microRNA相关单核苷酸多态性与肿瘤的关系

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梁璆荔, 李姝锦, 倪培华. microRNA相关单核苷酸多态性与肿瘤的关系. 检验医学,2014, 29(5): 435-440
LIANG Qiuli, LI Shujin, NI Peihua. Relationship between microRNA-related single nucleotide polymorphism and tumors.Labratory Medicine, 2014, 29(5): 435-440 复制到剪切板

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microRNA相关单核苷酸多态性与肿瘤的关系

梁璆荔¹, 李姝锦², 倪培华¹

1.上海交通大学医学院附属瑞金医院检验系,上海 200025

2.上海交通大学医学院附属瑞金医院医学检验2009级,上海 200025

作者简介：梁趚荔,女,1989年出生,学士,技师,主要从事检验医学教学工作。

通讯作者：倪培华,联系电话：021-64370045-610509。

摘要

微小RNA(miRNA)是一类高度保守的非编码小RNA,可作用于转录及转录后调控基因的表达。miRNA参与许多生物途径,可发挥癌基因或抑癌基因的作用。miRNA相关的单核苷酸多态性(SNP)对于肿瘤的发生、发展有一定影响,并与肿瘤的早期诊断、预后和治疗相关。本文综述了近年来发现的miRNA相关SNP与肿瘤关系的研究,并从miRNA基因自身多态性和miRNA靶基因的SNP两方面论述其对不同肿瘤的影响和作用。

关键词: 微小RNA; 单核苷酸多态性; 肿瘤

中图分类号:Q74 文献标志码:A 文章编号:1673-8640(2014)05-0435-06

Relationship between microRNA-related single nucleotide polymorphism and tumors

LIANG Qiuli¹, LI Shujin², NI Peihua¹

1. Faculty of Medical Laboratory Science, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China

2. Grade 2009, Department of Clinical Laboratory, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China

Abstract

MicroRNAs (miRNAs) are well-conserved small non-coding RNAs, which play roles in transcriptional and post-transcriptional regulation of gene expression. MiRNAs participate in diverse biological pathways and may act as oncogenes or tumor suppressors. Single nucleotide polymorphism(SNP) in miRNAs might promote carcinogenesis and tumor development, which may also affect early diagnosis, prognosis and treatment. Here, we highlight the association between miRNA-related SNP and tumors and describe the miRNA polymorphisms and SNP in miRNA target gene.

Keyword: MicroRNA; Single nucleotide polymorphism; Tumor

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微小RNA(microRNA,miRNA)是一类在不同物种间高度保守的小RNA分子(约19~22个核苷酸),能在多种组织中表达。miRNA的表达具有组织特异性和时序性,在调节生长发育、增殖、分化、细胞凋亡、应激反应等重要过程中发挥了关键作用。越来越多的研究证明,miRNAs可能具有癌基因或抑癌基因的功能,且miRNA相关的单核苷酸多态性(single-nucleotide polymorphism,SNP)与肿瘤易感性、发病年龄、肿瘤分期、药物反应性以及预后均存在一定关联。我们综述了近年来一些miRNAs相关的SNP,包括miRNAs基因和miRNAs靶基因的SNP与肿瘤的关系。

一、miRNA及其功能特性

miRNA是一类平均长度为22个核苷酸的小分子非编码RNA,最初由Lee等^{[ 1]}在秀丽隐杆线虫中发现。很多miRNA在基因组上聚集排列形成基因簇。在RNA聚合酶Ⅱ的参与下,miRNA编码基因在细胞核中转录生成较长的初级转录产物pri-miRNAs,接着pri-miRNAs与核糖核酸酶Ⅲ(ribonucleaseⅢ,RNaseⅢ)家族中的2种酶(Drosha和Dicer)结合,Drosha酶在核内将pri-miRNAs剪切成长度约为70个核苷酸的发夹状miRNA前体(pre-miRNA)^{[ 2]}。miRNA前体在Exportin-5的作用下被转运至细胞质,由Dicer酶将其进一步加工为长约20 bp的成熟miRNA/miRNA双链结构。成熟的单链miRNA包含在我们所知的miRNA核糖核蛋白复合体(micorRNA ribonucleoprotein complex,miRNP)、miRgonaute或miRNA诱导的沉默复合体(microRNA induced silencing complex,miRISC)中,而另一条链可能会被降解。这类复合体以mRNAs为目标靶分子,通过与mRNAs的3'非转录区(3'untranslated region,3'UTR)完全或不完全序列特异性互补,致使mRNA降解或翻译抑制,从而在转录后水平调控基因的表达^{[ 3]}。研究表明,人类基因组中约30%的基因受至少一个miRNA的调控^{[ 4]}。目前已发现1 600种Homo sapiens miRNA(hsa-miRNA)前体,2 042种成熟hsa-miRNA(miRBase,http://www.mirbase.org),其中许多编码miRNA的基因位于肿瘤相关的基因组区域或脆性位点,并且位于缺失区域的miRNAs在肿瘤样本中呈现低表达量^{[ 5]}。多数miRNA的高度保守性和组织特异性以及上述研究均提示miRNA可能在不同肿瘤中起不同的作用。

二、miRNA相关的SNP

SNP是指在基因组水平上由单个核苷酸变异引起的DNA序列多态性,是人类可遗传变异中最常见的一种。大量的单个核苷酸变异已被列入研究范围,且为阐明人类肿瘤发病机制、临床特点和疗效差异提供了新的研究方向和研究依据。SNPs可以直接或间接影响miRNA。pri-miRNA、pre-miRNA或成熟miRNA中的SNPs可影响miRNA的加工或其功能;miRNA基因启动子的SNPs能阻止转录因子与之结合,抑制pri-microRNA转录;miRNA中的SNPs能产生新的结合位点或破坏原本的结合位点,间接对miRNA产生影响^{[ 6]}。发生在成熟miRNA中的SNPs(特别是发生在种子区域的SNPs)可能影响基因沉默的特异性^{[ 7]},而发生在miRNA靶基因3'UTR的SNP可能更具靶位和通路特异性^{[ 8]}。Duan等^{[ 9]}发现,227个人类miRNA基因中存在323个SNP,其中有12个位于miRNA前体,1个位于成熟miRNA-125a的第8个核苷酸位点。而根据最新的数据显示,202个pre-miRNA中存在283个SNP。在已知的120 000个发生在3'UTRs的SNPs中,约17%的SNP破坏了推定的保守或非保守miRNA结合位点^{[ 10]}。通过对Patrocles数据库进行分析,发现有8.6%的SNP能产生预期的靶位点^{[ 10, 11]}。

三、miRNA相关的SNP与肿瘤的关系

近来研究发现,miRNA相关的SNP与不同类型的肿瘤有关,并且在多肿瘤中发现了miRNA的异常表达。Yu等^{[ 12]}在表达序列标签(expressed sequence tag,EST)数据库和SNP数据库中对肿瘤和正常组织中miRNAs靶基因的SNPs进行分析,发现在肿瘤组织中有12个miRNAs靶基因的SNPs出现了显著的异常等位基因。研究证实,不论是存在于miRNA基因的SNPs还是位于miRNA靶基因的SNPs,都能直接或间接影响miRNA,从而影响miRNA靶基因的表达和功能,因此可能与肿瘤密切相关。在已知的人类1 048个pre-miRNA中,共存在30 442 771个SNP,其中有178个SNP位于149个miRNA的成熟序列上,50个SNP位于41个miRNA的种子序列上,而种子序列上的SNP更有可能产生新的结合位点或破坏原有结合位点。如miRNA-499种子序列上的SNP(rs3746444 A>G)可导致miRNA-499与其靶基因 BCL2的结合位点丧失^{[ 13]}。肿瘤的发生是一个多因素参与的复杂的过程,miRNA的SNP可能会对肿瘤发生相关的mRNA的调节作用产生影响,并且很多miRNA的基因位于肿瘤相关的基因组区域或脆性位点。因此,研究miRNA的SNP与肿瘤发生的相关性有助于阐明一些肿瘤的发生机制。

(一)miRNA基因的SNPs与肿瘤的关系

1.miRNA-146a miRNA-146a的编码基因位于5号染色体长臂3区4带(5q34),SNP rs2910164(G/C)处于pre-miRNA-146a的茎环结构。研究发现,miRNA-146a具有潜在调节肿瘤坏死因子受体相关因子6和白细胞介素-1受体相关的激酶1基因的作用^{[ 14]}。这2种物质都是在细胞增殖和免疫识别中起重要作用的信号转导途径中Toll样受体和细胞因子受体重要的适配分子下游^{[ 14]}。Xu等^{[ 15]}发现, pre-miRNA-146a的rs2910164(G>C)与中国广州地区汉族男性对肝细胞癌的易感性密切相关(GG基因型男性个体的易感性超出CC基因型达2倍之多),同时G等位基因的pre-miRNA-146a能增加成熟miRNA-146a的量。Jazdzewski等^{[ 16]}对美国、芬兰、波兰的部分甲状腺乳头状癌(PTC)患者的rs2910164位点进行分析后发现,C等位基因的pre-miRNA-146a可减少成熟miRNA-146a的量,减弱对靶基因(其中一个靶基因为 PTC1,也称作CCDC6或H4,在PTC中常与 RET原癌基因一起基因重组)的抑制作用;杂合子GC基因型携带者有较高的PTC患病风险,并且这一多态性位点能通过体细胞突变在肿瘤发生中发挥重要作用。有研究指出,携带上述SNP的GG和GC型的年龄≤58岁、不吸烟的中国男性有较高的胃癌患病风险^{[ 17]},CC型rs2910164可显著提高日本人罹患胃癌的风险^{[ 18]}。而与上述研究结果不同的是,Shen等^{[ 19]}发现上述SNP的C等位基因的成熟miRNA-146a的表达水平显著高于G等位基因,且C等位基因数量的增加与美国人乳腺癌/卵巢癌确诊年龄的提前显著相关。Lian等^{[ 20]}对近年来miRNA-146a的研究成果进行Meta分析后发现,上述SNP的CC基因型可增加欧洲人乳腺癌的易感性。Zhou等^{[ 21]}发现,我国人群中携带至少一个G等位基因的原发性肝癌患者有更年轻的发病年龄,并有相对较好的肝脏功能。

