶性生长中起着重要作用。外泌体中的生物活性RNA和蛋白能够影响肿瘤的微环境,从而导致HCC的发展和转移 [18] [19] 。我们将从HCC侵袭转移、免疫逃避、诊断、治疗等方面阐述外泌体的作用。

3.1. 外泌体与肝癌的侵袭和转移

肿瘤源性外泌体中的RNAs和蛋白提供了肿瘤细胞间交流的“桥梁”,可能参与肿瘤细胞的招募与肿瘤内环境的再形成 [20] [21] 。HCC源性外泌体可以在低氧环境下激活miR-145/HIF-1a/PDK1通路,从而增强糖酵解过程,增加能量代谢,促进恶性增殖 [22] 。肝肿瘤干细胞(CSCs)主要通过释放血管生成因子和外泌体来驱动血管生成。另一方面,肿瘤微环境中的血管也通过juxtacrine和paracrine机制释放生长因子,以支持CSCs的生长并维持其干细胞特征。肝肿瘤血管生成与CSCs之间的正反馈循环加速形成了肿瘤进展的血管微环境 [23] 。有研究表明,抑制磷酸盐-STAT3导致miR-21的表达减少,PTEN增加,RECK和程序性细胞死亡4 (PDCD4)表达,以及HCC的迁移和侵袭减弱 [24] 。Lv等证明,HCC源性外泌体促进肝癌细胞生长、迁移和入侵,并有能力将miRNA传送到受体细胞。通过小RNA测序发现,VPS4A促进了外泌体中致癌miRNA和细胞中抑癌miRNA的积累和摄取 [25] 。

与非编码RNA一样,外泌体内的蛋白质也可以促进肿瘤细胞的侵袭潜能。RNA深度测序和蛋白质组分析揭示了从转移HCC细胞系中提取的外泌体携带大量的肿瘤基因和蛋白质,如MET、S100家族成员和微孔蛋白。He等 [26] 发现迁移HCC细胞株的外泌体可以显著增强非迁移MIHA细胞的迁移和侵袭能力。在MIHA中,对这些梭形分子的吸收可以触发PI3K/AKT和MAPK信号通路,并增加了活性MMP-2和MMP-9的分泌。HCC源性外泌体可以动员正常的肝细胞,这可能在转移过程中通过肝实质促进HCC细胞的侵袭活动。另有研究证实,HepG2细胞分泌的内皮素(VASN)可以通过受体介导的外泌体的内吞作用转移到人脐静脉内皮细胞(HUVECs),促进受体内皮细胞的迁移。可见,肿瘤细胞中表达的一种功能蛋白通过外泌体影响内皮细胞的迁移运动可能为肿瘤细胞侵袭运动的另一途径 [27] 。

3.2. 外泌体与免疫逃避

乙型肝炎病毒感染是HCC发生的主要原因。与EB病毒、HIV病毒一样,肝炎病毒可以通过外泌体形式入侵非感染细胞而且藏匿于外泌体中的病毒可以逃避抗病毒抗体的中和 [28] [29] [30] 。HBV、HCV感染过程中的免疫逃避使病毒在肝脏的复制过程更有效率,且HBV感染过程中外泌体能使蛋白、核酸改变以利于其复制。

在HCC免疫治疗方面,一方面在抗肿瘤药物的刺激下,HCC细胞可以分泌HSP耐受性外泌体以增强NK细胞的自溶作用和减弱HSP的抗肿瘤效应。另一方面,铂类和伊立替康等抗肿瘤药产生更多含HSP的外泌体,可能会上调并激活NK细胞受体CD69、NKG2D、NKp44的表达,同时下调CD94表达,增加了颗粒酶B的产生和激活NK细胞的细胞毒性反应 [31] 。脂肪源性间叶组织干细胞分泌的外泌体促进T细胞抗肿瘤效应 [32] 。可见,外泌体在肿瘤免疫中具有双面作用。

