Recent Advances of Relationship Between miRNA-related SNPs and Lung Cancer Susceptibility
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摘要:
肺癌是世界最常见的癌症，已成为癌症死亡的主要原因。microRNAs（miRNAs）是一类高度保守、内源性非蛋白编码、长度约21~24核苷酸的小分子单链RNA，在基因调控中扮演着重要的角色。miRNA相关单核苷酸多态性（miRNA-related single nucleotide polymorphisms或miR-SNPs）主要包括miRNA基因SNPs、生物合成通路相关基因SNPs和miRNA靶基因中的SNPs，可通过影响miRNA的成熟过程、表达水平及与靶mRNA的识别结合等，使miRNA调控网络发生异常，从而参与肿瘤的发生发展。本文对miRNA相关SNPs与肺癌遗传易感性关系的研究进展进行综述，旨在为肺癌等恶性肿瘤的预防和控制提供参考。
Abstract:Lung cancer is the most common cancer and the leading cause of cancer death worldwide. microRNAs (miRNAs) are a wide class of highly conservative, endogenous, non-coding, short (21-24 nt) and single-stranded RNA molecules, which play an important role in gene regulation. miRNA-related single nucleotide polymorphisms mainly include SNPs in miRNA genes, SNPs in miRNA biogenesis genes and SNPs in miRNA-binding sites. miR-SNPs can make the miRNA regulation network abnormal and have been implicated in cancer development, by influencing the mature process and expression level of miRNAs, and the identification with miRNA target sites. This review focus on the recent advances of relationship between miRNA-related SNPs and lung cancer susceptibility, thus to provide references for further researches, prevention and control of cancers, especially for lung cancer.
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Key words:
- Lung neoplasms /
- microRNAs /
- Single nucleotide polymorphism(SNP) /
- Genetic susceptibility
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0 引言
肺癌是世界最常见的癌症，国际癌症研究中心（IARC）发布的全球肿瘤流行病统计数据（GLOBOCAN 2012）显示，在全球范围新确诊的癌症病例中，肺癌所占比例最大（13.0%），且在恶性肿瘤死因顺位中居首位（19.4%）[1]。在我国，肺癌发病和死亡呈逐年上升趋势[2-3]，已成为威胁居民健康的重大公共卫生问题之一，探索有效的易感生物标志，筛选具有遗传易感性的高危人群，寻求有效的一级预防措施尤为重要。
肺癌的发生发展是基因与环境共同作用的复杂过程。单核苷酸多态性（single nucleotide polymorphism, SNP）是指个体间基因组DNA序列同一位置的人群频率大于1%的单个核苷酸变异。大量的研究表明SNPs与多种疾病（包括恶性肿瘤）密切相关。关于SNPs与肿瘤关联的研究，目前大多数仍注重于蛋白编码基因[4]。随着以miRNAs为代表的一大类非编码RNA的发现及miRNAs与肿瘤关系研究的增多，miRNA相关SNPs与肺癌的关联研究为肺癌发病机制的探索及肺癌防治策略的完善提供了一条崭新的路径。