2.miRNA-196a2 Pre-miRNA-196a2的SNP rs11614913(C/T)位于12号染色体(12q13.13),据推测,该miRNA能调节同源框基因家族(Homebox genes)的 Hox基因,这个基因能调控胚胎的细胞发育和分化方向^{[ 22]}。Hu等^{[ 23]}发现,hsa-miRNA-196a2的rs11614913(C>T)SNP与中国非小细胞肺癌患者的生存率相关,CC基因型携带患者的生存人数明显降低,且CC基因型可显著增加成熟has-miRNA-196a2的表达,并影响成熟has-miRNA-196a2-3p与靶mRNA的结合。在对日本人胃癌的研究中发现,上述SNP与胃炎的组织学严重性有关,且TT基因型是高度的单核细胞浸润的独立因素^{[ 18]}。Peng等^{[ 24]}发现,在中国汉族人群中,携带上述SNP CC基因型的个体有较高的胃癌风险,并且这个SNP位点能增加93%的非贲门胃癌患病风险,同时指出CC基因型纯合子与胃癌的淋巴结转移密切相关。最近一项研究指出,携带有miRNA-196a2的变异等位基因的沙特阿拉伯女性有更高的乳腺癌患病风险^{[ 25]}。

3.miRNA-27a miRNA-27a的编码基因位于19号染色体短臂1区3带1亚带3次亚带(19p13.13),SNP位点 rs895819 (A/G)位于miRNA-27a前体(pre-miRNA-27a)的茎环结构。研究发现,miRNA-27a的靶基因包括白细胞介素-6受体的一个前身链、Toll样受体8前体、白细胞介素-12受体β-1前身链、核因子κB激酶ε亚族的抑制因子、干扰素调节因子,这些都是与炎症反应和免疫应答相关的分子。另外, RET原癌基因前体、多种细胞凋亡相关分子(Fas 细胞凋亡抑制分子1、FAS相关死亡功能域、caspase-8前体、肿瘤坏死因子受体相关因子1、CASP8、FADD样细胞凋亡调节因子前体)、MAP激酶活性蛋白激酶3和维甲酸α受体也都是miRNA-27a的靶基因。Arisawa 等^{[ 26]}发现日本男性中miRNA-27a的SNP与胃黏膜萎缩有关,GG基因型的萎缩和化生评分显著高于其他基因型。Sun等^{[ 27]}首次发现has-miRNA-27a的rs895819通过调节miRNA-27a和其靶基因ZBTB10的表达来影响中国人的胃癌易感性。他们在中国汉族年龄>58岁的男性老年胃癌患者中观察到上述SNP的AG+GG基因型携带者的胃癌风险显著高于AA型携带者,此患病风险在不吸烟的患者病历中更为明显,与胃癌的淋巴结转移显著相关。Shi等^{[ 28]}指出,中国人群中rs895819的AG基因型杂合子能显著降低肾细胞癌的患病风险,AG和GG基因型有较低的肾细胞癌易感性。研究发现,miRNA-27a可作为原癌基因在肿瘤发生中发挥作用,SNP rs895819-G等位基因可一定程度地抑制miRNA-27a的成熟过程,从而减低某些癌症如乳腺癌的发病风险,并且研究人员推测,miRNA-27a可能参与雌激素依赖的调节通路,因此SNP rs895819的作用可能具有性别特异性^{[ 29]}。

4.miRNA-499 编码miRNA-499的基因位于20号染色体(20q11.22),SNP rs3746444(C/T)位于pre-miRNA-499的种子序列中。Liu等^{[ 30]}发现miRNA-499 SNP(rs3746444)的AG和GG基因型与减低白种人头颈部鳞状细胞癌风险有关。Hu等^{[ 31]}发现血清中的miRNA-499水平能作为非小细胞肺癌的预后因素。 Liu等^{[ 32]}发现在我国结直肠癌病例中,miRNA-499-5p能通过调节靶基因FOXO4和PDCD4进而促进体外癌细胞迁移和浸润,并促进体内肝和肺部转移。也有研究称,携带miRNA-499的CT基因型的沙特阿拉伯绝经后女性相对于CC和TT基因型有更高的乳腺癌患病风险^{[ 25]}。

5.其他 Huang等^{[ 33]}发现成熟miRNA-608的SNP(rs4919510:C>G)与我国汉族女性乳腺罹患癌风险有关,携带有变异等位基因(CG/GG)以剂量效应的方式使女性有更高的HER2阳性乳腺癌患病风险。Mu等^{[ 34]}发现,位于pre-miRNA-30c 的SNP(rs928508:A/G)通过调整成熟miRNA-30c的表达来影响我国人群罹患胃癌的风险,其中AA型携带者有更高的胃癌风险。Smith等^{[ 35]}研究发现CC型pre-miRNA-423(rs6505162:A>C)能减低澳大利亚女性乳腺癌患病风险。

(二)miRNA靶基因的SNPs与肿瘤的关系

miRNA靶基因SNP的能在一定程度上影响miRNA与mRNA的结合,从而通过调节miRNA-mRNA之间的相互作用对许多肿瘤的发生、发展产生影响。

在消化系统肿瘤中,Ma等^{[ 36]}发现DICER 3'UTR的rs1057035(C/T)可影响miRNA与DICER的结合,与我国人群罹患口腔癌的风险相关。RAS相关蛋白( RAP1 A)基因的3'UTR内存在miRNA-196a的结合位点,而该3'UTR的SNP(rs6573:A>C)可提高 RAP1 A基因的组成型表达。在对我国汉族的部分样本进行分析后发现, RAP1 A基因的高表达可见于食管鳞状细胞癌(ESCC)的大多数组织,并且与 RAP1 A的基因型以及淋巴结转移有关^{[ 37]}。MTMR3是miRNA-181a的结合位点,位于MTMR3的SNP(rs12537)被证实与我国南方地区汉族人胃癌患病风险以及预后有关,携带T等位基因的上述位点使得miRNA-181a的抑制作用增强,并且CT和TT型的rs12537有更高的胃癌罹患风险^{[ 38]}。Ryan等^{[ 39]}对结直肠癌患者进行研究后发现,GG基因型的has-miRNA-608的 (rs4919510:C/G)能显著增加白种人患者的死亡风险,而降低非裔美国患者的死亡风险。LCS6是KRAS 3'UTR中let-7的完全结合位点。最近研究发现 KRAS-LCS6中存在一个SNP,携带该SNP G等位基因的荷兰早期结直肠癌患者有较好的预后, KRAS-LCS6基因型有可能成为判定预后及选择治疗方案的指标^{[ 40]}。Naccarati等^{[ 41]}对捷克1 098例结肠直肠癌患者和1 469例健康人进行研究后发现,核苷酸切除修复(nucleotide excision repair, NER)基因3'UTR的miRNA结合位点的SNP与结直肠癌患病风险有关,并且与肿瘤位置密切相关。组蛋白甲基转移酶SET8的3'UTR是miRNA-502的结合位点。Guo等^{[ 42]}发现,位于该3'UTR的SNP(rs16917496)与我国肝细胞癌患者的生存期有关,携带SET8 CC基因型的患者有更长的术后生存期,低表达的SET8与更长的生存期有关。推测此现象可能与3'UTR的SNP所致的miRNA-502与其靶基因的结合亲和力改变有关。miRNA-106b-25在 MCM7的13内含子内成簇排列,可能在免疫应答和肿瘤发生中发挥部分作用。研究发现 MCM7的启动子区域存在一个SNP(rs999885)。在我国持续感染HBV的人群中,rs999885 AG基因型和GG基因型携带者的正常肝脏组织中miRNA-106b-25的表达量显著高于AA基因型携带者,并可能增加肝细胞癌的患病风险^{[ 43]}。

在头颈部癌中,Ma等^{[ 44]}发现,位于 DICER 3'UTR的SNP(rs1057035)可通过has-miRNA-574-3p抑制miRNAs与 DICER mRNA的结合,从而影响中国人群口腔癌的发病风险。有研究称 SMC1 B是miRNA靶基因。Zhang等^{[ 45]}发现位于 SMC1 B的SNP(rs3747238)与头颈癌的复发有关,与野生型相比,该SNP的变异型携带患者头颈癌的复发风险增加。

