2019, Vol. 46
2. 复旦大学肿瘤转移研究所 上海 200040
2. Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
肝细胞癌(hepatocellular carcinoma, HCC)(以下简称肝癌)是最常见的恶性肿瘤之一, 发病率在恶性肿瘤中居第6位, 死亡率居第3位, 而每年近半数的新发和死亡病例在中国[1]。肝癌患者常常合并门静脉癌栓(portal vein tumor thrombus, PVTT), 据临床资料显示其发生率为31.4%~34.0%[2], 在尸检中更高, 为44.0%~62.8%[3-4]。肝癌合并PVTT是影响肝癌患者预后的重要危险因素之一[5-6]。肝癌患者一旦出现PVTT, 病情发展迅速, 短时间内即可发生肝内外转移、门静脉高压症、黄疸和腹水, 如果不及时治疗, 患者中位生存期将小于6个月[7], 预后极差。因此, 寻找PVTT的有效干预措施对于改善预后具有重要意义。PVTT形成的分子机制目前仍不清楚, 本文从HCC自身改变和肿瘤微环境对PVTT形成的分子机制进行综述。
肿瘤细胞自身改变对PVTT的影响
基因表达谱的改变 肝癌细胞中某些基因表达谱改变会影响肿瘤细胞的生物学行为而导致PVTT的发生。通过转录组测序分析发现, 仅在PVTT中发生突变的基因包括KDM6A、CUL9、FDG6、AKAP3和RNF139, 这些基因可能有助于HCC侵袭[8]。HCC与PVTT之间差异表达基因主要和细胞外基质(extracellular matrix, ECM)受体相互作用途径(ECM-receptor interaction pathway)相关, 如PVTT组织中胶原型基因(如COL3A1、COL4A4、COL5A1、COL5A2、COL6A2和COL11A1)下调2~60倍。在PVTT样本中, ARID1A-GPATCH3、MDM1-NUP107、PTGES3-RARG、PRLR-TERT和C9orf3-TMC1发生基因融合, RPS24基因发生外显子跳跃的概率较高[9]。此外, CDK16在肝癌细胞中促进肿瘤细胞增殖、抑制细胞凋亡及诱导上皮间质转化(epithelial-mesenchymal transition, EMT)的过程中, 其表达上调与PVTT有关[10]。神经氨酸酶-1(neuraminidase 1, NEU1)基因在HCC中高表达, 通过影响剪接体的功能来促进HCC细胞的增殖和迁移, 从而易形成PVTT[11]。此外, 在肝癌细胞中染色体8p22-p23区域的ZDHHC2基因出现杂合性丢失, 其表达降低会增加细胞增殖和侵袭能力, 临床病理显示ZDHHC2的杂合性丢失与PVTT形成有关[12]。FOXP3不仅是Treg细胞的特征性标志物, 其在肿瘤细胞中也有表达, 表达程度和功能可能代表了一种新的肿瘤免疫逃避机制[13-14]。FOXP3基因的单核苷酸多态性与乙肝相关性HCC相关, 且在rs3761549处CC基因型与PVTT形成有关[15]。
肿瘤细胞表观遗传学改变对PVTT的影响 表观遗传学(epigenetics)是在基因的核苷酸序列不发生改变的情况下研究基因表达的可遗传的变化, 包括DNA的甲基化、组蛋白的转录后修饰、染色质空间结构的改变和非编码RNA的调控[16-17]。表观遗传的失调不仅在HCC发生中扮演重要角色[8, 18-19], 而且DNA甲基化与去甲基化和非编码RNA调控对PVTT的形成起到重要作用。
DNA甲基化修饰被认为是一种重要的表观遗传沉默机制[20], 在PVTT发展过程中起着重要作用。研究发现在HCC细胞中N-myc下游调节基因2(NDRG2)表达水平降低与启动子高甲基化有关, NDRG2低表达易形成PVTT[21]。抑癌基因XAF1[22]和FAM83D[23]同样在HCC中被高度甲基化, 且临床病理分析显示其与PVTT的形成有关。在HBV感染相关的HCC中, HBV编码的蛋白质X(HBx蛋白)被发现通过其转录激活特性上调DNA甲基转移酶的表达[24], 后者可介导某些抑癌基因甲基化, 从而影响PVTT的发生[25]。原癌基因去甲基化会促进肿瘤的进展[20]。蛋白激酶人单极纺锤体1(human monopolar spindle 1, hMps1/TTK)基因启动子的去甲基化会增加HCC中TTK的表达, TTK表达升高与PVTT呈正相关。进一步研究显示TTK以p53依赖性方式激活Akt/mTOR和MDM2/p53途径促进细胞增殖、迁移和生长, 进一步促成HCC肿瘤和PVTT的发生[26]。