1 miRNA的生成及作用机制
microRNAs（miRNAs）是一类高度保守的、内源性的、长度约21~24核苷酸（nucleotide, nt）的小分子单链非编码RNA（ncRNA），在进化上呈现高度保守性，能通过与靶mRNAs 3’非翻译区（3’UTR）的靶序列完全或部分互补结合，在转录后水平引起靶mRNAs的降解或翻译抑制，负调控基因表达，在基因调控中扮演重要的角色[5]。
目前，miRNA的生物合成过程已基本确定。首先在细胞核内，编码miRNA的基因序列被转录为长的初级miRNA（pri-miRNA），pri-miRNA被剪切为约60~70个核苷酸长度，具有茎环结构的miRNA前体（pre-miRNA）[6-8]。随后，pre-miRNA在转运蛋白Exportin5等作用下，从细胞核内运输到细胞质，被剪切成21~24个核苷酸长度的类似siRNA的不完全配对双链RNA[9-11]。最后在RNA解旋酶作用下生成miRNA*和成熟miRNA，成熟miRNA结合到RNA诱导的基因沉默复合物（RNA-induced silencing complex，RISC）中发挥作用，miRNA*则被降解。miRNAs主要通过两方面机制介导转录后基因调控：靶mRNAs的降解和翻译抑制。
基因表达调控紊乱是细胞癌变的重要机制之一。近年来许多研究发现，人类编码蛋白基因的30%受miRNAs调节，每一个miRNA对应成百上千的目的基因，而每个目的基因可能受到许多miRNAs的调控[12]，可见miRNA在基因表达调控中具有重要作用。已有研究表明，miRNAs与肿瘤发生、发展及预后相关[13-14]。miRNA既可以在肿瘤中表达上调，起到癌基因的作用，也可以在肿瘤中表达下调，起到抑癌基因的作用[15]。
2 miRNA相关单核苷酸多态性
miRNA相关单核苷酸多态性（miRNA-related single nucleotide polymorphisms或miR-SNPs）是可以导致miRNA基因调控功能紊乱或缺失的一类功能型SNPs的总称[16]，与包括肿瘤在内的许多复杂疾病存在关联[17]，miRNA相关SNPs与肿瘤的关联研究已逐渐成为新的研究热点。miRNA相关SNPs（miR-SNPs）主要包括miRNA基因SNPs（包括pri-miRNA、pre-miRNA、成熟miRNA的SNPs）、生物合成通路相关基因SNPs（生物合成中的各种酶，如DROSHA酶等）和miRNA靶基因中的SNPs[15]。miR-SNPs可通过影响miRNA的成熟过程、表达水平及与靶mRNA的识别结合等，使miRNA调控网络发生异常，从而参与肿瘤的发生发展。
2.1 miRNA基因上的miR-SNP影响miRNA的合成
与普通基因类似，miRNA基因的转录同样受启动子的调节[18]，miRNA基因上的miR-SNP与一般基因上的SNP作用机制相似，编码区和调控区的SNP均可对miRNA的转录造成影响，影响miRNA的合成。
2.2 miRNA生物合成通路相关基因上的miR-SNP影响miRNA的合成
miRNA生物合成通路相关基因上的miR-SNP会导致参与miRNA转录、剪切、加工、转运过程的相关酶类、蛋白的质或量发生改变，从而影响pri-miRNA、pre-miRNA的生成或转运，最终影响正常成熟miRNA的形成，导致原有miRNA调控系统发生紊乱而产生疾病。
2.3 miRNA靶基因上的miR-SNP影响miRNA与靶mRNA的结合
miRNA与靶mRNA结合导致其降解或翻译抑制的能力绝大部分取决于miRNA 5'端第2~8个碱基所谓“种子序列”的结合自由能[19]。miRNA靶基因上的miR-SNP可能导致自由能的显著改变或功能构象的消失，影响miRNA与靶序列的结合而丧失其原有的调控功能，减弱相应miRNA对靶基因的翻译抑制效应，增强靶基因表达。此外，miRNA靶基因上的miR-SNP也可能形成新的miRNA结合位点，抑制靶基因的表达，从而导致疾病的发生。靶基因调控元件上的miR-SNP也可阻碍miRNA与靶mRNA的结合[20]。
3 miRNA相关单核苷酸多态性与肺癌遗传易感性