在泌尿生殖系统的肿瘤中,研究发现位于 HOXB5 3'UTR的一个SNP 能影响miRNA-7与 HOXB5的结合活性和SNP相关mRNA的稳定性,从而调控 HOXB5的表达,并有望成为膀胱癌的预后指标^{[ 46]}。 BMPR1B的3'UTR是miRNA-125b的靶结合位点之一。位于该3'UTR的SNP(rs1434536)会影响miRNA-125b与 BMPR1B mRNA的结合,并对我国局部地区的汉族人群的前列腺癌易感性产生影响^{[ 47]}。而Wang等^{[ 48]}发现,SET8 CC基因型能减低中国女性卵巢上皮癌的患病风险。Liang等^{[ 49]}推测 PDGFC是miRNA-425的潜在靶基因,而位于 PDGFC的SNP(rs1425486:G/A)能影响miRNA-425对该基因表达的抑制作用,并且对卵巢癌的生存期和治疗反应产生影响。Wynendaele等^{[ 50]}在德国卵巢癌患者样本中发现 MDM4 3'UTR的一个SNP(rs4245739)可产生新的miRNA-191结合位点,miRNA-191只与携带 MDM4-C等位基因的3'UTR结合,致使 MDM4-C的表达下调,因而延缓卵巢癌的进展、减少肿瘤相关的死亡并提高患者对化疗的敏感性。而上述过程在一定程度上独立于p53抑癌途径。

四、总结与展望

miRNA已成为近年来分子生物科学领域的研究热点。miRNA基因的SNP能影响miRNA的生成,而位于靶mRNA 3'UTR的SNP能通过产生新结合位点或破坏原有的结合位点来影响与miRNA的结合,从而影响miRNA的生物调节作用。经过大量的研究,人们发现miRNA在肿瘤发生、分期、预后等方面均发挥一定的作用。但由于miRNA对mRNA的调节作用不具有特异性,因此相同的miRNA可能在不同组织中起到截然不同的调节作用,甚至在不同人种病例中发挥不同的作用,如减低或增加癌症风险。目前的研究都只能证实miRNA的SNP与部分研究人群的肿瘤发生、分期或预后相关,并且只有少数miRNA能作为一个明确的检测指标,同时这些指标在不同人种中的使用会受到限制。肿瘤发生、分期、预后都是多因素参与的过程。虽然有大量miRNA和其靶mRNA的SNP被陆续发现,但SNP很难作为独立因素对上述过程产生影响。所以,需要开展大规模的涉及多人种的研究来证实miRNA相关的SNP与肿瘤的关系。未来则有可能将miRNA相关的SNP列入肿瘤检测指标,并实现个体化的靶向治疗。

(收稿日期:2013-09-12)

(本文编辑:龚晓霖)

The authors have declared that no competing interests exist.

参考文献

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1993

31.957

0.0

. 1993, 75(5):null-null

The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14

... 一、miRNA及其功能特性miRNA是一类平均长度为22个核苷酸的小分子非编码RNA,最初由Lee等^[1]在秀丽隐杆线虫中发现 ...

2003

38.597

0.0

. 2003, 425(6956):415-419

The nuclear RNase III Drosha initiates microRNA processing

Nature is the international weekly journal of science: a magazine style journal that publishes full-length research papers in all disciplines of science, as well as News and Views, reviews, news, features, commentaries, web focuses and more, covering all branches of science and how science impacts upon all aspects of society and life.

... )家族中的2种酶(Drosha和Dicer)结合,Drosha酶在核内将pri-miRNAs剪切成长度约为70个核苷酸的发夹状miRNA前体(pre-miRNA)^[2] ...

2009

18.038

0.0

... 这类复合体以mRNAs为目标靶分子,通过与mRNAs的3'非转录区(3'untranslated region,3'UTR)完全或不完全序列特异性互补,致使mRNA降解或翻译抑制,从而在转录后水平调控基因的表达^[3] ...

2004

31.957

0.0

. 2004, 116(2):null-null

MicroRNAs: genomics,biogenesis,mechanism,and function

... 研究表明,人类基因组中约30%的基因受至少一个miRNA的调控^[4] ...

2004

9.737

0.0

PNAS. 2004, 101(9):2999-3004

Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers

George Adrian Calin* , †, Cinzia Sevignani* , †, Calin Dan Dumitru*, Terry Hyslop‡, Evan Noch*, Sai Yendamuri*, Masayoshi Shimizu*, Sashi Rattan*, Florencia Bullrich*, Massimo Negrini* , §,and Carlo M. Croce* , ¶

Departments of *Microbiology and Immunology and ‡Medicine, Division of Clinical Pharmacology, Biostatistics Section, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia,PA 19107; and §Dipartimento di Medicina Sperimentale e Diagnostica e Centro Interdipartimentale per la Ricerca sul Cancro, Università diFerrara, Ferrara 44100, Italy

A large number of tiny noncoding RNAs have been cloned and named microRNAs (miRs). Recently, we have reported that miR-15a and miR-16a, located at 13q14, are frequently deleted and/or down-regulated in patients with B cell chronic lymphocytic leukemia, a disordercharacterized by increased survival. To further investigate the possible involvement of miRs in human cancers on a genome-widebasis, we have mapped 186 miRs and compared their location to the location of previous reported nonrandom genetic alterations.Here, we show that miR genes are frequently located at fragile sites, as well as in minimal regions of loss of heterozygosity,minimal regions of amplification (minimal amplicons), or common breakpoint regions. Overall, 98 of 186 (52.5%) of miR genesare in cancer-associated genomic regions or in fragile sites. Moreover, by Northern blotting, we have shown that several miRslocated in deleted regions have low levels of expression in cancer samples. These data provide a catalog of miR genes thatmay have roles in cancer and argue that the full complement of miRs in a genome may be extensively involved in cancers.

... org),其中许多编码miRNA的基因位于肿瘤相关的基因组区域或脆性位点,并且位于缺失区域的miRNAs在肿瘤样本中呈现低表达量^[5] ...

2013

7.793

0.0

. 2013, 137(1):null-null

SNPing cancer in the bud: microRNA and microRNA-target site polymorphisms as diagnostic and prognostic biomarkers in cancer

... miRNA中的SNPs能产生新的结合位点或破坏原本的结合位点,间接对miRNA产生影响^[6] ...

2009

4.841

0.0

... 发生在成熟miRNA中的SNPs(特别是发生在种子区域的SNPs)可能影响基因沉默的特异性^[7],而发生在miRNA靶基因3'UTR的SNP可能更具靶位和通路特异性^[8] ...

2009

3.857

0.0

... 发生在成熟miRNA中的SNPs(特别是发生在种子区域的SNPs)可能影响基因沉默的特异性^[7],而发生在miRNA靶基因3'UTR的SNP可能更具靶位和通路特异性^[8] ...

2007

7.692

0.0

... Duan等^[9]发现,227个人类miRNA基因中存在323个SNP,其中有12个位于miRNA前体,1个位于成熟miRNA-125a的第8个核苷酸位点 ...

2010

35.0

0.0

. 2010, 10(6):389-402

Genetic variation in microRNA networks: the implications for cancer research

... 在已知的120 000个发生在3'UTRs的SNPs中,约17%的SNP破坏了推定的保守或非保守miRNA结合位点^[10] ...

... 6%的SNP能产生预期的靶位点^[10,11] ...

2006

0.856

0.0

... 6%的SNP能产生预期的靶位点^[10,11] ...

2007

8.278

0.0

... Yu等^[12]在表达序列标签(expressed sequence tag,EST)数据库和SNP数据库中对肿瘤和正常组织中miRNAs靶基因的SNPs进行分析,发现在肿瘤组织中有12个miRNAs靶基因的SNPs出现了显著的异常等位基因 ...

2012

5.213

0.0

. 2012, 33(1):254-263

Genome-wide identification of SNPs in microRNA genes and the SNP effects on microRNA target binding and biogenesis

Jing Gong 1,2 ,Yin Tong 1 ,Hong-Mei Zhang 1 ,Kai Wang 3 ,Tao Hu 1 ,Ge Shan 4 ,Jun Sun 2,* andAn-Yuan Guo 1,*

1Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Systems Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China 2Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 3Shanghai Bioladder Co., Ltd, Shanghai, China 4School of Life Science, University of Science and Technology of China, Hefei, China *Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

MicroRNAs (miRNAs) are studied as key regulators of gene expression involved in different diseases. Several single nucleotide polymorphisms (SNPs) in miRNA genes or target sites (miRNA-related SNPs) have been proved to be associated with human diseases by affecting the miRNA-mediated regulatory function. To systematically analyze miRNA-related SNPs and their effects, we performed a genome-wide scan for SNPs in human pre-miRNAs, miRNA flanking regions, target sites, and designed a pipeline to predict the effects of them on miRNA–target interaction. As a result, we identified 48 SNPs in human miRNA seed regions and thousands of SNPs in 3′ untranslated regions with the potential to either disturb or create miRNA–target interactions. Furthermore, we experimentally confirmed seven loss-of-function SNPs and one gain-of-function SNP by luciferase assay. This is the first case of experimental validation of an SNP in an miRNA creating a novel miRNA target binding. All useful data were complied into miRNASNP, a user-friendly free online database (http://www.bioguo.org/miRNASNP/). These data will be a useful resource for studying miRNA function, identifying disease-associated miRNAs, and further personalized medicine. Hum Mutat 33:254–263, 2012. © 2011 Wiley Periodicals, Inc.

... 如miRNA-499种子序列上的SNP(rs3746444 A>G)可导致miRNA-499与其靶基因BCL2的结合位点丧失^[13] ...