微RNA (microRNA, miRNA)是一类长17~25 nt的内源性单链非编码RNA, 是在细胞正常和病理状态下重要的调控分子[27]。许多研究证实miRNA通过抑制其靶mRNA的表达来促进肿瘤生长、侵入、血管生成和免疫逃避, 从而证明miRNA在肿瘤生物学中的重要性[28-29]。最近的研究发现某些miRNA与PVTT的形成密切相关。miR-135a在PVTT中显著上调, 同时体外和体内研究证实FOXM1转录调控miR-135a表达, 并通过抑制转移抑制因子Ⅰ的表达来促进肝癌细胞的侵袭, 促进PVTT的形成[30]。乙型肝炎病毒(hepatitis B virus, HBV)可通过影响miRNA来促进PVTT的形成[31]。HBV通过上调TGF-β活性, 抑制microRNA-34a转录, 从而促进CCL-22的表达, 后者可募集Treg细胞诱导免疫逃逸, 进一步促进肝癌细胞在门静脉系统中的定植。EMT是上皮细胞通过特定程序转化为具有间质表型细胞的生物学过程, 也是癌症转移过程中重要的环节。miR-449a在PVTT组织中表达明显减少, 机制研究显示miR-449a通过直接靶向抑制FOS和Met的表达来减弱EMT过程, 从而抑制PVTT形成[32]。
长非编码RNA(lncRNA)是一种由200到几千个核苷酸组成的非编码蛋白质的RNA[33]。lncRNA在不同的生物细胞过程(包括肿瘤发生发展)中发挥重要的调控作用[34-35]。比较PVTT和原发肿瘤的lncRNA表达谱, 发现约有100个lncRNA的表达水平存在显著差异, 这些lncRNA可能在肿瘤转移中发挥重要作用[36]。研究发现低表达lncRNA GAS5(grow arrest-specific 5)通过调节波形蛋白(vimentin)促进PVTT形成[37], 此外, 在表达细胞间黏附因子1(intercellular adhesion molecule 1, ICAM-1)的肿瘤干细胞(tumor stem cell, CSC)中发现了一种新的高表达的lncRNA(ICAM-1相关的ICR)。ICR可以通过形成RNA双链体来增加ICAM-1的mRNA的稳定性, 从而上调ICAM-1的表达, 进而调节ICAM-1阳性HCC细胞的CSC的黏附能力来促进PVTT的形成[38]。
肝癌细胞表面黏附分子对PVTT的影响 细胞表面存在一些细胞黏附分子(cell adhesion molecules, CAM), 介导了细胞间或细胞与ECM间互相接触和结合, 在癌细胞脱离原发灶、移动并附着浸润形成PVTT的过程中发挥着重要作用。这些CAMs包括钙黏蛋白、免疫球蛋白超家族、选凝素及整合蛋白[39]。
钙黏蛋白E-cadherin可维持细胞黏附性和极性, 亦可在细胞间传递信息[40]。研究发现E-cadherin在形成PVTT的肝癌组织中表达量较未形成PVTT的癌组织中表达量显著降低, E-cadherin使得肝癌细胞间黏附能力下降, 易于从原发灶脱落, 侵袭门静脉分支, 从而形成癌栓[41]。
免疫球蛋白超家族中ICAM-1在伴PVTT的HCC组织中显著高表达[42], 其可通过增加肿瘤细胞和血管内皮细胞之间的黏附力来促进肝癌细胞在门静脉的转移[43-44]。另一种免疫球蛋白超家族CD155是一种Ⅰ型跨膜糖蛋白[45], 是免疫细胞引发肿瘤排斥反应的重要配体[46]。PVTT的形成可能与CD155表达的丧失而导致HCC细胞的免疫逃逸有关[47]。
选凝素中E-选凝素(E-selectin)及其配体sLeX和sLeA在肝癌组织中高表达和PVTT的形成明显相关, 推测E-selectin结合肝癌组织表面sLeX和sLeA配体是PVTT形成的途径之一[48]。
整合蛋白是细胞与ECM相互作用的关键介质, 在存在ECM配体(例如胶原蛋白和层粘连蛋白)的情况下向细胞发送存活信号, 并在其未结合状态下诱导细胞的失巢凋亡[49]。EDIL3是一种肝癌细胞自分泌蛋白, 在肝癌细胞转移形成PVTT过程中与癌细胞表面整合蛋白αV结合通过FAK-Src-AKT信号通路抑制其失巢凋亡[50]。
