H19基因在肿瘤研究领域的研究进展

王晓东(综述) 王晓娟 赵鹏飞 陈文捷 吴慧哲 魏敏杰△(审校)

(1中国医科大学药药学院理学教研室 沈阳 110122; 2甘肃省卫生学校2012级护理双证书29班 兰州 730000)

H19基因在肿瘤研究领域的研究进展

王晓东(综述) 王晓娟2赵鹏飞1陈文捷1吴慧哲1魏敏杰1△(审校)

(1中国医科大学药药学院理学教研室 沈阳 110122;2甘肃省卫生学校2012级护理双证书29班 兰州 730000)

自人的印迹基因群11P15.5被发现以来,已被证明其与人体各种生理异常密切相关。而作为最早被鉴定的印记基因之一的非编码RNA分子H19 (lncRNA H19),不仅由于其与Beckwith-Wiedemann综合征(BWS)、罗素因综合征(SRS)相关,而且H19能够派生miRNA675的印记基因,与多种肿瘤相关,可产生反义编码的lncRNA 91H (功能尚不清楚)而引起学者关注。本文将首次从H19基因的印记属性、SNP变异、lncRNA属性及其可能的作用机制信号轴等方面就H19基因在肿瘤发生进程中的研究现状作一综述。

基因印记; 肿瘤; lncRNAH19; miR675

H19印迹基因位于人染色体11P15.5及鼠的7号染色体上,属于单拷贝基因,母系等位基因表达,父系印迹,受位于H19基因上游4 kb处的差异甲基化区域(differentially methylated region,DMR)调控[1],基因印迹的分子基础可能是DNA在胚胎发育的早期阶段的甲基化[2]和染色质结构的变化。在某些病理条件下,基因印迹异常会导致一系列病理生理学改变[3],Uribe-Lewis[4]等于2011发现其甚至会导致肿瘤的发生。哺乳动物一个等位基因突变(遗传或表观遗传)会导致一个或多个基因产物的缺乏,从而导致更多的印记紊乱[5],在肿瘤相关研究方面,印迹丢失已被广泛关注,其中H19/IGF2为最重要的研究内容之一[6]。长链非编码RNA(long non-coding RNA,lncRNA)是指长度超过200个核苷酸的在众多功能上,如可变剪接,染色质重构以及RNA代谢等[7]方面具有相关性的RNA,H19基因产物加工后生成的成熟H19全长为2.3 kb,是目前发现的唯一可以编码产生lncRNA的印迹基因,在mRNA水平发挥作用。本文从H19基因的各层属性出发总结H19基因在肿瘤研究领域的研究现状。

H19基因的印记基因属性与肿瘤的关系H19印迹基因簇的各个基因可作为原癌基因或者抑癌基因[2]发挥作用,H19基因的印迹异常参与了许多遗传病及肿瘤的发生。H19的印记基因属性在肿瘤研究中主要有以下模式:一是长期研究表明[8],IGF2/H19差异甲基化区域在肿瘤发展过程中具有促进作用,在横纹肌肉瘤细胞中,IGF2/H19基因上游(5’UTR区)的差异甲基化区域通过DNA高甲基化造成印迹丢失,从而增加促进其扩散的IGF2表达,降低miR675表达,导致miR675的靶基因IGF1R,INSR等表达增加而使横纹肌肉瘤细胞增殖;Gao等[9]发现肾上腺皮质恶性肿瘤组织CIMP[10](CpG island methylator phenotype)现象,据恶性肿瘤组织甲基化程度的不同,分为CIMP-high和CIMP-low,CIMP致使包括H19基因(此文认为H19基因是抑癌基因)在内的多种肿瘤抑制基因低表达,IGF2基因高表达[9],促进肾上腺皮质腺瘤的发生,且高甲基化与不良预后相关,其原因可能是高甲基化使一些肿瘤抑制基因沉默[10]而促进了肿瘤的发生。也有学者认为IGF2和H19基因的交互印迹导致甲基化状态差异,提出IGF2与H19基因共同竞争H19下游增强子的增强子学说[11],即在父源染色体上,H19启动子发生甲基化,致使IGF2的启动子被H19下游的增强子激活,IGF2得以表达;在母源染色体上,H19启动子未甲基化,则H19下游的增强子激活H19启动子,H19得以表达。以上研究偏向于认为,H19基因上游的甲基化差异导致H19低表达,影响某些肿瘤的发展进程。二是有学者对H19上游2 kb差异甲基化区域(DMR)的研究表明,区域的印记特性(甲基化状态)可以决定其是否与CTCF结合,通过这种结合可以调控下游基因是否表达而发挥作用[12-13]。三是Adriaenssens等[14]对乳腺癌和正常组织进行分析比较,观察H19基因的表达水平,发现乳腺癌组织中其检测阳性率远远高于正常乳腺组织,而在表达上调的乳腺癌组织中基质细胞占绝大多数。有研究[15]发现,雌激素在乳腺癌发展中起着至关重要的作用,lncRNAH19可诱导雌激素的产生,Berteaux等[16]进一步发现,乳腺癌组织中H19过表达并促进乳腺癌细胞由G1期向S期转变,H19作为活跃的参与者促进细胞增殖,增加肿瘤细胞的侵袭性,提示H19在乳腺癌细胞中促进致瘤。因此lncRNA H19在一些肿瘤如肾上腺皮质肿瘤中表达减少,却在另一些肿瘤(如乳腺癌)中表达增加,我们认为H19基因上游甲基化区的基因印记和在某些肿瘤环境下印记丢失与某些特定肿瘤的发展进程相关。

