ACM  >> Vol. 8 No. 10 (December 2018)

作者:  

李浩然,高 健,丁建勇:复旦大学附属中山医院胸外科,上海;
李泽环:复旦大学附属中山医院普通外科,上海

关键词:
肺癌LncRNA转移自噬肿瘤免疫Lung Cancer LncRNA Metastasis Autophagy Tumor Immunity

摘要:

肺癌是世界上致死率第一的癌症,主要原因在于肺癌的侵袭转移和复发。lncRNA是一类非编码RNA分子,研究发现其与包括肺癌在内的多种肿瘤密切相关。lncRNA不仅参与肺癌组织细胞的侵袭、迁移和增殖过程,并且与细胞自噬、肿瘤免疫联系紧密。因此,研究lncRNA与肺癌的关系具有重要意义。

Lung cancer is the most leading cancer death worldwide mainly due to the high metastasis and recurrence rate of lung cancer. LncRNA is non-coding RNA molecule that cannot translate into protein, which is associated with many carcinomas including lung cancer. LncRNA is not only in-volved in the invasion, migration and proliferation of lung cancer cells, but also close to cell au-tophagy and tumor immunity. Therefore, it is of great significance to study the relation between lncRNA and lung cancer.

1. 引言

肺癌是世界上致死率最高的癌症,每年因肺癌死亡的人数超过一百万人 [1] ,而侵袭转移 [2] [3] 和肿瘤复发 [4] 是主要的致死原因。肺癌在组织学上可以分为小细胞肺癌(SCLC)和非小细胞肺癌(NSCLC)两种,而SCLC约占15%,NSCLC约占85%,其中腺癌最常见 [5] [6] 。长链非编码RNA (lncRNA)是指长度多于200个碱基对的RNA [7] ,其在包括肺癌在内的多种人类肿瘤中常出现异常表达 [8] [9] 。本文就目前lncRNA在肺癌中的研究进展做简要综述。

2. LncRNA及其作用机制

长链非编码RNA (lncRNA)通常是指多于200个碱基对的RNA,且不具有编码蛋白质功能的核糖核酸分子。在人类基因组中,lncRNA的种类保守估计有23,000种,而其表达在不同正常的器官组织具有特异性 [8] [9] 。LncRNA具有多种生物学功能,如:基因表达,表观遗传以及染色体装配等 [10] 。

LncRNA调节基因表达可通过多种机制 [11] :1) lncRNA可以招募染色体修饰复合物对特定的靶基因位点进行特异性修饰,从而调节转录前的基因表达;2) 转录时,lncRNA可通过特定的转录因子直接影响RNA聚合酶的活性,如:lncRNA Evf2可以作为转录因子DLX2的协同刺激分子来调节DLX5和DLX6的基因转录 [12] ;3) 反义lncRNA可以调节RNA的剪接过程,如:lncRNA Zeb2 NAT可以覆盖Zeb2 mRNA的5’端未翻译位点以阻止基因内剪接,以上调Zeb2蛋白的表达而Zeb2 mRNA含量无明显改变 [13] ,从而形成转录后的调节机制。而不同lncRNA作用机制又不尽相同(表1)。

