肝癌中长链非编码RNA调控机制研究进展
Advances in the Research of Long Non-Coding RNA Regulation Mechanism in Liver Cancer

作者: 崔 凯 :山东大学附属山东省肿瘤医院肝胆外科,山东省医学科学院,山东 济南; 欧 洋 , 宁大为 :济南大学山东省医学科学院医学与生命科学学院,山东 济南;

关键词: 长链非编码RNA肝癌基因调控Long Non-Coding RNA Liver Cancer Gene Regulation

摘要:
LncRNA是一组转录本长度超过200个核苷酸序列的RNA分子,它们本身并不编码任何蛋白或者只是编码很短的多肽类分子。最新的编码数据库显示:编码蛋白质的转录本仅占人类基因组转录本2.94%。基因组和转录组测序证据表明:复杂的机体功能可能受一系列来自于基因组非编码区的短链或者长链非编码RNA (Long non-coding RNA, lncRNA)的调控。近年来研究表明,lncRNA参与X染色体失活、干细胞干性的维持、转录调节、表观遗传学调控等多种重要的生物过程。非编码RNA (non-coding RNA, ncRNA)参与了多种疾病尤其是肿瘤发生发展的调控过程,是近期研究热点之一。随着高通量筛选方法的完善,越来越多的长链ncRNA (long non-coding RNA, lncRNA)分子被发现,并有望成为新型肿瘤诊断标志物和肿瘤治疗的靶点。本文主要就几种常见的与HBV相关肿瘤调控有关的lincRNA的特征及其在肝癌中的功能进行阐述。

Abstract: Long non-coding RNA is a subgroup of non-coding RNAs greater than 200 nucleotides. They don’t encode any protein themselves or just encode very short peptides. The latest coding database shows that the transcripts encoding proteins account for only 2.94% of the human genome tran-scripts. Evidence from genome and transcriptome sequencing suggests that complex body functions may be regulated by a series of short-chain or long-chain non-coding RNAs derived from the non-coding regions of the genome. Recently, accumulating evidences have showed the lncRNA is playing the important biological processes, such as inactivation of X chromosome, maintenance of stem cell stemness, transcription regulation and epigenetic regulation. Non-coding RNA is involved in the regulation of many diseases, especially the development of tumors. It is one of the recent research hotspots. With the improvement of high-throughput screening methods, more and more long non-coding RNA molecules have been discovered and are expected to become new cancer diagnostic molecular markers and targets for cancer treatment. This review describes the characteristics of several common lincRNAs involved in the regulation of HBV related tumors and their function in liver cancer.

1. 引言

非编码RNA (non-coding RNA, ncRNA)参与了多种疾病尤其是肿瘤发生发展的调控过程,是近期研究热点之一。目前已有研究阐述了siRNA和miRNA的分子机制和功能 [1] 。本文主要就几种常见的与HBV相关肿瘤调控有关的lincRNA的特征及其在肝癌中的功能进行阐述。

2. LncRNA的定义

在人类基因组中转录生成蛋白质的基因不到2%,能被转录成RNA但是不编码蛋白质的序列超过90%,这些不能编码蛋白质的RNA分子称为LncRNA。这些曾经被认为是基因组中“暗物质”的lncRNA,包括小干扰RNA (siRNA)、微小RNA (miRNA)和长链ncRNA (lncRNA),其在细胞生命的各环节中都具有重要作用 [2] 。

3. LncRNA的功能

LncRNA是指一类转录长度超过200个核普酸的非蛋白质编码RNA [3] 。LncRNA通常由RNA聚合酶II转录生成,再经过共转录修饰,包括多聚腺普酸化和预RNA剪接 [4] 。但其具有时空表达特异性,由于缺少有效开放阅读框而不编码蛋白,直接以RNA的形式发挥作用。在多个层而上(表观遗传调控、转录调控以及转录后调控等)调控基因的表达水平。他们在生命活动中具有调节转录,转录后加工,蛋白质翻译等多种作用,同时可在多个水平调控基因的表达,在胚胎发育,细胞分化,疾病及肿瘤的发生过程中都起着重要作用 [3] [5] [6] 。在过去的几十年中,这些长链非编码被认为是转录的“噪音”或克隆的神器。大量的研究发现了1ncRNAs,但1ncRNAs的细胞功能仍有待于进一步的研究 [7] 。事实上,最近的研究已经确定了大量的lncRNAs对许多生物进程有着重要的调控作用,lncRNA可以作为亚细胞结构的组织框架并可调节蛋白质的活性。此外,一些1ncRNAs可以通过招募RNA聚合酶II或者诱导染色质重塑来调节反式或顺式基因表达,指导染色质重构蛋白复合物的形成,基因组印记,核分区,核交换,RNA剪接和翻译调控 [8] [9] 。