H19基因SNP位点变异与肿瘤的关系

H19基因上游甲基化区的SNP位点变异与肿瘤的关系 许多相关研究表明,H19基因有很高的缺失率和突变率[17],目前H19基因5’UTR区的SNP位点变异的研究目前主要集中在rs2107425、rs10732516、rs2251375、rs2071094等位点。rs2107425位点与肿瘤关系的研究主要集中在胰腺癌、乳腺癌、膀胱癌、卵巢癌等肿瘤,与乳腺癌相关研究的代表的观点主要有:O′Brien等[18]在白人和非洲美国人中发现rs2107425与乳腺癌(白人)发病风险呈负相关;而Odefrey[19]、Butt等[20]学者认为rs2107425位点变异与乳腺癌风险正相关;Riaz等[21]全基因组关联研究荷兰乳腺癌患者发现纯合性rs2107425(AA)与乳腺癌的不良预后显著相关;同时Barnholtz-Sloan等[22]亦发现rs2107425与非洲裔美国年轻妇女的乳腺癌积极相关联,而在白人女性中却呈负相关;Bhatti等[23]通过全基因组关联研究发现对于rs2107425位点而言,基因分型相关的乳腺癌风险随辐射剂量变化显著(P=0.001),以上研究提示rs2107425位点变异与乳腺癌发病风险相关。此外,Couch等[24]运用全基因组关联研究(GWAS)发现患者吸烟时rs2107425与胰腺癌发病风险显著相关;Song[25]、Quaye等[26]等亦发现rs2107425位点变异与卵巢癌发病风险相关;Verhaegh等[27]研究发现rs2107425CT基因型与膀胱癌风险的降低相关,由此认为H19基因的rs2107425位点基因型与胰腺癌、乳腺癌、膀胱癌、卵巢癌等肿瘤的发病风险密切相关。

rs10732516位点的相关研究主要集中在基因印记[28-29]以及新生儿的相关研究中,St-Pierre等[30]研究发现基因型为rs10732516(CC/CT)或者rs2107425(AA/AG)的母亲较基因型为rs10732516(TT)与rs2107425(GG)的母亲分娩的婴儿体重更重;而Coolen等[31]发现位于H19基因的印记调控区CTCF结合位点上的rs10732516[A]多态性与母系H19等位基因特定CpG位点上增强的超甲基化程度相关。rs2251375[32]、rs2071094[33]两位点的研究目前主要集中在新生儿有关研究中,在肿瘤研究领域鲜见这些位点的研究报道。

总结以上研究,我们发现H19基因上游甲基化区SNP变异与多种类型肿瘤的发生发展相关联,目前并没有H19基因上游甲基化与该区域SNP变异关系研究报道,也没有二者与肿瘤进展关系的研究报道。研究[14]发现IGF2等激素可以刺激相关细胞H19的转录,而某些激素则抑制这种效应,H19基因的表达可由化学致癌物,视黄酸、类固醇和肽激素,生长因子如肝细胞生长因子,组织修复因子,细胞因子和低氧压力[34]等多种因素诱导,此外,大量实验已经确定了各种转录因子E2F[16],HIF-1α[35],Slug[36],p53[37]和c-myc[38],可以调节H19表达。更有学者[39]发现H19基因上游导致H19过表达的序列,并将此序列与DTA(白喉毒素)构成DTA-H19质粒,Amit等[40]进一步采用H19和IGF2-P4双调控序列构建DTA质粒,克服了该质粒必须依赖H19高表达才能发挥作用的局限,使这一方法成功运用于卵巢癌、胰腺癌等多种肿瘤并进入临床试验[41-42]。综合Medrzycki等[43]的研究我们猜测,H19基因上游印记状态、某些状态下的印记丢失和SNP变异影响不同类型肿瘤中转录因子或其他生物大分子在该区域的结合,导致H19基因的表达能力有差异,影响特定肿瘤发生进程。