Table 1. Function mechanisms of lncRNA

表1. LncRNA的作用机制

3. LncRNA在肺癌中的异常表达

据报道,lncRNA在肺腺癌中的表达异常达953种,而在肺鳞癌中的异常表达有1014种 [14] 。

Jiang等利用TCGA数据库中RNA序列的大数据联合qRT-PCR技术在48组实验(NSCLC细胞和正常肺组织细胞)中对比发现LINC00961在NSCLC中的表达明显下降 [15] ,同时低水平的LINC00961与高肺癌组织的TNM分级(P = 0.001)、淋巴结的转移(P = 0.019)和生存期的缩短(Kaplan-Meier生存分析)密切联系。Wu等 [16] 发现在H1299,H1703,H520和PC-9相比A549和SPCA-1中GAS5-AS1的表达下降水平尤为显著;若上调GAS5-AS1的表达水平则可以抑制上皮-间质转化过程的标记分子(ZEB1, N-cadherin和Vimentin)的表达。Han等 [17] 在140组NSCLC组织和正常组织对比中发现PANDAR的表达下降82.9% (116/140);而低水平的PANDAR与肿瘤的高级别(P = 0.002)和较大癌肿(P < 0.001)明显相关;进一步研究表明PANDAR受p53基因的调节,并且p53可以直接与PANDAR的上游调控区域相结合。Han等 [18] 对比50组正常肺组织细胞和NSCLC细胞发现尽管GAS6-AS1在45组中NSCLC细胞中表达下降显著,但仍有5组样本呈现上升趋势;应用多因素分析发现GAS6-AS1表达与NSCLC病人的生存期缩短(P = 0.036),组织学类型(P = 0.023)以及肿瘤分级(P = 0.033)有关。Wang等 [19] 对比112组癌组织和正常组织中的TUSC7表达水平发现:88 (78.6%)组中TUSC7的表达显著下降;而卡方检验的结果则进一步显示TUSC7的表达与肿瘤的大小(P = 0.007)和肿瘤分期(P = 0.012)显著相关;若上调TUSC7的表达,NSCLC细胞则多数停留在G1期,从而抑制肿瘤细胞的增殖。

Wan等 [20] 运用58组NSCLC组织和正常组织对比发现PCAT6在癌组织中的表达比正常组织高出15倍(P < 0.0001),并且和肿瘤的大小(P = 0.0343),淋巴结的转移(P < 0.0001)和肿瘤的分期(P = 0.018)密切相关;当敲除PCAT6的表达时,实验结果显示CL1-5和H446细胞被诱导凋亡,尤其是早期凋亡。Li等 [21] 运用四种NSCLC细胞系(A549, H1299, H460和NCI-H1650)对比正常肺组织上皮细胞(BEAS-2B)发现:NEAT1表达在NSCLC细胞中明显升高(P < 0.05)并且与高分期肿瘤、远处转移和淋巴结转移相关。通过对比100组NSCLC细胞和正常肺细胞,Pan等 [22] 发现FAL1的表达在78%的NSCLC细胞中明显上调;PAN等进一步选用H1299细胞做体内实验发现FAL1的表达朔评时对照组的110倍。通过43组癌组织和正常组织的对比,Lu等发现SNHG1在肺癌组织表达显著提高;Lu等 [23] 进一步通过利用A549细胞株转染裸鼠后,测定miR-145-5p和MTDH (Metadherin)蛋白的mRNA表达水平,从而发现SNHG1/miR-145-5p/MTDH轴,明确SNHG1表达上调是通过miR-145-5p进一步作用于MDTH的表达促进NSCLC细胞的增殖和迁移。

4. LncRNA对肺癌肿瘤细胞增殖、迁移、侵袭的影响

LINC00473是细胞核来源的lncRNA,是由LKB1 (STK11)失活诱发的并且随后同其下游的环状AMP反应原件结合蛋白(CREB)/CREB调节转录因子(CRTC)共刺激激活 [24] 。LINC00473与LKB1失活具有最良好的相关性,而LKB1是一种肿瘤抑制基因,并且是AMP-激活蛋白激酶(AMPK)的上游关键激活因子,其突变在非小细胞肺癌中约有20%~30%,仅次于P53和Ras基因的突变 [25] [26] [27] 。

PANDAR的过表达可以抑制肿瘤的增殖,这一作用是通过凋亡途径介导的,并且与Bcl-2表达有关 [17] 。众所周知,P53基因突变在肺癌的发生机制中是最常见的基因突变,而P53可通过与PANDAR启动子上的P53反应原件相结合来诱导PANDAR的成功转录并且过表达的PADAR在转录水平可以抑制Bcl-2的表达。LINC01207是只在肺腺癌中上调的lncRNA,而在肺鳞癌中却无明显的变化,同时可以发现该分子的静默则可以抑制肺癌细胞系的增殖以及促进细胞的凋亡 [28] 。WANG等通过单因子和多因子分析可见TUSC7的低表达是NSCLC患者的一个独立的较差预后的预测因子,并且TUSC7的上调可以抑制肿瘤的增殖 [19] 。

