修回日期: 2012-09-19
接受日期: 2012-10-08
在线出版日期: 2012-10-28
大肠癌(colorectal cancer, CRC)的发生、发展是一个多因素多步骤的演进过程, 基因多态性是决定肿瘤发生、发展及预后的一个重要因素. 近年研究发现某些microRNA(miRNA)的单核苷酸多态性(single-nucleotide polymorphism, SNP)与CRC遗传易感性及预后相关, 阐明相关改变机制可为CRC的早期筛查、预防及预后监测提供新线索. 本文就相关研究进展作一综述.
引文著录: 颜红柱, 许蜜蝶, 李彬彬, 余宏宇. miRNA单核苷酸多态性与大肠癌的研究进展. 世界华人消化杂志 2012; 20(30): 2920-2925
Revised: September 19, 2012
Accepted: October 8, 2012
Published online: October 28, 2012
The occurrence and development of colorectal cancer (CRC) are a multifactorial, multi-step evolutionary process. Gene polymorphisms are often involved in tumor development and prognosis. Recent studies have found that certain microRNA (miRNA) single nucleotide polymorphisms were associated with genetic susceptibility to and prognosis of CRC. Understanding the relationship between miRNA single nucleotide polymorphisms and CRC can provide new clues to the detection, prevention, and prognostic evaluation of CRC.
- Citation: Yan HZ, Xu MD, Li BB, Yu HY. Advances in understanding relationship between miRNA single nucleotide polymorphisms and colorectal cancer. Shijie Huaren Xiaohua Zazhi 2012; 20(30): 2920-2925
- URL: https://www.wjgnet.com/1009-3079/full/v20/i30/2920.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v20.i30.2920
大肠癌(colorectal cancer, CRC)是临床常见恶性肿瘤之一, 截至2008年全球约有60万患者死于CRC, 居于肿瘤相关死亡率第2位[1], 而在我国其发病率和死亡率均呈逐年上升趋势[2]. 既往研究表明, CRC的发生、发展是一个多因素多机制多步骤的演进过程, 基因多态性是决定个体易感性和临床转归的一个重要因素[3]. microRNA(miRNA)是重要的表观遗传学水平调控分子, 其可通过与靶基因3'-UTR(非编码区)序列特异性结合对基因进行转录后水平负性调控进而参与肿瘤的发生发展[4]. 分子生物学研究表明多种miRNA存在单核苷酸多态性(single-nucleotide polymorphism, SNP), 并通过调控miRNA与靶基因结合进而影响靶基因表达, 这些基因多态性与CRC之间的关系已成为国内外研究热点[5,6]. 本文就相关研究进展作一综述.
miRNA是一类长度约21-25 nt的小分子非编码RNA, 可调控人体内约30%的蛋白编码基因表达[7]. 在细胞核内, miRNA首先转录为前体分子, 或为单个基因, 或形成基因簇[8]. miRNA经由RNA集合酶Ⅱ转录形成发卡结构pri-miRNA, 并被核内Rnase Ⅲ酶家族成员Drosha加工成为长约70 nt的茎环结构pre-miRNA, 后者则由exportin-5在Ran-/GTP模式下转运至细胞质中[9]. 最后, 细胞质中另一Rnase Ⅲ酶家族成员Dicer将pre-miRNA剪切成长约22 nt的双链miRNA[10,11], 与互补序列结合, 形成基因诱导沉默复合体(RNA-induced silencing complex, RISC)[12]. 在RISC的引导下, 成熟miRNA与靶mRNA的3'-UTR互补配对(若结合区域位于种子区域外, 可为不完全配对), 沉默或降解靶基因, 影响靶基因的翻译和稳定性, 进而调控基因表达[13]. 由于miRNA可与靶基因不完全配对, 其对靶mRNA表达的调控模式可为一对多, 也可为多对一, miRNA几乎参与所有细胞进程[14]. 近年研究表明, 多种miRNA可在CRC等恶性肿瘤中作为癌基因或抑癌基因发挥重要调控作用[15-18].