2006

9.737

0.0

PNAS. 2006, 103(33):12481-12486

NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses

Konstantin D. Taganov*, Mark P. Boldin*, Kuang-Jung Chang,and David Baltimore ‡

Division of Biology, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125

Activation of mammalian innate and acquired immune responses must be tightly regulated by elaborate mechanisms to controltheir onset and termination. MicroRNAs have been implicated as negative regulators controlling diverse biological processesat the level of posttranscriptional repression. Expression profiling of 200 microRNAs in human monocytes revealed that severalof them (miR-146a/b, miR-132, and miR-155) are endotoxin-responsive genes. Analysis of miR-146a and miR-146b gene expressionunveiled a pattern of induction in response to a variety of microbial components and proinflammatory cytokines. By means ofpromoter analysis, miR-146a was found to be a NF-κB-dependent gene. Importantly, miR-146a/b were predicted to base-pair withsequences in the 3′ UTRs of the TNF receptor-associated factor 6 and IL-1 receptor-associated kinase 1 genes, and we foundthat these UTRs inhibit expression of a linked reporter gene. These genes encode two key adapter molecules downstream of Toll-likeand cytokine receptors. Thus, we propose a role for miR-146 in control of Toll-like receptor and cytokine signaling througha negative feedback regulation loop involving down-regulation of IL-1 receptor-associated kinase 1 and TNF receptor-associatedfactor 6 protein levels.

... 研究发现,miRNA-146a具有潜在调节肿瘤坏死因子受体相关因子6和白细胞介素-1受体相关的激酶1基因的作用^[14] ...

... 这2种物质都是在细胞增殖和免疫识别中起重要作用的信号转导途径中Toll样受体和细胞因子受体重要的适配分子下游^[14] ...

2008

5.635

0.0

... Xu等^[15]发现, pre-miRNA-146a的rs2910164(G>C)与中国广州地区汉族男性对肝细胞癌的易感性密切相关(GG基因型男性个体的易感性超出CC基因型达2倍之多),同时G等位基因的pre-miRNA-146a能增加成熟miRNA-146a的量 ...

2008

9.737

0.0

PNAS. 2008, 105(20):7269-7274

Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma

Krystian Jazdzewski*, Elizabeth L. Murray † , Kaarle Franssila ‡ , Barbara Jarzab § , Daniel R. Schoenberg † ,and Albert de la Chapelle* , ¶

*Human Cancer Genetics Program, Comprehensive Cancer Center, Ohio State University, 850 Biomedical Research Tower, 460 West12th Avenue, Columbus, OH 43210;†Department of Molecular and Cellular Biochemistry, Ohio State University, 366 Hamilton Hall, 1645 Neil Avenue, Columbus, OH43210;‡Department of Pathology, Helsinki University Central Hospital, FIN-00029, Helsinki, Finland; and§Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology,Wybrzeze Armii Krajowej 15, Gliwice 44-101, Poland

Although papillary thyroid carcinoma (PTC) displays strong heritability, no predisposing germ-line mutations have been found.We show that a common G/C polymorphism (rs2910164) within the pre-miR-146a sequence reduced the amount of pre- and maturemiR-146a from the C allele 1.9- and 1.8-fold, respectively, compared with the G allele. This is matched by a similar decreasein the amount of each pre-miR generated from the corresponding pri-miR-146a in an in vitro processing reaction. The C allele also interfered with the binding of a nuclear factor to pre-miR-146a. The reduction inmiR-146a led to less efficient inhibition of target genes involved in the Toll-like receptor and cytokine signaling pathway(TRAF6, IRAK1), and PTC1 (also known as CCDC6 or H4), a gene frequently rearranged with RET proto-oncogene in PTC. In an associationstudy of 608 PTC patients and 901 controls, we found marked differences in genotype distribution of rs2910164 (P = 0.000002), the GC heterozygous state being associated with an increased risk of acquiring PTC (odds ratio = 1.62, P = 0.000007), and both homozygous states protective with odds ratio = 0.42 for the CC genotype (P = 0.003) and odds ratio = 0.69 for the GG genotype (P = 0.0006). Moreover, 4.7% of tumors had undergone somatic mutations of the SNP sequence. Thus, our data suggest that a commonpolymorphism in pre-miR-146a affects the miR expression, contributes to the genetic predisposition to PTC, and plays a rolein the tumorigenesis through somatic mutation. Preliminary evidence suggests that these effects are mediated through targetgenes whose expression is affected by the SNP status.

... Jazdzewski等 ^[16]对美国、芬兰、波兰的部分甲状腺乳头状癌(PTC)患者的rs2910164位点进行分析后发现,C等位基因的pre-miRNA-146a可减少成熟miRNA-146a的量,减弱对靶基因(其中一个靶基因为PTC1,也称作CCDC6或H4,在PTC中常与RET原癌基因一起基因重组)的抑制作用 ...

2010

2.547

1.0341

... 58岁、不吸烟的中国男性有较高的胃癌患病风险^[17],CC型rs2910164可显著提高日本人罹患胃癌的风险^[18] ...

2010

3.511

0.0

. 2010, 15(6):524-531

Association Between Common Genetic Variants in Pre-microRNAs and Gastric Cancer Risk in Japanese Population

Masaaki Okubo 1 ,Tomomitsu Tahara 1 ,Tomoyuki Shibata 1 ,Hiromi Yamashita 1 ,Masakatsu Nakamura 1 ,Daisuke Yoshioka 1 ,Joh Yonemura 1 ,Takamitsu Ishizuka 1 ,Tomiyasu Arisawa 2 andIchiro Hirata 1

1 Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan 2 Department of Gastroenterology, Kanazawa Medical University, Ishikawa, Japan *Reprint requests to: Masaaki Okubo, Department of Gastroenterology, Fujita Health University School of Medicine, 1-98 Dengakugakubo Kutsukake-cho, Toyoake, Aichi 470-1192, Japan. E-mail: <a href="mailto:masa2050309@yahoo.co.jp" title="Link to email address" shape="rect">masa2050309@yahoo.co.jp</a>

Background: Common single-nucleotide polymorphisms (SNPs) in microRNAs (miRNA) have been shown to be associated with susceptibility to several human cancers. We evaluated the associations of three SNPs (rs11614913, rs2910164, and rs3746444) in pre-miRNAs (miR-196a2, miR-146a, and miR-499) with the risk of gastric cancer (GC) and peptic ulcer diseases, and with the severity of Helicobacter pylori-induced gastritis in Japanese population.

... 58岁、不吸烟的中国男性有较高的胃癌患病风险^[17],CC型rs2910164可显著提高日本人罹患胃癌的风险^[18] ...

... 在对日本人胃癌的研究中发现,上述SNP与胃炎的组织学严重性有关,且TT基因型是高度的单核细胞浸润的独立因素^[18] ...

2008

5.635

0.0

... 而与上述研究结果不同的是,Shen等^[19]发现上述SNP的C等位基因的成熟miRNA-146a的表达水平显著高于G等位基因,且C等位基因数量的增加与美国人乳腺癌/卵巢癌确诊年龄的提前显著相关 ...

2012

3.73

0.0

PLoS ONE. 2012, 7(2):e31615-null

Increased Risk of Breast Cancer Associated with CC Genotype of Has-miR-146a Rs2910164 Polymorphism in Europeans

Jingmin Zhang 3 ,Hai Lian 1 ,Lei Wang 2

1 Department of Pathology, The Eleventh Institute of Academy of Military Medical Sciences, Changchun, China 2 Electrical Diagnosis Division, Chaoyang District People's Hospital, Changchun, China 3 School of Pharmacy, Jilin University, Changchun, China

Background

Emerging evidence suggests that microRNAs play a critical role in the pathogenesis of breast cancer. Several molecular epidemiological studies were conducted in recent years to evaluate the association between has-miR-146a rs2910164 polymorphism and breast cancer risk in diverse populations. However, the results remain conflicting rather than conclusive.

Methodology/Principal findings

We performed a meta-analysis of 6 case-control studies that included 4238 breast-cancer cases and 4469 case-free controls. We assessed the strength of the association, using odds ratios (ORs) with 95% confidence intervals (CIs). Overall, this meta-analysis showed that the rs2910164 polymorphism was not associated with a significantly increased risk of breast cancer in all genetic models (for GC vs GG: OR = 1.00, 95% CI = 0.90−1.09, P_{heterpgeneity} = 0.364; for CC vs GG: OR = 1.16, 95% CI = 0.98−1.36, P_{heterpgeneity} = 0.757; for GC+CC vs GG: OR = 1.02, 95% CI = 0.93−1.12, P_{heterpgeneity} = 0.562; for CC vs GC+GG: OR = 1.10, 95% CI = 0.96−1.26, P_{heterpgeneity} = 0.441). However, in the stratified analysis by ethnicity, we found the rs2910164 polymorphism was associated with increased breast cancer risk among Europeans in homozygote comparison (CC vs. GG: OR = 1.29, 95%CI = 1.02−1.63, P_{heterpgeneity} = 0.950, P = 0.032) and recessive model (CC vs. GC+GG: OR = 1.31, 95%CI = 1.05−1.65, P_{heterpgeneity} = 0.839, P = 0.019). No publication bias was found in the present study.

Conclusions/Significance

This meta-analysis suggests, for the first time, that the CC homozygote of rs2910164 may contribute to breast cancer susceptibility in Europeans.

... Lian等^[20]对近年来miRNA-146a的研究成果进行Meta分析后发现,上述SNP的CC基因型可增加欧洲人乳腺癌的易感性 ...

2012

2.344

0.0

... Zhou等^[21]发现,我国人群中携带至少一个G等位基因的原发性肝癌患者有更年轻的发病年龄,并有相对较好的肝脏功能 ...

2012

2.536

0.0

... 13),据推测,该miRNA能调节同源框基因家族(Homebox genes)的Hox基因,这个基因能调控胚胎的细胞发育和分化方向^[22] ...

