长链非编码RNA与胃癌相关性的研究进展

长链非编码RNA与胃癌相关性的研究进展

时间:2016-08-11    来源:360期刊网    浏览:371

  长链非编码RNA与胃癌相关性的研究进展

  黄艳霞张靖王歌朱金水

  摘要:长链非编码RNA(lncRNA)因其长度大于20()个核苷酸,缺乏编码蛋白能力而得名。在表观遗传 学控制、转录和转录后调控等多个层面,IncRNA参与了机体多种生理及病理过程的调节。研究已经证明, IncRNA在胃癌生物学的调节过程中起关键的作用,IncRNA与胃癌的发生、发展、侵袭、转移及预后密切相 关。该文对IncRNA在胃癌中的研究进展作一综述。

  关键词:lncRNA;胃癌;转移

  IX )1: 10. 3%9/j. issn. 1673-534X. 2016. 03. 005

  长链非编码RNA (IncRNA)因其长度大于2(K> 个核苷酸,缺乏编码蛋白能力而得名。IncRNA Xist 为哺乳动物中t先被发现的IncRNA,可导致染色质 结构4组成的重塑。尽管IncRNA发挥了重要的生 物学功能,但多数情况下仍被认为是转录中的;噪 音”。其后发现IncRNA HOTAIR吋与多梳蛋白复合 体相互作用,参与机体生长、发育过程的调节。随着 高通量测序等生物信息学技术的快速发展,已发现 IncRNA在表观遗传学控制、转录和转录后调控等多 个层面参与丫机体多种生理及病理过程的调节。

  1丨ncRNA的结构、分类及功能

  IncRNA可位于细胞核和细胞质中,多由RNA 聚合酶丨丨转录。其长度变异性较大,部分可延长至 1()() kb。人类基因组约有15 00()种IncRNA,其转 录水平远低于蛋白编码基因,且具有组织特异性。 丨r前分子结构明确的IncRNA所占比例甚少,Niazi 等对204种功能性IncRNA进行分析后发现,内 含子数量少、鸟嘌呤(G)和胞嘧啶(C)含量低、起始 密码子和开放阅读框架的缺乏可能是IncRNA的一 些结构特征。根据IncRNA基因与编码基因间的位 置关系,RJ■以将其分为正义IncRNA、反义IncRNA、 双向IncRNA、内含子IncRNA和基因间IncRNA 五类IncRNA的异常表达与人类疾病密切相 关,如老化相关的阿尔茨海默病及认知障碍相关疾 病都被认为与IncRNA的异常表达有关;其在心血 管疾病、内分泌疾病(如糖尿病)中亦发挥丫作 用[3]。值得关注的是,IncRNA与肿瘤的发东发展 密切相关,IncRNA在前列腺癌、结直肠癌、乳腺癌、膀胱癌、肝细胞癌及胃癌等多种恶性肿瘤中均有异 常表达,n]•作为致癌或抑癌因子参与肿瘤细胞转 录、染色质電塑、微血管侵袭等过程的调控。

  2 IncRNA与胃癌

  IncRNA AC0%655首先被发现与胃癌相关,并 被命名为GACAT1W。2012年Yang等[5]发现 IncRNA H19表达上调对促进胃癌细胞增殖。其后 IncRNA在胃癌中的重要性得到越来越多的关注, 它们几乎参与胃癌发生发展的全过程,包括肿瘤细 胞增殖、凋亡、侵袭、转移、预后及耐药性等多个方 面。此外,IncRNA对胃癌的诊断也有帮助,n]•能是 胃癌诊断的潜在分子标志物。

  2.1 IncRNA在胃癌中的生物学功能

  IncRNA在胃癌的发生发展中具有促癌或抑癌 双重作用。如 IncRNA H19、HULC、Linc0()152、 HOTAIR、PVT1、HIF1A-AS2、UNCO(觀、 MALAT1及SPRY4-IT1等具有促进月中瘤细胞增 殖、入侵及转移的作用[6_M],而IncRNA MEG3、 GAS5、FENDRR、LEIGC、FER1L4 及 WT1-AS 等 具有抑制肿瘤细胞增殖、促进肿瘤细胞凋亡的作 用[15 2"]。此外,IncRNA在胃癌组织中的表达水平 也不一致,IncRNA的表达水平与胃癌临床病理特 征的关系见表1。

  2.2 IncRNA在胃癌耐药中的作用

  肿瘤细胞耐药是化学治疗失败的重要原因之一, 越来越多的研究发现IncRNA参与肿瘤细胞耐药的 调节,如21^«等[29]的研究发现IncRNA PVT1在对 顺铂耐药患者的胃癌组织及胃癌细胞中高表达,过表 达IncRNA PVT1促进了胃癌细胞耐药。rang等[3°] 亦证实IncRNA PVT1表达升高能促进胃癌细胞对紫 杉醇的耐药。此外,癌细胞中高表达的IncRNA MRUL促进了胃癌耐药细胞中ABCB1的表达,从而促进了胃癌细胞对药物的耐药性[31]。然而,一些的作用,如发现IncRNA LEIGC可增加胃IncRNA却具有提高肿瘤细胞对化学治疗药物敏感性 癌细胞对5-氟尿嘧啶的敏感性。

