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长链非编码RNA调控乳腺癌发生发展的研究进展

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  摘要:乳腺癌是女性最常见的疾病之一,由于本身的复杂性和异质性,使其仍然是公共卫生领域的一大难题。近几年来随着技术的发展,长链非编码RNA(lncRNA)受到了广泛的关注。大量研究表明,长链非编码RNA由于其关键的生物调控功能,在肿瘤的发生、发展中发挥着重要作用。尽管长链非编码RNA的具体分子机制尚未完全明确,但最近的研究表明,许多长链非编码RNA在多种肿瘤中表达异常,其中包括乳腺癌。本文主要对长链非编码RNA与乳腺癌的最新研究进行了综述,并进一步探索长链非编码RNA在影响乳腺癌增殖、凋亡、侵袭、转移中的分子机制。
  关键词:长链非编码RNA;乳腺癌;分子机制;细胞增殖,侵袭;转移;凋亡
  中图分类号:R737.9                                 文献标识码:A                                 DOI:10.3969/j.issn.1006-1959.2019.12.014
  文章编号:1006-1959(2019)12-0040-06
  Abstract:Breast cancer is one of the most common diseases in women. Due to its complexity and heterogeneity, it is still a major problem in the field of public health. In recent years, with the development of technology, long-chain non-coding RNA (lncRNA) has received extensive attention. A large number of studies have shown that long-chain non-coding RNA plays an important role in the occurrence and development of tumors due to its key biological regulatory functions. Although the specific molecular mechanisms of long-chain non-coding RNA are not fully understood, recent studies have shown that many long-chain non-coding RNAs are abnormally expressed in a variety of tumors, including breast cancer. This article reviews the recent research on long-chain non-coding RNA and breast cancer, and further explores the molecular mechanism of long-chain non-coding RNA in affecting breast cancer proliferation, apoptosis, invasion and metastasis.
  Key words:Long-chain non-coding RNA;Breast cancer;Molecular mechanism;Cell proliferation; Invasion;Metastasis;Apoptosis