GAS5-AS1的表达下调可以影响NSCLC细胞的迁移和侵袭:利用Boyden室透孔分析实验,在SPC-AS1细胞中,敲除GAS5-AS1的表达不改变细胞增殖、细胞周期和细胞凋亡进程,但是显著提高肿瘤细胞的迁移和侵袭 [16] 。实验进一步表明,组蛋白的去乙酰化修饰是在NSCLC细胞中GAS5-AS1的主要调节途径 [16] 。敲除PCAT6的表达则可以促进肺癌细胞的早期凋亡和侵袭转移,但是对晚期凋亡和细胞坏死的影响不大;随后运用免疫沉淀法和相关抗体发现,PCAT6的表达与Cyc和P53基因的表达具有密切联系 [20] 。LncRNA AF118081在肺肿瘤中常常表达增加,当敲除lncRNA AF118081时则可以抑制细胞增殖,迁移以及肿瘤细胞的侵袭 [29] 。HOXA11-AS或许通过各种信号传导途径来调节其在肺肿瘤发生中的影响癌细胞侵袭转移的作用,特别是DOCK8和TGF-β两途径 [30] 。lncRNA HOTAIR和NEAT1的表达与肺癌的转移和侵袭进展息息相关,而当敲除这两个基因时,只有HOTAIR基因的敲除可以抑制肿瘤细胞的迁移和运动 [31] 。

上皮-间质转化通常是指由于细胞表型的间质化,使得细胞的粘附性下降而移动性增加的过程,包括上皮细胞表型标志的丢失和间质细胞表型标志的获取两个基本部分 [32] [33] 。上皮-间质转化不仅仅在上皮组织修复和胚胎发育期多见,而且常常与包括肺癌在内的肿瘤侵袭和转移密切相关 [34] 。部分lncRNA也可以影响上皮-间质过程,从而促进或抑制肿瘤细胞的侵袭和转移。如:过表达的GAS5-AS1可以通过减少诸如ZEB1、N-cadherin、Vimentin等的分子来抑制上皮-间质转化的过程,从而抑制肺癌发展 [16] ;而linc00460则增加以上分子的表达来促进上皮间质的转化,进而促进肺癌的转移和进展 [35] 。

5. lncRNA对自噬的影响

自噬是旨在降解已损坏的细胞器或长寿命的蛋白质的一个非常保守的、多步骤的经溶酶体作用的过程 [36] 。通常情况下,自噬过程是将需要降解的细胞器或蛋白经囊泡运送到溶酶体进行的,同时在此过程中会形成一个双层膜结构的自噬囊泡也就是自噬小体。研究表明,自噬在不同的人类疾病中都有重要作用,如:细菌病毒感染、神经退行性疾病、心脏疾病和肿瘤等疾病 [37] [38] 。在恶性肿瘤发生早期,自噬可通过消除功能异常的细胞器和蛋白质来抑制肿瘤的发生发展过程;但是在肿瘤晚期,自噬则可以通过减少细胞对微环境压力的反应来促进肿瘤的演进 [39] 。

目前,至少已经发现有37种自噬相关基因(ATG)存在于酵母细胞中,同时也有多种ATG类似物存在于人体中 [40] 。LncRNA通过ATG来调节自噬过程,并且lncRNA对自噬过程的调节渗透于自噬过程的各个阶段,如自噬的起始过程,吞噬泡的形成,自噬小体的组装以及自噬溶酶体的融合等(Ref. 40: table 1)。