  表1 IncRNA的表达与胃癌崎床病理特征的关系

  2.3 IncRNA在胃癌侵袭转移中的作用

  侵袭和转移是恶性肿瘤的重要特征之一。越 来越多的证据表明,上皮-间质转化(EMT)及肿瘤 细胞间的黏附能力下降,可能参与了肿瘤转移的重 要环节。Zhao等[8]的研究发现,IncRNA I」nc00152 能抑制胃癌细胞中EMT的进程。Han等[32]研究 了 IncRNA LEIGC在胃癌细胞中的作用,敲低其表 达水平后,胃癌细胞发生了 EMT。该研究进一步检 测了与EMT相关的一些蛋白,研究结果与此一致, 因此可以认为IncRNA LEIGC在胃癌细胞中是一 个潜在的EMT抑制剂。Zhao等[7]的研究发现, IncRNA HULC可抑制胃癌细胞凋亡、促进胃癌细 胞增殖,其作用机制可能与诱导细胞自噬,促进EMT 有关。转化生长因子-(3(TGF-p)信号通过miR-2()()家 族和ZEB1/2之间的双负反馈循环调节肿瘤 ,EMT^,Saito 等[34]的研究发现,IncRNA ATB 通过 TGF-p诱导胃癌EMT变化以促进转移发生。Xu 等[17]发现过表达IncRNA FENDRR能诱导胃癌肺转 移结节增多,并使肿瘤细胞间的黏附分子FN1表达 下降,证明了 IncRNA FENDRR可能通过影响FN1 来调节胃癌细胞的转移。

  2.4 IncRNA与胃癌的诊断

  IncRNA可存在于血浆、胃液及组织中,目前部 分血桨中的IncRNA已被作为潜在的肿瘤标志物。 Zhou等[35]的研究发现血浆中IncRNA H19能为早 期胃癌的诊断提供可靠依据。胃液中IncRNA的获 得相对容易,并能够为胃癌提供有效的诊断。 Zheng等收集了 49份胃液标本(26份胃癌患者 标本和23份健康者标本),发现胃癌标本中 IncRNA UCA1的水平高于健康标本。Yang等[37] 研究了 130份胃液标本(包括胃良性病变、胃不典型 增生、胃癌癌前病变和胃癌患者),发现胃癌患者的 胃液中IncRNA ABHD11-AS1水平显著高于正常 胃、萎缩性胃炎、胃溃疡,并与胃癌患者的性别、肿 瘤大小、分期、劳伦分型及血清中癌胚蛋白(CEA) 水平相关。值得注意的是,胃液中IncRNA ABHD11-AS1作为诊断胃癌的标志物时,早期胃癌的诊断率 提高到71. 4%。

  2. 5 IncRNA可能的作用机制

  IncRNA的调节机制复杂且多样化:可调控下 游基因转录或作为分子阻断剂阻断该分子发生作 用;亦可通过与蛋白结合,定位到特定的DNA序列上;也可与多个相关转录因子结合发挥作用;还可 竞争性结合miRNA以调控基因表达。Cai等发 现IncRNA FRLncI可通过调节FOXM1参与肿瘤 生长及血管生成。Wang等™研究了 IncRNA MALAT1的功能,发现其可能通过调节SF2/ASF 来促进胃癌细胞增殖。有研究表明,IncRNA GAS5 通过下调E2F1和P21的表达来诱导胃癌细胞增 殖[16],而IncRNA WT1-AS则通过抑制细胞外信号 调节激酶(ERK)蛋白磷酸化水平来阻止胃癌 发生M。

  竞争性内源RNA (ceRNA)在转录后调节及肿 瘤的发生发展中具有重要的作用[38]。ceRNA通过 竞争性结合miRNA以调节基因表达,是RNA之间 相互作用的一种新机制。如I」u等[39]发现胃癌中 IncRNA HOTAIR可通过竞争性抑制miR-3;M-3p 来调节表皮生长因子受体2( HER2)的表达,增加了 转录后调控的水平。IncRNA H19可通过调控 miR-675抑制RUNX1而促进肿瘤细胞增殖 IncRNA H1F1 A-AS2在胃癌发展中发挥了重要的 作用,通过调节与肿瘤相关的缺氧诱导因子-la (HIF-la)途径促进肿瘤发展。丨ncRNA ANRIL在 胃癌组织中表达上调,通过表观沉默miR-9%/ miR-449aM进肿瘤生长[11]。

  3问题与展望

  IncRNA在组织生理及病理过程中发挥了重要 的调节作用,其作用机制仍有待进一步探索。 IncRNA在疾病发生发展中的作用是错综复杂的, 一方面〇!能是由于IncRNA在物种间的低保守性, 使得物种中IncRNA的功能不确定;另一方面由 于缺乏相关的研究工具,IncRNA的数据库还不够 充足,很难全面揭示IncRNA的生物学功能;此外, IncRNA与肿瘤转移或耐药的机制研究尚不成 熟[4243]。无论当前研究显示IncRNA是抑癌基因或 是促癌基因,可以确定的是IncRNA与胃癌有着密 切的联系,以IncRNA为靶点的药物有望在胃癌的 临床治疗中起到重要的作用。因此,明确_lncRNA 在胃癌及其他疾病中的具体作用尤为重要,有助于 全面深人地认识胃癌的发生发展机制,并为临床治 疗胃癌提供更多的途径。 ,

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