  美国癌症协会发布的数据表明,2018年美国新增癌症1735350例,癌症死亡609640例[1]。乳腺癌是全世界范围内的女性最常见的癌症,其病死率居于第2位,仅次于肺癌[2]。其发病率有逐年上升的趋势,对女性的身心健康有严重的危害。尽管近20年来,乳腺癌的早期诊断和治疗方面取得了较大的进展,但乳腺癌仍然是一个重大的公共卫生问题。随着下一代测序技术的进步,有研究表明,至少75%的人类基因组被转录成RNA,但是只有不到2%的转录本被翻译成蛋白质[3]。这些不编码蛋白质的RNA称为非编码RNA,根据其长度可分为长链非编码RNA和短鏈非编码RNA。短链非编码RNA长度小于200个核苷酸,包括小干扰RNA、转移RNA、微小RNA。长链非编码RNA长度大于200个核苷酸,有时可以达到100 kb[4]。在过去的20年,短链非编码RNA,尤其是微小RNA得到了广泛的关注与研究,许多微小RNA的生物学功能已经阐明[5]。然而,由于长链非编码RNA通常被认为是进化“废物”和转录“噪音”,目前对长链非编码RNA的生物学功能的认识是相当有限的。在这篇文章中,我们将回顾长链非编码RNA在人类癌症,特别是在乳腺癌中的生物学作用。
  1长链非编码RNA的定义和分类
  长链非编码RNA是一类长度为200 nt~100 kb,缺少开放阅读框的内源性RNA分子。基于它们的位点,特性以及与相邻基因的关系,可将其分为六类:①基因间长链非编码RNA[6];②内含子长链非编码RNA[7];③双向长链非编码RNA[8-10];④反义长链非编码RNA[11];⑤重叠长链非编码RNA[12];⑥微小RNA宿主长链非编码RNA[13]。
  2长链非编码RNA的功能
  长链非编码RNA缺乏显著的开放阅读框和编码蛋白质的功能,它以RNA的形式参与表观遗传水平、转录水平和转录后水平的基因表达调控。   2.1转录水平  ①长链非编码RNA可以作为信号分子或诱导物质促进或抑制基因表达[14];②长链非编码RNA可以作为支架分子,通过在特定位点组装染色质修饰复合物调控基因表达[15];③长链非编码RNA可以作为miRNA的分子海绵(又称竞争性内源性RNA),逆转了miRNA对靶基因的抑制[16]。同样的,长链非编码RNA在恶性乳腺肿瘤中也可能作为miRNA的分子海绵发挥作用。Feng W[17]等研究表明,长链非编码RNA KCNQ1OT1作为miR-145的竞争性内源性RNA,通过调节miR-145的靶基因细胞周期蛋白E2(CCNE2)的表达,促进肿瘤生长。
  2.2转录后水平  长链非编码RNA通过与mRNA形成双链RNA[18],或者通过结合来调控蛋白的稳定性。长链非编码RNA ATB通过结合IL-11 mRNA和刺激信号传导与活化转录因子3(STAT3)信号通路促进结直肠癌恶化。在三阴性乳腺癌中,长链非编码RNA PVT1与锌指蛋白转录因子5(KLF5)蛋白结合并增加其稳定性[19]。此外,长链非编码RNA还是miRNA的前体物质。据报道,长链非编码RNA H19是miR-675的前体[20]。
  2.3表观遗传学水平  ①长链非编码RNA通过调控下游基因启动子区域的DNA甲基化,使其沉默[21];②长链非编码RNA通过与组蛋白修饰因子协同作用改变组蛋白的甲基化、乙酰化或泛素化[22];③长链非编码RNA可以直接与染色质修饰复合物结合,重建染色质或改变其构象,调控靶基因转录。值得注意的是,长链非编码RNA发挥作用的分子机制远比想象的更灵活[23]。
  3长链非编码RNA在乳腺癌中的功能
  长链非编码RNA在各种肿瘤中都发挥着重要的作用,尤其是在乳腺癌中。许多长链非编码RNA在乳腺癌中异常表达例如:长链非编码RNAMALAT1[24],长链非编码RNADANCR[25],长链非编码RNAPDCD4-AS1[26]等。在乳腺癌中,一部分长链非编码RNA发挥着促癌基因的作用,例如ARNILA[27]、Lnc015192[28]、ITGB2-AS1[29]、NEAT1[30]、AC026904.1[31]这些长链非编码RNA促进了乳腺癌的侵袭转移,GACAT3[32]、PVT1[19]则对乳腺癌的生长增值具有促进作用,CHET1[33]、TUG1[34]对乳腺癌的生长增殖和侵袭转移都具有促进作用;另外一部分长链非编码RNA则发挥着抑癌基因的作用,例如ANCR[35]、MEG3[36]、PTENP1[37]、MAGI2-AS3[38]、XIST[39,40]、PDCD4-AS1[26]这些长链非编码RNA抑制了乳腺癌的恶性进程。