2008

12.812

0.0

... Hu等 ^[23]发现,hsa-miRNA-196a2的rs11614913(C>T)SNP与中国非小细胞肺癌患者的生存率相关,CC基因型携带患者的生存人数明显降低,且CC基因型可显著增加成熟has-miRNA-196a2的表达,并影响成熟has-miRNA-196a2-3p与靶mRNA的结合 ...

2010

2.26

0.0

. 2010, 55(8):2288-2293 DOI:10.1007/s10620-009-1007-x

Association of microRNA-196a-2 gene polymorphism with gastric cancer risk in a Chinese population

1.The Fourth Affiliated Hospital of Soochow University Department of Anesthesiology 214062 Wuxi People’s Republic of China 2.Shihezi University Intensive Care Unit of the First Affiliated Hospital of Medical College 832008 Shihezi People’s Republic of China 3.Affiliated Hospital of Nantong University Department of General Surgery 226001 Nantong People’s Republic of China

Background

It has been proposed that single nucleotide polymorphisms (SNPs) in microRNAs (miRNAs) could affect the expression of the miRNA and contribute to the susceptibility of human tumors. However, the role of genetic variant (T/C) in miR-196a-2 in gastric cancer susceptibility is still unknown.

... Peng等^[24]发现,在中国汉族人群中,携带上述SNP CC基因型的个体有较高的胃癌风险,并且这个SNP位点能增加93%的非贲门胃癌患病风险,同时指出CC基因型纯合子与胃癌的淋巴结转移密切相关 ...

2012

3.73

0.0

PLoS ONE. 2012, 7(2):e30049-null

Differential Expression Profile and Genetic Variants of MicroRNAs Sequences in Breast Cancer Patients

Tarique N. Hasan 1 ,Mohammed A. Alsaif 3 ,Amal A. Al-Hazzani 2 ,Naveed Ahmed Syed 1 ,Abdulaziz A. Alsaif 4 ,Ali A. Alshatwi 1 ,Gowhar Shafi 1

1 Molecular Cancer Biology Research Lab (MCBRL), Department of Food Sciences and Nutrition, College of Food and Agricultural Sciences, King Saud University, Riyadh, Saudi Arabia 2 Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia 3 College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia 4 College of Medicine, King Saud University, Riyadh, Saudi Arabia

The technology available for cancer diagnosis and prognosis is not yet satisfactory at the molecular level, and requires further improvements. Micro RNAs (miRNAs) have been recently reported as useful biomarkers in diseases including cancer. We performed a miRNA expression profiling study using peripheral blood from breast cancer patients to detect and identify characteristic patterns. A total of 100 breast cancer patients and 89 healthy patients were recruited for miRNA genotyping and expression profiling. We found that hs-miR-196a2 in premenopausal patients, and hs-miR-499, hs-miR-146a and hs-miR-196a2 in postmenopausal patients, may discriminate breast cancer patients from healthy individuals. In addition, we found a significant association between two microRNA polymorphisms (hs-miR-196a2 and hs-miR-499) and breast cancer risk. However, no significant association between the hs-miR-146a gene and breast cancer risk was found. In summary, the study demonstrates that peripheral blood miRNAs and their expression and genotypic profiles can be developed as biomarkers for early diagnosis and prognosis of breast cancer.

... 最近一项研究指出,携带有miRNA-196a2的变异等位基因的沙特阿拉伯女性有更高的乳腺癌患病风险^[25] ...

... 也有研究称,携带miRNA-499的CT基因型的沙特阿拉伯绝经后女性相对于CC和TT基因型有更高的乳腺癌患病风险^[25] ...

2007

2.26

0.0

. 2007, 52(7):1691-1697 DOI:10.1007/s10620-006-9648-5

A polymorphism of microRNA 27a genome region is associated with the development of gastric mucosal atrophy in Japanese male subjects

1.Fujita Health University, School of Medicine, 1-98, Dengakugakubo Department of Gastroenterology Kutsukake-cho Toyoake 470-1192 Japan

Noncoding microRNAs regulate the expression of various mRNAs. We attempted to clarify the relationship between miR-27a genome polymorphism and chronic gastritis. The study was performed in 179 patients with no evidence of gastric malignancy. The severity of histologic chronic gastritis was classified according to the updated Sydney system. The frequency of miR-27a G allele was 34.6%. Although the frequencies of miR-27a G allele were increased in subjects with peptic ulcer or severe mucosal atrophy, no significant differences were seen. The miR-27a polymorphism showed an interaction with gender in relation to gastric mucosal atrophy (P=.090). In only male subjects, the miR-27a polymorphism was associated with the gastric mucosal atrophy (P=.039) and both atrophy and metaplasia scores in G/G group were significantly higher than those in the other groups. The miR-27a genome region polymorphism may be an important definitive factor to develop the gastric mucosal atrophy in Japanese male subjects.

... Arisawa 等^[26]发现日本男性中miRNA-27a的SNP与胃黏膜萎缩有关,GG基因型的萎缩和化生评分显著高于其他基因型 ...

2010

3.479

0.0

. 2010, 101(10):2241-2247

Hsa-mir-27a genetic variant contributes to gastric cancer susceptibility through affecting miR-27a and target gene expression

Qingmin Sun 1,†,* ,Haijuan Gu 2,† ,Ying Zeng 3,† ,Yi Xia 3 ,You Wang 1 ,Yali Jing 4 ,Li Yang 5 andBin Wang 3,*

1 Department of Pharmacy, The Affiliated Wuxi Hospital for Maternal and Child Health Care of Nanjing Medical University, Wuxi, Jiangsu 2 Department of Pharmacy, Nantong Tumor Hospital, Nantong, Jiangsu Province 3 Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu Province 4 Department of Endocrinology, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu Province 5 Department of General Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China * To whom correspondence should be addressed. E-mail: <a href="mailto:binwang@njmu.edu.cn" title="Link to email address" shape="rect">binwang@njmu.edu.cn</a>; <a href="mailto:qingminsun@gmail.com" title="Link to email address" shape="rect">qingminsun@gmail.com</a>

Aberrant microRNA (miRNA) expression is presently proposed to correlate with various human cancers and common single-nucleotide polymorphisms (SNP) at miRNA genes can influence the maturation of miRNAs or miRNA-mediated transcriptional regulation. However, whether miRNAs SNP alter gastric cancer susceptibility is still unclear. Here we investigated the possible role of a common A/G polymorphism (rs895819) within hsa-mir-27a in the development or progression of gastric cancer, and assessed the effect of rs895819 on the expression of miR-27a and its target gene Zinc finger and BTB domain containing 10 (ZBTB10). In the present case-control study, we found that subjects with the variant genotypes (AG + GG) showed a significantly increased risk of gastric cancer relative to AA carriers (adjusted odds ratio = 1.48, 95% confidence interval 1.06–2.05; P = 0.019). The elevated risk was especially evident in older subjects (age >58 years), men, nonsmokers and rural subjects. A significant association of hsa-mir-27a variant genotypes with lymph node metastasis was also observed. Further functional analyses indicated that variant genotypes might be responsible for elevated miR-27a levels and reduced ZBTB10 mRNA. Moreover, an inverse correlation was found between ZBTB10 and miR-27a levels. In conclusion, we were the first to show that a common polymorphism (rs895819) in hsa-mir-27a, by modulating miR-27a and ZBTB10 levels, acted as an important factor of the gastric cancer susceptibility. (Cancer Sci 2010)

... Sun等^[27]首次发现has-miRNA-27a的rs895819通过调节miRNA-27a和其靶基因ZBTB10的表达来影响中国人的胃癌易感性 ...

2012

3.73

0.0

PLoS ONE. 2012, 7(10):e46566-null

A Genetic Variant in pre-miR-27a Is Associated with a Reduced Renal Cell Cancer Risk in a Chinese Population

Danni Shi 1,2,3 ,Qiang Lv 4 ,Changjun Yin 4 ,Chao Qin 4 ,Meilin Wang 2,3 ,Na Tong 3 ,Pu Li 4 ,Fu Yan 2 ,Zhengdong Zhang 1,2,3 ,Lan Ma 1,2 ,Dongyan Zhong 2,3 ,Haiyan Chu 1,2 ,Wei Wang 2

1 State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, China 2 Department of Molecular & Genetic Toxicology, the Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China 3 Department of Occupational Medicine and Environmental Health, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China 4 Department of Urology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China

Background

MicroRNAs (miRNAs) are a class of small non-coding RNAs to regulate cell differentiation, proliferation, development, and apoptosis. The single nucleotide polymorphism (SNP) rs895819 is located at the terminal loop of pre-miR-27a. Here, we aimed to investigate whether SNP rs895819 was associated with the development of renal cell cancer (RCC) in a Chinese population.

Methods

In this case-control study, we recruited 594 RCC patients and 600 cancer-free controls with frequency matched by age and sex. We genotyped this polymorphism using the TaqMan assay and assessed the effect of this polymorphism on RCC survival. Logistic regression model was used to assess the genetic effects on the development of RCC and interactions between rs895819 polymorphism and risk factors.

Results

Compared with AA homozygote, individuals carrying AG/GG genotypes had a statistically significant reduced susceptibility to RCC (adjusted OR = 0.71, 95% CI = 0.56–0.90). Furthermore, AG/GG genotypes were associated with reduced RCC susceptibility in localized clinical stage (adjusted OR = 0.71, 95% CI = 0.55–0.91), and similar effects were observed in well differentiated and poorly differentiated RCC (adjusted OR = 0.71, 95% CI = 0.55–0.93 for well differentiated, adjusted OR = 0.51, 95% CI = 0.28–0.93 for poorly differentiated). We also observed that rs895819 had multiplicative interactions with age and hypertension. However, the polymorphism did not influence the survival of RCC.