H19基因编码区SNP位点变异与肿瘤的关系

基因的SNP不仅存在于基因的非编码区,也存在于基因的编码序列中,lncRNA H19在RNA水平参与细胞以及肿瘤细胞的生长过程中,其rs217727、rs2067051与rs2839698位点研究较多。在非肿瘤领域,Tragante[44],Gao[45]等研究发现H19基因rs217727与血压及冠状动脉疾病(CAD)风险的增加相关,具体机制尚待研究;Hewage等[46]研究发现母亲H19基因rs217727TT基因型与新生儿更重的体重相关;rs2067051的研究主要集中在冠状动脉疾病(CAD)[45]和新生儿体重[32]方面。在肿瘤研究领域,Yang等[47]研究发现rs217727T和rs2839698T等位基因表现出增加胃癌(GC)风险的特性;Verhaegh等[27]2008年发现rs2839698TC基因型与膀胱癌降低相关,同时发现rs217727TT基因型或携带T基因型携带者与这种降低无关,且采用生物信息学预测发现lncRNA H19的rs217727位点在TT与CC基因型下折叠结构存在差异,rs2839698位点TT与CC基因型时亦是;Li等[48]2016年发现rs2839698A基因型与大肠癌发病风险升高相关,并发现rs2839698位点有可能影响lncRNA H19的折叠而改变lncRNA H19的靶标microRNAs,从而影响肿瘤的发生发展;Xia等[49]的研究显示rs217727CT+TT基因型与怀孕2次以上的女性患乳腺癌的发病风险降低相关。以上研究结果启示,H19基因编码区的SNP变异可能影响lncRNA H19的二级结构,进而影响lncRNA H19的生物学功能、影响肿瘤的发生发展。因此,不仅应研究lncRNA H19作为RNA生物大分子在肿瘤发展中的功能,而且要研究其SNP变异的不同基因型,为肿瘤的个体化诊断和施治奠定理论和实践基础。

lncRNA H19与肿瘤的关系 lncRNAH19基因全长2.5 kb,共含有5个外显子(第一个外显子派生出miR675)和4个内含子,位于近端粒区域,与肿瘤发生有密切相关性。到目前为止,越来越多的lncRNA被证明与肿瘤的发生及转移有关[50];研究显示,H19作为lncRNA能使许多与肿瘤细胞的侵袭、迁移及血管形成密切相关的基因表达上调[51],在一些癌症如乳腺癌、膀胱癌和胃癌中上调并扮演重要角色[52],并且H19的表达情况与术后早期复发现象有明显的关系,可作为判断术后早期复发的检测指标。lncRNAH19在多种恶性肿瘤印迹丢失而过度表达,因此有必要从H19的lncRNA属性去探讨H19与肿瘤发生发展的关系。

lncRNA H19可通过多种机制影响肿瘤的进程。Tran等[53]指出H19在乳腺癌中反义RNA过度表达促进父源的IGF2过表达,lncRNA水平在膀胱癌组织中也显著升高,上调的H19通过抑制E-钙黏蛋白(E-cadherin)的表达促进膀胱癌细胞在体内外的恶变[54],更有学者发现胃癌组织表达更多的lncRNA H19,促进了胃癌细胞的扩散、恶变、侵袭和转移[55]。lncRNA H19作为RNA分子,在肿瘤中主要通过以下几条途径发挥作用:一是通过lncRNA H19/miR-675信号轴影响肿瘤发展,二是lncRNA H19发挥lncRNA的“miRNA sponge”作用影响肿瘤发展,三是由于发挥具有lncRNA的普遍生物学特性而影响肿瘤的发展。

LncRNA H19/miR-675信号轴与肿瘤的关系

H19基因通过miR-675发挥作用[2],且H19/miR-675信号轴在肿瘤发生过程中具有重要作用[56],Cai[57]和Wang[52]等学者更是认为lncRNA H19以miR-675的pri-miRNA发挥促肿瘤生长的功能。近期研究[36]发现lncRNA H19可以在体外促进肺癌细胞恶变,其作用原理是通过上调Slug的表达从而抑制E-cad的表达、促进上皮间质转化过程,miR-675参与该过程;也有人[55]推断H19在胃癌中的作用可能通过上调ISM1以及通过miR-675间接地下调CALN1的表达从而影响肿瘤的进程;同时Tsang等[56]发现在大肠癌中H19派生miR-675,miR-675对其下游靶基因RB蛋白质产生靶向抑制促进大肠癌的发展;Zhuang等[58]研究发现H19基因通过miR-675调控抑癌基因RUNX1来影响胃癌的发生发展,即通过“lncRNA H19派生miR-675,miR-675靶向抑制其下游靶基因”的“lncRNA H19/miR-675信号轴”促进肿瘤的发生和发展,这个结论在Liu等[59]的研究中亦得到确证。此外在神经胶质瘤中,高级神经胶质瘤组织比低级神经胶质瘤组织表达更高的lncRNAH19,H19通过派生miR-675及抑制性的CDH13[60],调节神经胶质瘤细胞的侵袭。以上研究结果说明生物大分子lncRNA H19通过“lncRNA H19/miR-675信号轴”影响肿瘤发生发展的机制得到了广泛的认可,通过“lncRNA H19/miR-675信号轴”解释肿瘤发展日趋成熟,并可能成为新的肿瘤治疗靶点。