近年来，miRNA在肺癌发生发展中的作用逐渐受到关注，miRNA相关SNPs与肺癌的关联也成为新的研究热点。miRNA相关SNPs可以导致miRNA基因调控功能紊乱或缺失，使miRNA调控网络发生异常，参与肺癌的发生发展。
3.1 miRNA基因上的miR-SNP与肺癌
miRNA基因上的miR-SNP可以影响miRNA的合成，使miRNA基因调控功能紊乱，与肿瘤遗传易感性相关。Tian等[21]开展病例对照研究对4种pre-miRNAs上的SNPs与肺癌易感性的关联进行了探讨，发现miR-196a2中的SNP rs11614913和肺癌易感性相关，基因型CC相对于TT和CT肺癌发病风险高出25%，OR及其95%CI: 1.25（1.01~1.54）。Meta分析[22]也表明miR-196a2 SNP rs11614913的等位基因C可增加亚洲人群的肺癌发病风险，（C vs. T: OR=1.12, 95%CI: 1.03~1.22, P=0.008；CC vs. TT:OR=1.26, 95%CI: 1.07~1.49, P=0.007），其他几个Meta分析[23-27]也证明了此结果。
Jeon等[28]在韩国人群中发现pre-miR-146a SNP rs2910164的CG+GG基因型（相对于CC基因型）可降低肺癌发病风险，调整OR值为0.80（95%CI: 0.66~0.96）；进一步按吸烟程度分层（分为非吸烟者、轻度和重度吸烟者），发现rs2910164 C＞G（CG+GG vs. CC）与肺癌的关联仅出现在非吸烟者中，调整OR值为0.66（95%CI: 0.45~0.96）。Meta分析[25]也表明在东亚人群中，miR-146a基因rs2910164与肺癌的易感性相关，G vs. C: OR=0.92, 95%CI: 0.85~0.99；CG+GG vs. CC: OR=0.86, 95%CI: 0.76~0.99。在中国人群中，也有研究表明[29]miR-146a rs2910164与非小细胞肺癌发病风险相关，相比于对照组，非小细胞肺癌患者中CC基因型和C等位基因的频率分布更大（P=0.03）。但也有Meta分析结果[27]表明并未发现miR-146a rs2910164与肺癌易感性的关联。
作为目前研究最广泛的miRNA家族，let-7在肺癌的发生发展中发挥重要作用。有研究发现[30]let-7家族启动子区域的SNP rs10877887与肺腺癌的易感性相关，相对于TT基因型，携带CT+CC基因型的中国人群患肺腺癌的风险增大（OR=2.03, 95%CI: 1.02~4.05），进一步分层分析发现，该关联强度在60岁以上的女性中更大（CT+CC vs. TT: OR=6.86, 95%CI: 1.43~33.01, P=0.012）。
3.2 miRNA生物合成通路相关基因上的miR-SNP与肺癌
miRNA生物合成通路相关基因上的miR-SNP可通过改变miRNA的表达水平影响肿瘤的发生发展。Kim等[31]进行了两阶段的研究，探索miRNA生物合成通路相关基因上的miR-SNP与肺癌的发病风险，该课题组首先在100例肺癌患者和100例健康对照组中，对来自miRNA生物合成通路的11个相关基因（DROSHA、DGCR8、RAN、XPO5、DICER、AGO1、AGO2、HIWI、GEMIN3、GEMIN4和TRBP）的24个SNPs进行了基因分型，筛选出AGO1 rs636832 A>G SNP位点。进一步在552对病例和对照中进行分析，结果发现：与AA基因型相比，至少携带1个rs636832 G等位基因的个体患肺癌的风险降低（调整OR值为0.67, 95%CI: 0.53~0.84），且AGO1 rs636832 A＞G与肺癌发病风险呈负相关（Ptrend<0.001），该结果在两阶段的研究中一致。
3.3 miRNA靶基因上的miR-SNP与肺癌
3.3.1 形成新的miRNA结合位点抑制靶基因表达
miRNA靶基因中的miR-SNP可通过加强或减弱miRNA与靶mRNA的结合参与肿瘤的发生发展[32]。某些miRNA靶基因中的miR-SNP可能形成新的miRNA结合位点，抑制靶基因表达。作为肿瘤干细胞的重要表面抗原，CD133分子的表达与肺癌发生有关，Cheng等[33]对位于CD133基因上的13个多态性位点与肺癌的关联进行了较大样本的病例对照研究，结果发现位于CD133基因3'UTR上的SNP rs2240688 A>C与肺癌的关联最为密切，携带CA+CC基因型个体的肺癌发病风险降低（OR=0.80, 95%CI: 0.72~0.90），功能性试验表明rs2240688 A-C的颠换形成了新的hsa-miR-135a/b结合位点，从而减弱了CD133的基因表达。