Conclusion

Our results suggest that the pre-miR-27a rs895819 polymorphism can predict RCC risk in a Chinese population. Larger population-based prospective studies should be used to validate our findings.

... Shi等^[28]指出,中国人群中rs895819的AG基因型杂合子能显著降低肾细胞癌的患病风险,AG和GG基因型有较低的肾细胞癌易感性 ...

2010

4.469

0.0

. 2010, 121(3):693-702 DOI:10.1007/s10549-009-0633-5

A genetic variant in the pre-miR-27a oncogene is associated with a reduced familial breast cancer risk

1.German Cancer Research Center (DKFZ) Helmholtz-University Group Molecular Epidemiology Im Neuenheimer Feld 581 69120 Heidelberg Germany 2.University of Heidelberg Division Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics 69120 Heidelberg Germany 3.German Cancer Research Center (DKFZ) Division of Molecular Genetic Epidemiology Im Neuenheimer Feld 580 69120 Heidelberg Germany 4.Karolinska Institute Department of Biosciences at Novum 14157 Huddinge Sweden 5.University of Heidelberg Institute of Human Genetics 69120 Heidelberg Germany 6.University of Heidelberg, Medical Faculty of Mannheim Institute of Transfusion Medicine and Immunology, Red Cross Blood Service of Baden-Württemberg-Hessen Mannheim Germany 7.Clinical Center University of Cologne Division of Molecular Gynaeco-Oncology, Department of Gynaecology and Obstetrics 50931 Cologne Germany 8.Klinikum rechts der Isar, Technical University of Munich Department of Gynaecology and Obstetrics 81675 Munich Germany 9.Humboldt University Institute of Human Genetics, Charité Augustenburger Platz 1 13353 Berlin Germany

MicroRNAs (miRNAs) regulate pathways involved in cell differentiation, proliferation, development, and apoptosis by degradation of target mRNAs and/or repression of their translation. Although the single nucleotide polymorphisms (SNPs) in miRNAs target sites have been studied, the effects of SNPs in miRNAs are largely unknown. In our study, we first systematically sequenced miRNA genes reported to be involved in breast cancer to identify/verify SNPs. We analyzed four SNPs, one located in the pre-miRNA and the other three located in miRNA flanking regions, for a putative association with breast cancer risk. The SNP rs895819, located in the terminal loop of pre-miRNA-27a, showed a protective effect. In a large familial breast cancer study cohort, the rare [G] allele of rs895819 was found to be less frequent in the cases than in the controls, indicating a reduced familial breast cancer risk ([G] vs. [A]: OR = 0.88, 95% CI 0.78–0.99, P = 0.0287). Furthermore, age stratification revealed that the protective effect was mainly observed in the age group < 50 years of age ([G] vs. [A]: OR = 0.83, 95% CI 0.70–0.98, P = 0.0314), whereas no significant effect was observed in the age group ≥ 50 years of age, indicating a possible hormone-related effect. It has been shown that artificial mutations in the terminal loop of miR-27a can block the maturation process of the miRNA. We hypothesize that the G-variant of rs895819 might impair the maturation of the oncogenic miR-27a and thus, is associated with familial breast cancer risk.

... 研究发现,miRNA-27a可作为原癌基因在肿瘤发生中发挥作用,SNP rs895819-G等位基因可一定程度地抑制miRNA-27a的成熟过程,从而减低某些癌症如乳腺癌的发病风险,并且研究人员推测,miRNA-27a可能参与雌激素依赖的调节通路,因此SNP rs895819的作用可能具有性别特异性^[29] ...

2010

5.201

0.0

. 2010, 116(20):4753-4760

Genetic variants in selected pre-microRNA genes and the risk of squamous cell carcinoma of the head and neck

Zhensheng Liu MD, PhD 1 ,Guojun Li MD, PhD 1,2 ,Sheng Wei MD, PhD 1 ,Jiangong Niu PhD 1 ,Adel. K. El-Naggar MD 3 ,Erich M. Sturgis MD, PhD 1,2 andQingyi Wei MD, PhD 1,4,†,*

1Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 2Department of Head and Neck Surgery, The University ofTexas M. D. Anderson Cancer Center, Houston, Texas 3Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 4Program in Human and Molecular Genetics, The University of Texas Graduate School of Biomedical Sciences, Houston, Texas *Department of Epidemiology, Unit 1365, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030

BACKGROUND:

Single nucleotide polymorphisms (SNPs) in microRNAs (miRNAs) may alter the processing, transcription, and expression of miRNAs and, thus, may contribute to cancer development. The authors hypothesized that common polymorphisms in pre-miRNAs are associated individually and (more likely) collectively with the risk of squamous cell carcinoma of the head and neck (SCCHN).

... Liu等^[30]发现miRNA-499 SNP(rs3746444)的AG和GG基因型与减低白种人头颈部鳞状细胞癌风险有关 ...

2010

18.038

0.0

... Hu等^[31]发现血清中的miRNA-499水平能作为非小细胞肺癌的预后因素 ...

2011

5.635

0.0

... Liu等^[32]发现在我国结直肠癌病例中,miRNA-499-5p能通过调节靶基因FOXO4和PDCD4进而促进体外癌细胞迁移和浸润,并促进体内肝和肺部转移 ...

2012

3.73

0.0

PLoS ONE. 2012, 7(5):e35252-null

Polymorphism rs4919510:C>G in Mature Sequence of Human MicroRNA-608 Contributes to the Risk of HER2-Positive Breast Cancer but Not Other Subtypes

Lei Fan 1 ,Ke-Da Yu 1 ,Zhi-Ming Shao 1 ,A-Ji Huang 1 ,Jing Li 1

1 Department of Breast Surgery, Cancer Center and Cancer Institute, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China

Background

A few polymorphisms are located in the mature microRNA sequences. Such polymorphisms could directly affect the binding of microRNA to hundreds of target mRNAs. It remains unknown whether rs4919510:C>G located in the mature miR-608 alters breast cancer susceptibility.

Methods

The association of rs4919510:C>G with risk and pathologic features of breast cancer were investigated in two independent case-control studies, the first set including 1,138 sporadic breast cancer patients (including 927 invasive ductal carcinoma patients, 777 of them with known subtypes: 496 luminal-like, 133 HER2-positive, and 148 triple-negative) and 1,434 community-based controls, and the second set including 294 familial/early-onset breast cancer patients and 500 hospital-based cancer-free controls. Odds ratios (ORs) were estimated by logistic regression. Predicted targets of miR-608 and complementary sequences containing rs4919510:C>G were surveyed to reveal potential pathological mechanism.

Results

In the first set, although rs4919510:C>G was unrelated to breast cancer in general patients, variant genotypes (CG/GG) were specifically associated with increased risk of HER2-positive subtype (Adjusted OR = 1.97, 95% CI, 1.34−2.90 in the recessive model). Variant G-allele was the risk allele with OR of 1.62 (95% CI, 1.23−2.15). Patients carrying GG-genotype also had larger HER2-positive tumors (P for Kruskal-Wallis test = 0.006). The relationship between rs4919510:C>G and risk of HER2-positive subgroup was validated in the second set (Bonferroni corrected P = 0.06). The adjusted combined OR (total 164 HER2-positive cases) in the recessive model was 1.97 (95% CI, 1.43−2.72) for GG genotype (corrected P = 1.1×10⁻⁴). Bioinformatic analysis indicated that, HSF1, which is required for HER2-induced tumorigenesis, might be a target of miR-608. The minimum free-energy of ancestral-miR-608 (C-allele) binding to HSF1 is −35.9 kcal/mol, while that of variant-form (G-allele) is −31.5 kcal/mol, indicating a lower affinity of variant-miR-608 to HSF1 mRNA.

Conclusion

rs4919510:C>G in mature miR-608 may influence HER2-positive breast cancer risk and tumor proliferation.

... 其他 Huang等^[33]发现成熟miRNA-608的SNP(rs4919510:C>G)与我国汉族女性乳腺罹患癌风险有关,携带有变异等位基因(CG/GG)以剂量效应的方式使女性有更高的HER2阳性乳腺癌患病风险 ...