  3.1长链非编码RNA参与乳腺癌细胞的生长增殖  癌细胞的增殖是由多种信号通路诱导的[41]。最近的研究表明,多种长链非编码RNA通过激活或者抑制乳腺癌中特定的信号通路来介导细胞的生长增殖[41,42]。
  3.1.1 Akt信号通路  Akt信号通路参与抑制细胞凋亡,刺激细胞增殖等多种生物反应[43]。有研究发现,H19是一种致癌基因,其长度为2.3 kb,并由母体等位基因编码,H19能驱使miR-675下调c-Cb1和Cb1-b蛋白,激活表皮生长因子受体(EGFR)和c-Met的表达,从而激活Akt信号通路,使乳腺癌细胞增殖得到促进[44]。Zhang CY[45]等研究发现,长链非编码RNA MEG3的过表达不仅导致乳腺癌细胞G0/G1期阻滞,还通过下调Akt信号通路抑制乳腺癌小鼠模型的肿瘤生长。此外,Chen S[46]等研究表明,長链非编码RNA PTENP1通过下调丝裂原活化蛋白激酶(MAPK)和Akt信号通路抑制乳腺癌细胞的增殖。
  3.1.2 MAPK信号通路  丝裂原活化蛋白激酶(MAPK)是丝氨酸-苏氨酸激酶家族的一部分,广泛参与细胞的增殖、分化、迁移、衰老和凋亡[47]。乳腺癌中,长链非编码RNA CAMTA1通过结合miR-20b,竞争抑制其对MAPK激活剂表皮生长因子受体(VEGF)的抑制作用,从而促进了人乳腺癌细胞的增殖[48]。同时,Wang L[49]等在4种乳腺癌亚型中发现了12~44个长链非编码介导的交叉通路,他们发现长链非编码RNA LIFR-AS1是一种肿瘤抑制因子,通过调控IL1R和TGFBR的表达,进而激活MAPK信号通路,促进乳腺癌细胞增殖。Peng WX[50]等利用CRISPR/Cas9技术敲除MCF-7细胞中的linc-ROR,并发现linc-ROR能促进乳腺癌细胞中雌激素独立生长并激活MAPK通路。
  3.1.3 Wnt信号通路  Wnt信号通路是一种高度保守的信号通路,可通过标准或非标准途径激活。前者在乳腺癌的发生发展中起着至关重要的作用[51,52]。长链非编码RNA能与标准途径中MYC和β-catenin等关键分子相互作用,从而激活Wnt信号通路。有研究表明,长链非编码RNA CCAT2是一种定位于8q24的长链非编码RNA,在乳腺癌组织和乳腺癌细胞系中均显著上调,CCAT2通过上调Wnt信号的主要下游效应器β-catenin促进乳腺癌的生长增殖[53]。此外,长链非编码RNA CRNDE乳腺癌中通过竞争抑制miR-136激活Wnt/β-catenin信号,从而促进肿瘤细胞增殖[54]。
  3.1.4 MYC信号通路  原癌基因MYC能激活参与细胞周期、细胞生长和血管生成的各种下游基因[55]。Wang Z[56]等观察到长链非编码RNA EPIC1通过与MYC相互作用,并增强其与几个靶基因的结合促进细胞周期进程和增殖。长链非编码RNA SNHG12在三阴性乳腺癌中高表达,且与肿瘤大小和淋巴结转移显著相关。此外,SNHG12是MYC的直接靶基因,沉默SNHG12表达可抑制乳腺癌细胞的增殖[57]。   3.1.5其他信号通路  Li J[58]等发现沉默长链非编码RNA ASAH2B-2可以抑制mTOR信号通路,从而抑制乳腺癌细胞生长。同时,研究表明bcl-2家族成员bcl-w可以促进肿瘤细胞增殖、迁移和侵袭,位于HOX基因位点的长链非编码RNA HOTAIR,通过调节miR-206介导的bcl-w信号通路,促进乳腺癌以及其他癌症细胞的增殖[59]。
  3.2长链非编码RNA参与乳腺癌细胞的侵袭  转移癌症的侵袭转移是指原发肿瘤细胞通过血液或淋巴细胞的途径扩散到远处的次生器官然后再增殖的多步骤过程,其导致了超过90%的癌症死亡[60]。以下列出了长链非编码RNA参与乳腺癌侵袭转移的几条通路。
  3.2.1 STAT3信号通路  STAT3的激活在多种癌症转移中起着重要作用[61]。长链非编码RNA HOTAIR在多种肿瘤中均上调,尤其是在乳腺癌中[62]。miR-7是STAT3以及乳腺癌侵袭转移的负向调节因子,研究表明,HOTAIR通过间接抑制miR-7的表达激活STAT3信号通路,从而促进促进乳腺癌的侵袭转移[63]。此外,在乳腺癌细胞中,lnc-BM通过促进ICAM1和CCL2的STAT3依赖性表达,促进乳腺癌细胞的脑转移[64]。