LncRNA H19与肿瘤的关系机制的其他解释

癌细胞内H19作用机制还存在其他相关假说。研究发现H19通过抑制E-钙黏蛋白表达,也可抑制miR-630表达而使EZH2表达量上升,促进鼻咽癌的侵袭[61]。Wu等[62]亦通过研究发现H19基因的上调可以抑制miR-148a-3p的表达导致miR-148a-3p下游靶基因的DNMT1表达上调,促进喉鳞状细胞癌的进展,说明H19发挥miRNA海绵(miRNA sponge)作用促进肿瘤发展。此外,Han等[63]也通过研究发现lncRNA H19可通过招募eIF4A3促进结直肠癌细胞的增殖,因此lncRNA H19同样具有作为新的结直肠癌和其他肿瘤治疗靶标的潜在可能。H19作为lncRNA,可以通过发挥lncRNA普遍具有的生物学功能而促进肿瘤的发生发展,H19作为lncRNA促肿瘤的更多作用机制有待深入研究。

结语H19基因在正常组织鲜有表达而在异常组织(比如肿瘤组织)表达,且是目前发现的唯一属于lncRNA的印记基因,H19基因作为肿瘤生物标记分子和治疗靶点已经成为事实[64]。本文首次从H19基因的印记属性、SNP变异、lncRNA属性及其可能的作用机制信号轴等方面就H19基因在肿瘤发生进程中的研究现状作了全面综述,以全面探讨H19与肿瘤的关系。我们总结认为H19基因的作用模式可以分为lncRNA H19表达前和表达后两个时段,一是lncRNA H19表达前,H19作为印记基因,很多因素影响其表达,比如H19基因上游甲基化区的印记状态、特定环境下的印记丢失、SNP变异、生物大分子等都会影响H19基因编码,造成lncRNA H19的生成量差异,影响肿瘤发生发展,这方面的研究将有助于肿瘤治疗的个体化和精准化;二是lncRNAH19表达后,由于H19基因编码区SNP变异导致lncRNA H19折叠结构的改变,可能导致产生不同的生物学效应,更重要的是lncRNA H19不仅具有普通lncRNA的一切生物学功能,而且可以派生miR-675、产生反义的91H,导致lncRNA H19在肿瘤发展过程中的机制复杂多样,这方面的研究将有助于肿瘤的个体化施治和一批新肿瘤治疗靶标的产生。因此,我们认为对H19基因的研究不能局限于某一个层面,而应该依据H19的各层特性交叉全面研究,全面认知H19参与肿瘤发生、发展过程中可能的调控功能和调控机制,将十分有助于未来将H19运用于肿瘤临床诊治各个环节。

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Research progress ofH19 gene in the field of tumor research

WANG Xiao-dong1, WANG Xiao-juan2, ZHAO Peng-fei1, CHEN Wen-jie1, WU Hui-zhe1, WEI Min-jie1△

(1DepartmentofPharmacology,SchoolofPharmacy,ChinaMedicalUniversity,Shenyang110122,LiaoningProvince,China;2NursingDouble-CertificateClass29,Grade2012,GansuProvinceHealthSchool,Lanzhou730000,GansuProvince,China)

Since human imprinted genes in 11P15.5 was found,it had been proved that various human physiological abnormality associated with it.As one of the first identified imprinted non-coding RNA genes,more attention is paid to lncRNA H19 by many scholars not only because it’s linked with Beckwith-Wiedemann syndrome (BWS) and Russell syndrome (SRS),but alsoH19 gene is the only imprinted gene belonging to long non-coding RNA related with a variety of tumors which can also produce microRNA675 and lncRNA 91H coming fromH19 gene antisense-coding.This paper will review possible mechanisms ofH19 gene in tumorigenesis process and its research status in Cancer therapy from four aspects:imprinting feature,single nucleotide polymorphisms,lncRNA character and its possible action signal axis in cancer.

gene imprinting; tumor; lncRNAH19; miR675

国家自然科学基金(81572898,81402948)

R730

B

10.3969/j.issn.1672-8467.2017.02.017

2016-04-14;编辑:张秀峰)

△Corresponding author E-mail:mjwei@hotmail.com

*This work was supported by the National Natural Science Foundation of China (81572898,81402948).