2012

2.147

0.0

. 2012, 29(3):1723-1732 DOI:10.1007/s12032-011-0115-6

Polymorphism in pre-miR-30c contributes to gastric cancer risk in a Chinese population

<li>1.Department of Cell Biology, Capital Medical University, Beijing, 100069, China</li><li>2.Clinical Medical Research Center of the Affiliated Hospital, Inner Mongolia Medical College, 1 Tongdao North Street, Hohhot, 010050, China</li>

Abstract
To explore the association between single nucleotide polymorphisms (SNPs) A/G in pre-miR-30c and gastric cancer risk and to assess various genotypes that affected the survival of patients, we performed a hospital-based, case–control study in Inner Mongolia autonomous region of China. A total of 240 gastric cancer patients and 240 age- and sex-matched cancer-free controls collected from 2006 to 2011 were enrolled in this study. Polymorphism rs928508 in pre-miR-30c was analyzed by TaqMan SNP genotyping assay. The expression of mature miR-30c was detected by real-time quantitative reverse transcription PCR in 48 gastric cancer specimens. Survival analysis was analyzed by the Kaplan–Meier survival curves. The genotype frequencies of pre-miR-30c A/G in gastric cancer patients were obviously different from those in the controls (P = 0.022). AA genotype carriers were associated with an increased risk of gastric cancer compared with GG genotype (adjusted odds ratio (OR) = 1.83, 95% confidence interval (CI): 1.07–3.15, P = 0.029). Moreover, the gastric cancer risk especially elevated in older individuals (aged >60 years), males, nonsmokers, and Helicobacter pylori (H. pylori)-infected individuals (adjusted OR = 2.66, 95% CI: 1.38–5.13, P = 0.004; adjusted OR = 1.90, 95% CI: 1.10–3.27, P = 0.022; adjusted OR = 1.94, 95% CI: 1.12–3.35, P = 0.018; adjusted OR = 1.83, 95% CI: 1.08–3.10, P = 0.024, respectively). Further stratified analysis indicated that AA genotype facilitated developing of gastric cancer with lymph node metastasis (adjusted OR = 2.23, 95% CI: 1.07–4.64, P = 0.032). Expression analysis detected that rs928508 AA showed a significantly increased level of mature miR-30c compared with GG or AG/GG genotype (P = 0.011 or P = 0.013). Patients with AA genotype were associated with unfavorable outcome in overall survival compared with AG/GG genotype (Log rank 5.848, P = 0.016). This study demonstrates that pre-miR-30c A/G polymorphism may be associated with an increased risk of gastric cancer in a Chinese population through altering mature miR-30c expression. However, their role as novel biomarkers for the diagnosis and prognosis of gastric diseases still needs to be systematically evaluated.

... Mu等^[34]发现,位于pre-miRNA-30c 的SNP(rs928508:A/G)通过调整成熟miRNA-30c的表达来影响我国人群罹患胃癌的风险,其中AA型携带者有更高的胃癌风险 ...

2012

0.0

... Smith等^[35]研究发现CC型pre-miRNA-423(rs6505162:A>C)能减低澳大利亚女性乳腺癌患病风险 ...

2012

3.73

0.0

PLoS ONE. 2012, 7(10):e47544-null

Genetic Variations in Key MicroRNA Processing Genes and Risk of Head and Neck Cancer: A Case-Control Study in Chinese Population

Zhiyao Yuan 3 ,Ruixia Wang 3 ,Hua Yuan 2,3 ,Yue Jiang 1,2 ,Hongbing Shen 1,2 ,Ning Chen 3 ,Zhibin Hu 1,2 ,Chenjie Yu 4 ,Hongxia Ma 1,2

1 Department of Epidemiology and Biostatistics, MOE Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China 2 Section of Clinical Epidemiology, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Centre, Nanjing Medical University, Nanjing, China 3 Institute of Stomatology, Nanjing Medical University, Nanjing, China 4 Department of Otorhinolaryngology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China

MicroRNAs (miRNAs) have been reported to play a key role in oncogenesis. Genetic variations in miRNA processing genes and miRNA binding sites may affect the biogenesis of miRNA and the miRNA-mRNA interactions, hence promoting tumorigenesis. In the present study, we hypothesized that potentially functional polymorphisms in miRNA processing genes may contribute to head and neck cancer (HNC) susceptibility. To test this hypothesis, we genotyped three SNPs at miRNA binding sites of miRNA processing genes (rs1057035 in 3′UTR of DICER, rs3803012 in 3′UTR of RAN and rs10773771 in 3′UTR of HIWI) with a case-control study including 397 HNC cases and 900 controls matched by age and sex in Chinese. Although none of three SNPs was significantly associated with overall risk of HNC, rs1057035 in 3′UTR of DICER was associated with a significantly decreased risk of oral cancer (TC/CC vs. TT: adjusted OR= 0.65, 95% CI= 0.46–0.92). Furthermore, luciferase activity assay showed that rs1057035 variant C allele led to significantly lower expression levels as compared to the T allele, which may be due to the relatively high inhibition of hsa-miR-574-3p on DICER mRNA. These findings indicated that rs1057035 located at 3′UTR of DICER may contribute to the risk of oral cancer by affecting the binding of miRNAs to DICER. Large-scale and well-designed studies are warranted to validate our findings.

... 在消化系统肿瘤中,Ma等^[36]发现DICER 3'UTR的rs1057035(C/T)可影响miRNA与DICER的结合,与我国人群罹患口腔癌的风险相关 ...

2012

5.635

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... 在对我国汉族的部分样本进行分析后发现,RAP1A基因的高表达可见于食管鳞状细胞癌(ESCC)的大多数组织,并且与RAP1A的基因型以及淋巴结转移有关^[37] ...

2012

5.635

0.0

... MTMR3是miRNA-181a的结合位点,位于MTMR3的SNP(rs12537)被证实与我国南方地区汉族人胃癌患病风险以及预后有关,携带T等位基因的上述位点使得miRNA-181a的抑制作用增强,并且CT和TT型的rs12537有更高的胃癌罹患风险^[38] ...

2012

3.73

0.0

PLoS ONE. 2012, 7(5):e36306-null

rs4919510 in hsa-mir-608 Is Associated with Outcome but Not Risk of Colorectal Cancer

Carlo Croce 3 ,Dillon Robinson 1 ,Nicola Valeri 3 ,Elise D. Bowman 1 ,Ana I. Robles 1 ,Bríd M. Ryan 1 ,Alessio Paone 3 ,Andrew C. McClary 1,2 ,Curtis C. Harris 1

1 Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America 2 Howard Hughes Medical Institute, National Cancer Institute, Bethesda, Maryland, United States of America 3 Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, United States of America

Background

Colorectal cancer is the third most incident cancer and cause of cancer-related death in the United States. MicroRNAs, a class of small non-coding RNAs, have been implicated in the pathogenesis and prognosis of colorectal cancer, although few studies have examined the relationship between germline mutation in the microRNAs with risk and prognosis. We therefore investigated the association between a SNP in hsa-mir-608, which lies within the 10q24 locus, and colorectal cancer.

Methods and Results

A cohort consisting of 245 cases and 446 controls was genotyped for rs4919510. The frequency of the GG genotype was significantly higher in African Americans (15%) compared to Caucasians (3%) controls. There was no significant association between rs4919510 and colorectal cancer risk (African American: OR_{GG vs. CC} 0.89 [95% CI, 0.41–1.80]) (Caucasian: OR_{GG vs. CC} 1.76, ([95% CI, 0.48–6.39]). However, we did observe an association with survival. The GG genotype was associated with an increased risk of death in Caucasians (HR_{GG vs. CC} 3.54 ([95% CI, 1.38–9.12]) and with a reduced risk of death in African Americans (HR_{GG vs. CC} 0.36 ([95% CI 0.12–1.07).

Conclusions

These results suggest that rs4910510 may be associated with colorectal cancer survival in a manner that is dependent on race.

... Ryan等^[39]对结直肠癌患者进行研究后发现,GG基因型的has-miRNA-608的 (rs4919510:C/G)能显著增加白种人患者的死亡风险,而降低非裔美国患者的死亡风险 ...

2011

2.914

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... 最近研究发现KRAS-LCS6中存在一个SNP,携带该SNP G等位基因的荷兰早期结直肠癌患者有较好的预后,KRAS-LCS6基因型有可能成为判定预后及选择治疗方案的指标^[40] ...

2012

5.635

0.0

... Naccarati等^[41]对捷克1 098例结肠直肠癌患者和1 469例健康人进行研究后发现,核苷酸切除修复(nucleotide excision repair,NER)基因3'UTR的miRNA结合位点的SNP与结直肠癌患病风险有关,并且与肿瘤位置密切相关 ...

2012

1.941

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. 2012, 131(6):1318-1322

A polymorphism at the miR-502 binding site in the 3′-untranslated region of the histone methyltransferase SET8 is associated with hepatocellular carcinoma outcome

Zhanjun Guo 1,† ,Chensi Wu 1,† ,Xiaoling Wang 2 ,Cuiju Wang 3,4 ,Ruixing Zhang 1 andBaoen Shan 5,‡,*

1Department of Gastroenterology and Hepatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China 2Department of Pathology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China 3Department of Gynaecology Ultrasound, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China 4Hebei Key Lab of Laboratory Animal Science, Hebei Medical University, Shijiazhuang, People's Republic of China 5Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China *Research Center, The Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang 050011, People's Republic of China

MicroRNAs (miRNAs) can bind to the 3′-untranslated regions (UTRs) of messenger RNAs, where they interfere with translation and thereby regulate cell differentiation, apoptosis and tumorigenesis. Genetic polymorphisms in the 3′-UTRs targeted by miRNAs alter the strength of miRNA binding in a manner that affects the behavior of individual miRNAs. The histone methyltransferase SET8 has been reported to methylate TP53 and regulate genomic stability. We analyzed a single-nucleotide polymorphism (rs16917496) within the miR-502 miRNA seed region for the 3′-UTR of SET8 in Chinese patients with hepatocellular carcinoma (HCC). The SET8 CC genotype was independently associated with longer postoperative survival in patients with HCC by multivariate analysis (relative risk, 0.175; 95% CI = 0.053–0.577; p = 0.004). The SET8 CC genotype was associated with reduced SET8 protein levels based on the immunostaining of 51 HCC tissue samples. We also found that the low SET8 levels were associated with longer HCC survival. Our data suggest that SET8 modifies HCC outcome by altering its expression, which depends, at least in part, on its binding affinity with miR-502. The analysis of genetic polymorphisms in miRNA binding sites can help to identify patient subgroups that are at high risk for poor disease outcomes.