自噬相关蛋白包括p62,NBR1和LC3等,其中LC3 I与LC3 II之间的比值翻转可以反映自噬活性。MALAT1是多物种来源的大于8000碱基对的lncRNA,其在多种组织如肺、胰腺、肝脏等均有表达 [41] 。而MALAT1的表达在非小细胞肺癌上调显著。GUO等利用NSCLC相应的恶性细胞系,如:A549细胞,与正常肺组织比较得出相应结论,同时发现了MALAT1是CXCL5的上游调节分子,并且其可由甲基化作用调节 [42] 。而MALAT-1下调则通过抑制自噬活性可抑制A549细胞的增值扩增、抑制A549细胞的细胞循环演进、抑制A549细胞的侵袭转移和促进A549细胞的凋亡,同时发现,静默MALAT-1的表达可以抑制A549细胞的自噬过程,但是具体机制尚不明确 [43] 。

6. LncRNA对肿瘤免疫的影响

当人体发生肿瘤的时候,免疫系统就会发动针对肿瘤细胞的杀伤清除作用,其基本形式包括天然免疫和适应性免疫两种。而适应性免疫又可以分为针对肿瘤细胞的以CD8+T细胞杀伤为主要作用细胞的细胞免疫和以针对循环中抗原为主的以特异性抗体为主要杀伤作用物质的体液免疫。一般情况下,针对实体瘤的免疫反应以细胞免疫为主。肿瘤抗原可以分为肿瘤特异性抗原(TSA)、肿瘤相关抗原(TAA)和肿瘤-胚系抗原(CTA)三大类 [44] [45] 。TSA是指在正常人体组织不表达,只特异性存在于肿瘤表面的抗原表位,这种抗原极少产生免疫耐受并且有可能成为靶向治疗肿瘤的靶点。TAA是指在人体正常组织表达,而在肿瘤发生时存在异常表达的抗原表位或者是异常表达的蛋白质,这种抗原具有免疫耐受的倾向。CTA是指正常情况下表达于睾丸、卵巢和滋养层细胞的抗原表位,但也可以表达于包括肺癌在内的肿瘤细胞,具有严格的组织特异性,是免疫治疗极具前景的治疗靶点 [46] 。

LncRNA参与调节天然免疫的调节和T细胞的成熟、分化以及激活过程。AGER (advanced glycosylation end-product specific receptor)属于免疫球蛋白超家族,也是目前为止唯一在肺癌表面发现的天然免疫模式识别受体。在肺癌中,调节AGER的lncAGER由于过度甲基化而表达下调,同时其表达下降与T细胞状态密切相关 [47] 。lncAGER在肺癌中通过肿瘤细胞的增殖、凋亡、细胞周期、癌细胞迁移等机制发挥抑癌作用。

在T细胞分化、成熟和作用的各个阶段,lncRNA的调节具有阶段特异性,并且对于不同种的T细胞(如:Th1细胞和Th2细胞)参与调节的lncRNA也不尽相同(48%~57%的特异性) [48] 。例如:STAT4激活并协同数种lncRNA (如LincR-Gng2-5’)可以刺激T细胞向Th1细胞方向分化;而STAT6则激活并协同数种不同的lncRNA (如LincR-Epas1-3’AS)刺激T细胞向Th2细胞分化。因此,多种lncRNA参与肿瘤免疫,并且作用于各个阶段(Ref.49, table1) [49] 。

7. 结论

lncRNA在肺癌中的作用非常广泛且多种多样,与肺癌的发生、转移、侵袭息息相关,并且参与自噬、肿瘤免疫等诸多过程。不同种类的lncRNA作用机制也不尽相同,而且由于lncRNA的广泛改变,靶向作用于lncRNA从而达到治疗目的也成为一种可能。需要进一步明确的是,靶向作用lncRNA是否可以达到治疗目的,仍需要进一步的临床试验。

文章引用:
李浩然, 李泽环, 高健, 丁建勇. LncRNA在肺癌中的研究进展[J]. 临床医学进展, 2018, 8(10): 915-921. https://doi.org/10.12677/ACM.2018.810152

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