4. LncRNA对肝癌发生发展的调控机制

目前研究发现与肝癌相关的lncRNA有6个:H19、HULC、MALAT1、MEG3、HOTAIR、UCA1和TUC338等 [10] 。

4.1. H19

H19是第一个被发现的lncRNA基因,定位于染色体11p15.5,全长约2.3 kb,是唯一从母代等位基因表达的1ncRNA. H19在细胞生长和发展中起到重要作用 [11] [12] [13] [14] 。

LncRNA H19在胚胎发育过程中呈高表达,而在出生后表达迅速下降 [15] ,但是在肿瘤形成过程中又开始升高 [16] ,表明H19在肿瘤中起癌基因的作用。然而Yoshimizu等 [17] 通过肝癌小鼠模型发现缺乏H19的小鼠成瘤能力与肿瘤生长速度均强于正常小鼠,表明H19在肝癌中又起抑癌基因的作用。因此H19的功能还需进一步探索。国内有研究利用实时荧光定量聚合酶链反应技术检测发现H19在肝癌组织中表达明显高于正常肝组织,并且过表达H19导致肝癌细胞增殖能力增强,而敲除H19后增殖和侵袭能力明显减弱,说明H19过表达可以用于肝癌的诊断,又可以作为一个潜在的治疗肝癌的靶点 [18] 。近来研究发现H19还可以作为ceRNA竞争性结合miR-let-7家族、miR-17-5p家族等在正常生理及疾病发展过程中发挥作用 [19] [20] 。

4.2. 肝癌高表达转录本(Highly Up-Regulated in Liver Cancer, HULC)

HULC被认为是第一个在HCC特异性高度上调的lncRNA,由染色体6p24.3转录得到,全长500 nt [10] 。

Panzitt等 [10] 于2006年首次发现HULC在肝癌组织中的表达量明显上调,并在肝癌患者的血液中检测出HULC的表达,且检出率明显高于正常人、肝炎或肝硬化患者,因此认为HULC可能是个潜在的肝癌标志物。随后,Xie等 [21] 进一步证明了此观点,而且还发现HULC在血浆中的检出率随着肝癌分期或乙型肝炎病毒DNA拷贝量的增高而增高,进一步证明HULC是一个新的肝癌诊断及预后的标志物。研究发现 [22] ,HULC启动子区存在环磷酸腺苷反应元件结合蛋白(CREB)的结合位点,磷酸化的CREB可通过磷酸激酶A途径上调HULC的表达;HULC升高后可与miR-372结合,从而解除miR-372对其下游靶mRNA蛋白激酶A催化亚单位B (PRKACB)的抑制作用而使其上调,上调的PRKACB进一步促进CREB的磷酸化;磷酸化的CREB人核后再促进HULC的表达。相反,当miR-372表达升高后,也可以与HULC结合而抑制CREB与HULC的结合,并促进p300的解离,导致组蛋白甲基化等一系列变化,由此影响肝癌的发生发展。

4.3. 转移相关的肺腺癌的转录因子1 (Metastasis Associated Lung Adenocarcinoma Transcript 1, MALAT1)

MALAT1是一个长度大于8000 bp的lincRNA [23] ,在多个物种中高度保守,表明其有很重要的生物功能 [24] 。Lai等 [25] 报道MALAT1在肝癌组织和细胞系中表达均异常增高,多变量分析发现该基因是肝细胞癌复发的独立预测因素,且其表达量越高患者预后越差,抑制MALAT1的表达可以明显抑制肝癌细胞的增殖和侵袭能力,提示MALAT1可能具有很重要的临床价值,可作为治疗靶点来消灭术后残留或扩散的肿瘤细胞。研究发现MALAT1是通过调控细胞中的sR剪接因子来影响pre-mRNA的选择性剪接,从而调控基因表达 [26] ,而Gutschner等 [27] 则认为MALAT1是通过调控相关基因的表达而非可变剪接在肿瘤的侵袭转移中发挥作用。研究发现microRNA-9的异常表达在多种肿瘤的发展进程中均起到重要作用 [28] [29] ,其可以通过在细胞核内与MALAT1直接结合调控其表达量,进而导致MALAT1的异常表达 [30] 。

4.4. 母系表达基因3 (Maternally Expressed Gene 3, MEG3)