  3.2.2 NF-κB信号通路  NF-κB是在肿瘤微环境下,炎症与肿瘤之间的重要联系分子[65]。Liu B[66]等研究表明,长链非编码RNA NKILA做为一种肿瘤抑制因子,通过结合NF-κB并抑制NF-κB信号通路,调节乳腺癌细胞的侵袭转移。另一研究表明,在乳腺癌中,长链非编码RNA NKILA通过阻断NF-κB信号通路,抑制上皮间质化, 从而抑制乳腺癌细胞的侵袭转移[67]。
  3.2.3 TGF-β信号通路  转化生长因子-β(TGF-β)是一种多功能细胞因子。TGF-β信号通路有助于调节细胞增殖分化、细胞凋亡、侵袭、细胞外基质生产、血管生成和免疫反应等细胞活动[68]。在乳腺癌中,TGF-β信号通路具有两面性,在乳腺癌早期,它能抑制上皮细胞周期进程并促进细胞凋亡;然而,在晚期它作为一种致癌基因,促进肿瘤的进展和转移[69]。长链非编码RNA ANCR通过调节TGF-β信号通路,抑制乳腺癌细胞上皮间质化的进程和侵袭转移[70]。此外,研究表明,长链非编码RNA HIT,是一种新的乳腺癌相关的长链非编码RNA,其对TGF-β介导的乳腺癌细胞的侵袭转移具有显著的促进作用[71]。
  3.3长链非编码RNA参与乳腺癌细胞的凋亡  细胞凋亡是正常组织发育所必须的程序性细胞死亡,细胞凋亡的失调促使肿瘤的发生。研究表明,许多长链非编码RNA与乳腺癌细胞凋亡相关[72]。
  3.3.1 p53信号通路  p53是一种肿瘤抑制蛋白,调节多种参与细胞凋亡、生长停滞和抑制细胞周期进展和分化的基因的表达[73]。而有研究表明,长链非编码RNA是参与p53信号通路的关键成分[74]。p53介导的长链非编码RNA GUARDIN能维持乳腺癌生长,并抑制乳腺癌细胞的凋亡[75]。此外,位于染色体11q13.1的长链非编码RNA MALAT1,通过与SIRT1和DBC1竞争p53结合,调控p53的乙酰化,从而减少乳腺癌细胞的凋亡[76]。
  3.3.2 Caspase信号通路  半胱氨酸天冬氨酸特异性蛋白酶(caspases)是一类由于细胞凋亡而协同作用的半胱氨酸蛋白酶[77]。Chen DQ[78]等发现,长链非编码RNA LINC00628在乳腺癌中显著下调,LINC00628过表达导致细胞周期G0/G1期阻滞,并通过调控caspase-3、Bax、Bcl-2的表達促进细胞凋亡。TUG1是一种参与多种癌症进展的长链非编码RNA。Li T[79]等研究发现TUG1的下调可增加caspase-3和caspase-9的活性,进而促进乳腺癌细胞的凋亡。
  4前景和挑战
  长链非编码RNA从最初被认为是转录噪音,到现在人们普遍认为其在基因表达和肿瘤发生发展中起着重要的调节作用,经历了很长一段时间。长链非编码RNA是人类癌症诊断,治疗和预后的潜在靶点。长链非编码RNA的异常表达与乳腺癌有关。与能编码蛋白质的信使RNA和人们所熟识的微小RNA不同,人们对长链非编码RNA的认识还处于初级阶段,对长链非编码RNA的认识还有许多空白。首先,只有小部分的长链非编码RNA得到了研究。对于长链非编码RNA的异常表达到底是肿瘤发生的原因还是结果,目前尚不明确;其次,随着检测到的长链非编码RNA的数量增加,其在癌症中的生物学功能和作用机制有待进一步挖掘;最后,尽管多项研究表明循环长链非编码RNA是多种类型肿瘤的潜在生物标志物,但是关于循环长链非编码RNA在肿瘤中的研究才刚起步。要将循环长链非编码RNA作为肿瘤诊断,预后和治疗的生物标志物,仍需要进行进一步的广泛研究。
  总之,长链非编码RNA的发现为癌症的研究打开了新世界的大门,长链非编码RNA可在癌症的诊断,治疗和预后方面发挥重要作用,使肿瘤患者受益。
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  收稿日期:2019-3-12;修回日期:2019-3-21
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