... Guo等^[42]发现,位于该3'UTR的SNP(rs16917496)与我国肝细胞癌患者的生存期有关,携带SET8 CC基因型的患者有更长的术后生存期,低表达的SET8与更长的生存期有关 ...

2012

3.73

0.0

PLoS ONE. 2012, 7(2):e32230-null

A Genetic Variant in the Promoter Region of miR-106b-25 Cluster and Risk of HBV Infection and Hepatocellular Carcinoma

Yixin Zhang 2 ,Shandong Pan 1 ,Li Liu 2,3 ,Jianguo Chen 5 ,Yao Liu 1 ,Juan Wen 1 ,Xiangjun Zhai 4 ,Jibin Liu 2 ,Hongbing Shen 1,6,7 ,Zhibin Hu 1,6,7

1 Department of Epidemiology and biostatistics, MOE Key Laboratory of Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China 2 Department of Hepatobiliary Surgery, Nantong Tumor Hospital, Nantong, China 3 Institute of Digestive Endoscopy and Medical Center for Digestive Diseases, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China 4 Department of Infection Diseases, Jiangsu Province Center for Disease Prevention and Control, Nanjing, China 5 Qidong Liver Cancer Research Institute, Qidong, China 6 Section of Clinical Epidemiology, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China 7 State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China

Background

MiR-106b-25 cluster, hosted in intron 13 of MCM7, may play integral roles in diverse processes including immune response and tumorigenesis. A single nucleotide polymorphism (SNP), rs999885, is located in the promoter region of MCM7.

Methods

We performed a case-control study including 1300 HBV-positive hepatocellular carcinoma (HCC) cases, 1344 HBV persistent carriers and 1344 subjects with HBV natural clearance to test the association between rs999885 and the risk of HBV persistent infection and HCC. We also investigated the genotype-expression correlation between rs999885 and miR-106b-25 cluster in 25 pairs of HCC and adjacent non-tumor liver tissues.

Results

Compared with the HBV natural clearance subjects carrying rs999885 AA genotype, those with AG/GG genotypes had a decreased risk of chronic HBV infection with an adjusted odds ratio (OR) of 0.79 [95% confidence intervals (CIs) = 0.67–0.93]. However, the AG/GG genotypes were significantly associated with an increased HCC risk in HBV persistent carriers (adjusted OR = 1.25, 95% CIs = 1.06–1.47). Expression analysis revealed that the expression level of miR-106b-25 cluster was significantly higher in AG/GG carriers than those in AA carriers in non-tumor liver tissues.

Conclusions

These findings indicate that the A to G base change of rs999885 may provide a protective effect against chronic HBV infection but an increased risk for HCC in HBV persistent carriers by altering the expression of the miR-106b-25 cluster.

... 在我国持续感染HBV的人群中,rs999885 AG基因型和GG基因型携带者的正常肝脏组织中miRNA-106b-25的表达量显著高于AA基因型携带者,并可能增加肝细胞癌的患病风险^[43] ...

2012

3.73

0.0

PLoS ONE. 2012, 7(10):e47544-null

Genetic Variations in Key MicroRNA Processing Genes and Risk of Head and Neck Cancer: A Case-Control Study in Chinese Population

Zhiyao Yuan 3 ,Ruixia Wang 3 ,Hua Yuan 2,3 ,Yue Jiang 1,2 ,Hongbing Shen 1,2 ,Ning Chen 3 ,Zhibin Hu 1,2 ,Chenjie Yu 4 ,Hongxia Ma 1,2

... 在头颈部癌中,Ma等^[44]发现,位于DICER 3'UTR的SNP(rs1057035)可通过has-miRNA-574-3p抑制miRNAs与DICER mRNA的结合,从而影响中国人群口腔癌的发病风险 ...

2010

5.635

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... Zhang等^[45]发现位于SMC1B的SNP(rs3747238)与头颈癌的复发有关,与野生型相比,该SNP的变异型携带患者头颈癌的复发风险增加 ...

2012

3.73

0.0

PLoS ONE. 2012, 7(6):e40127-null

A MicroRNA-7 Binding Site Polymorphism in HOXB5 Leads to Differential Gene Expression in Bladder Cancer

Qingqing Cai 2 ,Hui Huang 4 ,Eddie Chan 7 ,Chi-fai NG 7 ,Junhua Luo 1 ,Wang He 1 ,Hong Zeng 5 ,Weixi Deng 6 ,Tianxin Lin 1,6 ,Jian Huang 1 ,Hao Yu 1 ,Wei Wang 3

1 Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 2 Department of Internal Medicine, Cancer Center, Sun Yat-sen University, Guangzhou, China 3 Department of Urology, Guangzhou General Hospital of Guangzhou Military Command (Guangzhou Liuhuaqiao Hospital), Guangzhou, China 4 Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 5 Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 6 Lin Bai-xin Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 7 Division of Urology, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China

Purpose

To investigate the biological function of HOXB5 in human bladder cancer and explore whether the HOXB5 3′-UTR SNP (1010A/G), which is located within the microRNA-7 binding site, was correlated with clinical features of bladder cancer.

Methods

Expression of HOXB5 in 35 human bladder cancer tissues and 8 cell lines were examined using real-time PCR and immunohistochemistry. Next, we explored the biological function of HOXB5 in vitro using cell proliferation, migration and colony formation assays. Using bioinformatics, a SNP (1010A/G) was found located within the microRNA-7 binding site in the 3′-UTR of HOXB5. Real-time PCR was used to test HOXB5 expression affected by different alleles. Finally, multivariate logistic regression analysis was used to determine the relationship between SNP (1010A/G) frequency and clinical features in 391 cases.

Results

HOXB5 was frequently over-expressed both in bladder cancer tissues and cell lines. Inhibition of HOXB5 suppressed the oncogenic function of cancer cells. Next, we demonstrated that a SNP (1010A/G), located within the microRNA-7 binding site in the 3′-UTR of HOXB5, could affect HOXB5 expression in bladder cancer mainly by differential binding activity of microRNA-7 and SNP-related mRNA stability. Finally, we also showed the frequency of 1010G genotype was higher in cancer group compared to normal controls and correlated with the risk of high grade and high stage.

Conclusion

HOXB5 is overexpressed in bladder cancer. A miRNA-binding SNP (1010A/G) located within 3′-UTR of HOXB5 is associated with gene expression and may be a promising prognostic factor for bladder cancer.

... 在泌尿生殖系统的肿瘤中,研究发现位于HOXB5 3'UTR的一个SNP 能影响miRNA-7与HOXB5的结合活性和SNP相关mRNA的稳定性,从而调控HOXB5的表达,并有望成为膀胱癌的预后指标^[46] ...

2012

2.506

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. 2012, 39(1):369-373 DOI:10.1007/s11033-011-0747-9

A miR-125b binding site polymorphism in bone morphogenetic protein membrane receptor type IB gene and prostate cancer risk in China

<li>1.Department of Urology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China</li><li>2.Department of Molecular and Genetic Toxicology, Cancer Center of Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, China</li><li>3.Department of Urology, BenQ Affiliated Hospital of Nanjing Medical University, 71 Hexi Road, Nanjing, 210019, China</li>

Abstract
Recently, a C>T polymorphism (rs1434536) in a miR-125b binding site in the 3′ untranslated region (3′UTR) of bone morphogenetic protein membrane receptor type IB gene (BMPR1B) has been found to contribute to cancer susceptibility. To investigate whether it plays an important role in the development of prostate cancer in southern Chinese Han population, we performed a case–control study. 247 prostate cancer and 278 control subjects were included in the cancer association study and dual-luciferase reporter assay was used to test the binding ability of miR-125b to BMPR1B-C or -T vectors. The effect of CT/TT genotype on prostate cancer risk was found to be significant for localized disease (OR = 1.60, 95% CI = 1.01–2.53, P = 0.044) and among subgroups of aged >70 years (OR = 1.90, 95% CI = 1.15–3.15, P = 0.015) compared with CC genotype. Moreover, C-allele gave a reduced luciferase activity relative to T-allele in dual-luciferase reporter assay. Our findings show that rs1434536 in the 3′UTR of BMPR1B gene affects the binding ability of miR-125b to BMPR1B mRNA and contributes to the genetic predisposition to localized prostate cancer and patients aged >70 years.

... 位于该3'UTR的SNP(rs1434536)会影响miRNA-125b与BMPR1B mRNA的结合,并对我国局部地区的汉族人群的前列腺癌易感性产生影响^[47] ...

2012

1.915

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. 2012, 205(7-8):null-null

A polymorphism at the miR-502 binding site in the 3' untranslated region of the SET8 gene is associated with the risk of epithelial ovarian cancer

... 而Wang等^[48]发现,SET8 CC基因型能减低中国女性卵巢上皮癌的患病风险 ...

2010

8.65

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... Liang等^[49]推测PDGFC是miRNA-425的潜在靶基因,而位于PDGFC的SNP(rs1425486:G/A)能影响miRNA-425对该基因表达的抑制作用,并且对卵巢癌的生存期和治疗反应产生影响 ...

2010

8.65

0.0

... Wynendaele等^[50]在德国卵巢癌患者样本中发现MDM4 3'UTR的一个SNP(rs4245739)可产生新的miRNA-191结合位点,miRNA-191只与携带MDM4-C等位基因的3'UTR结合,致使MDM4-C的表达下调,因而延缓卵巢癌的进展、减少肿瘤相关的死亡并提高患者对化疗的敏感性 ...