母系表达基因3 (maternally expressed gene 3, MEG3)是Miyoshi等在2000年首次发现的小白鼠母系表达基因,定位于染色体14q32.3,长度约为1.6 kb。MEG3是捕获基因座2 (gene trap locus 2, Gt12)的人类同系物。它是第一个被发现有肿瘤抑制功能的lncRNA,在多种正常组织中均有表达 [31] 。已发现MEG3有12个亚型 [32] 。

MEG3在肝细胞癌组织和细胞系中普遍呈低表达,过表达后肿瘤细胞生长受到抑制、凋亡率增加。其低表达的原因主要与MEG3启动子区高甲基化有关,而miR-9可以通过抑制DNA甲基转移酶(DNMT)1和3b,实现MEG3的上调 [33] 。此外,Anwar等 [34] 也认为DLK1-MEG3在肝细胞癌中处于失调状态,下调DNMT1后MEG3差异甲基化区域的甲基化减少,随后MEG3水平升高。研究表明 [35] P53是MEG3的一个作用靶点。正常情况下,由于泛素蛋白连接酶2(MDM2)介导的泛素化导致P53含量很低,所以抑制MDM2的作用对于维持P53的稳定性是非常重要的。而实现MEG3过表达后,MDM2表达降低,P53含量明显升高,表明MEG3激活P53是通过下调MDM2实现的,但在P53缺失的情况下,MEG3也可以抑制细胞增殖,表明MEG3可以通过P53依赖或非依赖的方式发挥抑癌作用。

4.5. HOX基因的反义基因间RNA (HOX Antisense Inter Genic RNA, HOTAIR)

HOTAIR是第一个被发现具有反义转录调控作用的lincRNA,位于HOX位点,长度为2.2kb的基因。

Tsai等 [36] 研究发现HOTAI可作为支架连接至少2种组蛋白修饰复合物,通过与其表面结合来组装选择组蛋白修饰酶,进而指定靶基因组蛋白修饰模式。研究发现 [37] [38] [39] HOTAIR在肝细胞癌组织中表达量明显升高,且与淋巴结转移成正相关,表达量越高的患者术后复发风险也越高。Geng等 [38] 在63例HCC术后患者中,发现癌组织HOTAIR的表达量较癌旁组织明显上升(P < 0.05),HOTAIR的表达量与HCC的复发及淋巴结转移密切相关(P = 0.003);干扰HOTAIR的表达后,肿瘤细胞的增殖能力下降,MMP-9、VEGFR的表达量亦降低,提示HOTAIR可能是一个潜在的肿瘤转移的标志物。Ding等 [39] 发现RNA结合基元蛋白(RBM38)在肝细胞癌组织中明显下调,敲除HOTAIR后,RBM38表达上调,细胞侵袭转移能力减弱,而敲除RBM38后细胞侵袭能力又恢复,表明抑制HOTAIR导致的细胞侵袭能力减弱可能是通过上调RBM38实现的,RBM38可能是HOTAIR的一个抑制性靶点。

4.6. 尿路上皮癌相关转转录本1 (Urothelial Cancer Associated, UCA1)

表达的长非编码RNA分子,并命名为UCA1。UCA1定位于19p13.12,cDNA全长为1442 by,其5’末端具有TATA盒(TATAAA),3’末端具有加尾信号(ATTAAA)和poly A尾,包含3个外显子和2个内含子。

UCA1与肝细胞癌是全世界泛发和进展迅速的恶性肿瘤。Wang等 [40] 发现UCA1在肝癌组织中的表达显著上调,并且与TNM分期、转移和术后生存期相关。体内、外实验表明,敲除UCA1能阻止肝癌细胞的生长和转移。此外,UCA1可以像内源性海绵吸附miR-216b,并下调miR-216b的表达。同时UCA1可以逆转miR-216b,进而抑制肝癌细胞生长、转移的能力,这可能与成纤维生长因子受体1 (FGFRl)表达的去阻滞有关。FGFR1是miR-161b的靶基因,并且是ERK信号传导通路的激活物。最新研究表明,在肝癌中存在一种新兴的lncRNA-miRNA-mRNA调节网络,即UCAl/miR16b/FGFRl/ERK通路,这更能清晰地解释肝癌的病理发生机制,并带来了探查长非编码RNA用于肝癌的诊断和治疗的可行性。