同样，有研究发现[34]位于MDM4基因3'UTR上的SNP rs4245739 A＞C形成了新的miR-191-5p或miR-887-3p结合位点，从而减少了致癌基因MDM4的表达，携带rs4245739 AC+CC基因型的中国人群个体（与携带AA基因型相比）小细胞肺癌的发病风险降低，该结果在两个地区的病例对照研究中一致，OR值及95%CI分别为0.53（0.32~0.89）和0.47（0.26~0.88），且rs4245739与吸烟存在相乘交互作用。
NBS1基因的编码蛋白参与DNA双链断裂修复，Yang等[35]发现NBS1基因3'UTR上的SNP rs2735383 G>C产生新的结合位点，通过miRNA-629与NBS1基因的结合以减弱NBS1基因表达，进而增加肺癌的发病风险。相对于GG+GC基因型，携带CC基因型的个体患肺癌的风险增加，OR=1.40（95%CI: 1.18~1.66）。
3.3.2 减弱对靶基因的翻译抑制增强靶基因表达
Xiong等[36]进行病例对照研究（包括666例小细胞肺癌和758例对照），探索位于MYCL1基因3’UTR上的2个SNPs（rs3134615、rs2291854）与小细胞肺癌的遗传易感性，结果发现携带rs3134615 T等位基因可增加小细胞肺癌的发病风险，与GG基因型相比，携带GT+TT基因型患小细胞肺癌的调整OR值及95%CI为2.08（1.39~3.21），可能的机制是rs3134615 G>T的颠换阻碍了hsa-miR-1827与MYCL1致癌基因的结合，从而增加了小细胞肺癌的发病风险。Zu等[37]发现位于BIRC5基因3’UTR上的SNP rs2239680 T>C可通过减弱miR-335与BIRC5基因的结合，使致癌基因BIRC5表达升高，从而增加肺癌发病风险，与TT基因型相比，携带CT或CC基因型的个体肺癌发病风险升高，OR值及95%CI分别为1.50（1.20~1.89）和2.29（1.64~3.18）。
Yang等[38]发现，在中国人群中，位于SET8基因3’UTR miR-502结合位点上的SNP rs16917496 C>T与非小细胞肺癌的遗传易感性相关，相对于SET8 CC基因型，携带SET8 TT基因型的个体非小细胞肺癌的发病风险增高，OR值及95%CI为2.17（1.05~4.52），SET8基因可能是一个重要的致癌因子，且SET8基因与TP53密码子72的多态性有潜在的基因-基因相乘交互作用。
Ryan等[39]对欧洲和日本两个不同的人群进行研究，均发现CXCR2基因3'UTR的SNP rs1126579 C>T可降低肺癌的发病风险，欧洲：ORTT vs. CC=0.56（0.37~0.88），日本：ORTT vs. CC =0.62（0.38~1.00），进一步功能研究发现SNP rs1126579 C>T阻碍了miR-516a-3p与CXCR2基因的结合，导致CXCR2基因表达升高，增加了MAPK信号转导，rs1126579-T等位基因对肺癌具有保护作用。Zhang等[40]发现REV3L基因3’UTR上的SNP rs465646 T>C与肺癌易感性相关，与TT基因型相比，携带TC/CC基因型的个体肺癌发病风险降低，OR=0.69（P<0.05），SNP rs465646 T-C的转换阻碍了miR-25/32与REV3L抑癌基因的结合，进而使该抑癌基因表达增高，可能是其机制所在。
4 总结与展望
miRNA相关SNPs在各环节影响miRNA的合成及与靶序列的识别结合，使miRNA调控网络发生异常，从而参与肺癌的发生发展。关于miR-SNP与肺癌遗传易感性的研究，目前大多集中在miRNA靶基因3’UTR的SNP上，miRNA生物合成通路相关基因上的miR-SNP与肺癌易感性的关联研究尚少，miRNA基因上的miR-SNP与肺癌易感性的关联研究也局限在少数几个SNP位点上。目前多数研究只探索了单个miR-SNP与肺癌易感性的关联，所得到的大多属于单个微效易感性生物标志，结论尚不够全面。随着相关研究的进一步开展，更多关于miR-SNP的肺癌易感性生物标志将会被发现，基因-基因、基因-环境交互作用的研究将为肺癌的防治提供更为重要的科学依据。
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