肝癌细胞其他蛋白对PVTT形成的影响 肝癌细胞某些蛋白分子调节细胞的生物学特性可促进PVTT的形成。由神经纤维瘤病Ⅱ型肿瘤抑制基因(Nf2)编码的merlin蛋白能够调节细胞增殖、运动、存活和信号通路[51]。野生型Merlin(wtMerlin)通过限制HCC细胞的迁移和侵袭能力抑制PVTT形成, 而缺乏外显子2、3、4编码序列的D2-4Merlin则通过诱导EMT过程和激活细胞干性基因来促进PVTT形成[52]。另外RPB结合蛋白(RPB-mediating protein, RMP)是RNA聚合酶Ⅱ(RNA polymerase Ⅱ, RNAP)第五亚基的调节蛋白, RMP可通过调节IL-6的转录来增强肿瘤起始细胞(tumor-initiating cell, T-IC)的自我更新能力, 从而诱导EMT过程, 促进PVTT的形成[53]。
肿瘤微环境对PVTT的影响 HCC肿瘤微环境的改变为PVTT的形成提供不可缺少的条件, 肿瘤微环境中的基质金属蛋白酶(matrix metalloproteinase, MMP)、趋化因子、低氧、Treg细胞、血管生长因子、凝血酶调节素(thrombomodulin, TM)以及载脂蛋白等与PVTT形成有关。
基质金属蛋白酶 ECM是肿瘤侵袭转移的组织学屏障[54]。MMP几乎能降解ECM中的各种蛋白质成分, 在肿瘤侵袭转移中起到关键作用[55]。MMP-2和MMP-9在伴PVTT的HCC组织中明显高于无PVTT者, 推测PVTT形成与MMP-2和MMP-9降解ECM有关[56]。
趋化因子 趋化因子是一类能驱化细胞定向移动的小分子分泌蛋白质, 由70~100个氨基酸组成, 除了对免疫细胞有定向驱化作用外, 还介导细胞的定向迁移, 可能解释肝癌细胞容易侵犯门静脉的机制[57]。CXCR4是趋化因子CXCL12的受体, 主要在细胞膜和细胞质中表达。在PVTT中CXCR4的表达水平显著高于原发性肝癌组织。低表达CXCR4可以抑制PVTT细胞的转移, 推测CXCR4在PVTT形成过程中发挥重要作用[58]。趋化因子CCL15在肝癌样本中过度表达, 比较临床病理结果发现其表达水平和肿瘤大小、PVTT形成和TNM分期有关, CCL15可能通过促进白细胞浸润和调节肿瘤细胞运动促进癌症的进展[59]。
低氧 低氧促进PVTT的形成[60]。低氧使肿瘤细胞14-3-3ζ和缺氧诱导因子-1α (hypoxia inducible factor-1α, HIF-1α)增加:14-3-3ζ可以通过招募HDCA4来增强HIF-1α蛋白的稳定性, 抑制HIF-1α乙酰化[61]; 而HIF-1α增加肿瘤细胞CCL20的分泌, 后者招募单核细胞来源的巨噬细胞以CCL20依赖性方式诱导吲哚胺-2, 3-双加氧酶的表达, 抑制T细胞增殖并促进免疫抑制性Treg细胞的扩增, 形成一个免疫抑制的肿瘤微环境, 促进PVTT的形成[60, 62]。
血管生长因子 血管生长因子对肿瘤血管生成起到关键作用[63]。在对抗碱性成纤维细胞生长因子、血管内皮生长因子(vascular endothelial growth factor, VEGF)、血小板衍化内皮细胞生长因子与肝癌微血管密度及PVTT形成的研究中发现, bFGF、VEGF、PD-ECGF对肿瘤血管形成具有协同作用, 组织血管生长因子阳性表达数目越多, PVTT形成概率越高[64]。
凝血酶调节素 TM存在于癌细胞胞质及细胞表面, 与PVTT密切相关, 单发性肿瘤或无PVTT患者术前血浆TM水平明显高于多发性肝癌患者或PVTT, 提示低TM可能与肝内转移和PVTT的形成有关[65]。TM阳性患者的肝内转移频率、PVTT发生率和包膜浸润率均显著低于TM阴性的患者。产生TM的HCC肝内扩散较慢, 表明TM可能因抗凝血活性而抑制肿瘤细胞对门静脉的黏附, 从而减少肝内外转移[66]。
载脂蛋白A1 载脂蛋白A1(apolipoprotein A-1, ApoA-1)作为高密度脂蛋白的主要蛋白成分, 可抑制肿瘤血管生成[67], 诱导抗肿瘤免疫微环境, 限制肿瘤的进展[68]。在HCC患者血清中ApoA-1水平显著降低[69-70], 而在伴PVTT的HCC患者血清中ApoA-1水平更低[71]。ApoA-1可通过促进细胞周期停滞来抑制增殖和下调MAPK通路促进细胞凋亡; ApoA-1可能通过减弱肿瘤细胞降解ECM的能力来抑制PVTT的形成[72]。
结语 肝癌合并PVTT是临床治疗中面临的难点, 严重影响患者预后。虽已证实肿瘤细胞自身改变(如基因表达谱、表观遗传和细胞分子等)和肿瘤微环境(MMP、趋化因子、低氧、Treg细胞、血管生长因子、TM和ApoA-1等)与PVTT的形成相关, 但PVTT形成的机制尚不明确, 需要进一步深入探索, 以改善患者预后。
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