Yang等 [41] 基于表达谱GSE36376将肿瘤组织中的长非编码RNA表达和肝癌患者的生存与临床病理特征联系起来。研究涉及8种长非编码RNA,其中包含了UCA1。己有研究报道,UCA1在膀肤移行细胞癌中相对癌旁组织高表达,并且能促进细胞的增殖和侵袭,Hu等在肝癌临床病例中观察到了与此相异的表达谱,提示HBx上调的UCAI参与肝癌的发生发展过程有其独特的机制 [42] 。

4.7. TUC338 (Transcribed Ultra-Conserved Region 338)

TUC338人类全基因组测序时发现存在一类特殊的lncRNA,在人类、鼠类等基因组中100%一致,这类高度保守的lncRNA称超保守RNA。

Braconi等 [43] 发现有56种ucRNA、在肝癌细胞系HepG2中异常表达,其中uc.338差异变化最大,且与癌旁组织相比,uc.338在人类肝癌组织中表达显著升高(P < 0.05)。uc.338可克隆出一段长590 by RNA分子,称为TUC338。用小干扰RNA (siRNA)干扰TUC338后可抑制肝癌细胞生长,降低HepG2和Huh一细胞增殖并明显降低S期细胞数量(P < 0.01),同时发现肿瘤抑制剂P16INK表达上调了5倍,而CDK4, CDK6, cyc1inD1则分别下调了2.76、2.65、1.37倍。这些细胞周期蛋白的改变显著影响肝癌细胞增殖。值得一提的是TUC338在胆管细胞癌中并无异常表达,提示TUC338可能具有肝组织特异性。

4.8. 其他lncRNA

乙型肝炎病毒X蛋白(HBX)下调表达lncRNA (Dreh)在肝细胞癌发展中起抑癌基因的作用,研究发现 [44] Dreh在乙型肝炎病毒相关的肝细胞癌组织中和HBX转基因小鼠的肝细胞中均明显下调,进一步研究表明Dreh可以与中间丝蛋白中的波形蛋白(VIM)结合并抑制其表达,从而改变细胞骨架结构和形态。此外,VIM还参与细胞粘附、转移、增殖和信号转导等过程,因此,Dreh通过抑制VIM的表达来抑制肝癌细胞的增殖与转移。另一个在乙型肝炎相关性肝癌中明显升高的lncRNA是肝细胞癌高表达IncRNA (HEIH) [45] ,其表达与肿瘤的复发密切相关,且是独立的预后因子。研究发现 [45] lncRNA HEIH在细胞G0/G1期阻滞中起重要的作用,而且可以与果蝇Zeste基因同源物增强子2 (EZH2)结合来共同调控EZH2相关靶基因的表达(EZH2为组蛋白甲基化酶PRC2复合物的一个亚单位)。Yuan等 [46] 通过215例肝癌组织发现与肝细胞癌微血管侵犯相关的lncRNA (MVIH)过表达的患者微血管侵犯率、淋巴结转移率较高,生存期较短;进而在小鼠模型中发现MVIH可以通过抑制磷酸甘油酸激酶1的分泌激活肿瘤血管生成,促进肿瘤生长和肝内转移。研究发现 [47] 长链非编码RNA肌动蛋白纤维相关蛋白l-反义RNA1(AFAP1-AS1)在肝癌组织中表达水平低于癌旁组织,并与肝癌的临床分期和淋巴结转移密切相关,提示AFAP1-AS1可能参与肝癌的发生发展,进一步分析其与淋巴结转移的关系提示AFAP1-AS1可能是一个潜在的肝癌转移分子标志物而应用于肝癌的预后诊断。调节基因重组的lincRNA ROR [48] 高表达于化疗抵抗的肝细胞癌细胞及胞外囊泡,而转化生长因子β不仅可以丰富ROR在囊泡中的含量,还可以通过促进CD133+细胞增殖来加强癌细胞的化疗抵抗,然而敲除ROR后上述作用明显减弱,化疗敏感性增强。表明lincRNA ROR化疗耐药反应中起重要的作用,可以作为一个潜在靶点来改善化疗敏感性。

5. 结论

综上所述,随着基因测序和分析技术的进步,越来越多的证据表明:在肝癌中多种lncRNA发生变化并发挥重要作用,深入探讨研究lncRNA在肝癌诊断和治疗方面的作用具有良好的临床应用前景。

基金项目

山东省医药卫生科技发展计划,2013WS0362。

NOTES

*通讯作者。

文章引用: 崔 凯 , 欧 洋 , 宁大为 (2018) 肝癌中长链非编码RNA调控机制研究进展 。 世界肿瘤研究, 8, 100-107. doi: 10.12677/WJCR.2018.83016

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