3.3. 外泌体与肝癌的早期分子诊断和复发预测

外泌体广泛存在于人体血液、尿液中,稳定、易获得,故外泌体内含物具有潜在生物标记功能,可成为较理想的临床诊断和疾病复发预测的生物标记物。与血清miR-21相比,血清外泌体miR-21水平在HCC中较正常人、乙肝或肝硬化患者升高更明显 [33] 。Sohn等 [34] 发现HCC患者血清外泌体miR-18a、miR-221、miR-222和miR-224水平均较慢性乙肝或肝硬化患者升高(P < 0.05)。此外,血清外泌体miR-101、miR-106b、miR-122和miR-195的水平较慢性乙肝患者低(P = 0.014,P < 0.001,P < 0.001,P < 0.001)。尽管血清AFP已作为HCC的生物标记物,但外泌体miRNA作为早期HCC分子生物标志物仍值得进一步研究。

Liu等发现HCC患者外泌体miR-125b可作为一种新型的血清学生物标记物预测HCC患者术后复发率和生存率(ROC曲线下面积 = 0.739,敏感性 = 0.83,特异性 = 0.679)。此类发现有助于指导复发风险高、预后不良的HCC患者综合治疗方案的选择 [35] 。另有学者发现,在肝移植术后复发的人群中血清外泌体miR-718显著增高,其靶基因HOXB8DE上调预示着预后不良 [36] 。我们的初步研究发现,肝癌血清和肿瘤组织、转移结节组织外泌体circRNA-100338较对照组显著增高,而miR-141-3p显著降低(P < 0.01,即将发表),为肝癌转移复发的分子机制研究和干预策略制定提供一定的参考价值。

3.4. 外泌体与肝癌的治疗

外泌体在机体中的低免疫原性、低毒性和高稳定性,使得其有望成为比合成体(如脂质体)更好抗肿瘤药物载体 [37] 。在大鼠动物模型中,将链霉素用电穿孔法导入未成熟的树突状细胞分泌的外泌体中,再将外泌体注入肿瘤组织,肿瘤生长被明显抑制而未出现明显的毒性 [38] 。为精准将药物运送到靶细胞,提高治疗效果,可以运用基因工程技术改造外泌体的膜蛋白。有学者通过将编码抗EGFR的质粒转染细胞,细胞分泌的外泌体中成功出现GPI锚定的信号肽,能特异性结合EGFR [39] 。很明显,外泌体中的蛋白和miRNA在肿瘤微环境的调节中有着重要作用,但其具体机制仍不清楚。最近发现,淋巴细胞、肝细胞中的RNA特异分拣元件EXO-和hEXO-可能在外泌体特异miRNA装载过程中起着重要作用 [40] [41] 。

在肿瘤化疗耐药性方面,TGF-β降低了HCC细胞对索拉菲尼和链霉素的敏感性。具体机制为HCC细胞内及分泌的外泌体中linc-ROR高度表达,导致肿瘤细胞表面CD133表达及TGF-β增加,从而增加了化疗耐药性 [42] 。HCC源性外泌体内CD9和CD63激活HGF/c-MET/AKT信号通路诱导索拉菲尼抗体产生,并抑制索拉菲尼诱导的细胞凋亡。此外,高侵袭肿瘤细胞外泌体CD9和CD63表达更强,因而更易发生索拉菲尼耐药 [43] 。

4. 展望

本文旨在总结外泌体生物学特性及其在肝癌发生发展、诊断和治疗中的作用作一简要综述。外泌体作为机体内广泛存在的“信息载体”,其研究尚处于初步阶段。随着研究的进一步深入,其在肝癌等肿瘤的分子发病机制中的作用将不断明确。未来,新的外泌体源性生物标记物可被用于肝癌的早期快速诊断。新的基于外泌体研究的靶向药物应用于肿瘤的治疗,更加精准地杀伤肿瘤细胞。

基金项目

中美联合培养学者/留学生转化医学课题(UCTMP2015-03C001);上海交通大学医工(理)交叉基金资助(项目编号YG2017MS13);国家自然科学基金面上项目(81272401);六院预研基金(LYZY-0229)。

文章引用:
张腾飞, 黄修燕. 外泌体生物学特性及其在肝癌中的作用研究[J]. 世界肿瘤研究, 2018, 8(1): 12-17. https://doi.org/10.12677/WJCR.2018.81003

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