既往针对miRNA的研究多集中于其差异性表达对靶基因及蛋白水平的影响, 对其本身基因多态性及突变的研究极少. 而鉴于结合位点的序列互补性及相关热力学在miRNA与其靶点相互结合中的重要性, SNP等受到越来越多学者的关注[19]. SNP是指在基因组水平上由单个核苷酸的变异所引起的DNA序列多态性, 是人类最常见的一种可遗传变异, 占所有已知多态性类型的90%以上[20]. 通常由单个碱基的转换(C←→T, 在其互补链上则为G←→A)或颠换(C←→A, G←→T, C←→G, A←→T)所引起, 也可由碱基的插入、缺失或框移突变所致[21]. 人体内存在3种形式miRNA相关SNP: miRNA核酸序列SNP, miRNA生物合成基因SNP和miRNA结合位点SNP[22]. 这些SNP可通过调控pri-miRNA转录, 影响pri-miRNA加工为pre-miRNA, 改变miRNA生成量甚至产生新的miRNA, 影响miRNA与靶基因结合, 对多种细胞信号通路产生影响. 而由于miRNA水平的些微改变即可对靶基因的表达产生巨大影响, miRNA相关基因的SNP对细胞内蛋白质翻译的调控作用极具意义[23]. 研究表明, miRNA相关SNP不仅可影响个体的正常发育, 参与多种疾病的形成, 更可影响肿瘤发病风险, 是miRNA调节多种生命进程的重要决定因素[24,25]. 此外, miRNA相关SNP还有望成为肿瘤预后监测和临床治疗结果预测的重要分子标志[26,27].
miRNA相关SNP与CRC的发生、发展以及预后有密切关系. 目前已有多种方法应用于检测和鉴定功能性miRNA相关SNP, 由于临床样本量的相对限制, 运用病例对照研究对这些SNP生物学意义的评估还处于初始阶段, 目前已证实与CRC显著相关的miRNA相关SNP共有21个(表1).
| 多态性(基因) | SNP ID | 突变 | 可能相关miRNA | 相关性 | 人群 | |
| miRNA结合位点 | ||||||
| RPA2 | rs7356 | A/G | miR-3149, miR-1188 | 患癌风险 | 捷克[46] | |
| GTF2H1 | rs4596 | G/C | miR-518a-5p | 患癌风险 | 捷克[46] | |
| MBL2 | rs10082466 | C/T | miR-27a | 患癌风险 | 美国[47] | |
| KIAA0182 | rs709805 | G/A | miR-324-3p | 患癌风险 | 捷克[48] | |
| NUP210 | rs354476 | T/C | miR-125a, miR-125b | 患癌风险 | 捷克[48] | |
| CD86 | rs17281995 | G/C | miR-337,miR-582, miR-200a*,miR-184, miR-212 | 患癌风险 | 捷克[41] | |
| INSR | rs1051690 | G/A | miR-612, miR-618 | 患癌风险 | 捷克[41] | |
| IC53 | rs2737 | T/C | miR-379 | 迟发 | 中国[49] | |
| DHFR | / | C/T | miR-24 | miR-24的肿瘤 抑制活性 | 德国[50] | |
| KRAS-LCS6 | rs61764370 | T/G | let-7 | 预后 | 多人群[43-45] | |
| pri-miRNA | ||||||
| miR-100 | rs1834306 | C/T | miR-100 | 预后 | 高加索[23] | |
| miR-26a-1 | rs7372209 | C/T | miR-26a-1 | 预后 | 高加索[23] | |
| pre-miRNA | ||||||
| miR-149 | rs2292832 | C/T | miR-149 | 患癌风险 | 中国[51] | |
| miR-423 | rs6505162 | C/A | miR-423 | 预后 | 中国[33] | |
| miR-608 | rs4919510 | C/G | miR-608 | 预后 | 中国[33] | |
| miR-492 | rs2289030 | C/G | miR-492 | 预后 | 韩国[52] | |
| miR-605 | rs2043556 | A/G | miR-605 | 患癌风险 | 中国[51] | |
| 成熟miRNA | ||||||
| miR-196a2 | Rs11614913 | C/T | miR-196a2 | 患癌风险 | 中国, 韩国[37,38] | |
| miR-219-1 | rs213210 | C/T | miR-219-1 | 患癌风险 | 美国[40] | |
| miR-608 | rs4919510 | C/G | miR-608 | 预后 | 美国[40] | |
| miRNA合成基因 | ||||||
| AGO2 | 框移 | 微卫星稳定性 | 韩国[29] | |||
| TNRC6A | 框移 | 微卫星稳定性 | 韩国[29] | |||
| XPO5 | rs11077 | A/C | 预后 | 高加索[23] | ||
参与miRNA生物合成的蛋白包括RNA集合酶Ⅱ、Drosha/Pasha、核孔复合体、Exportin/Ran-GTP、Dicer酶以及argonau蛋白复合体/RISC复合体. 这些蛋白编码基因的SNP可影响成熟miRNA的生物合成和表达, 继而影响miRNA介导的细胞内生命进程[28]. 对高加索人7个miRNA合成相关蛋白的SNP进行分析发现, CRC患者XPO5基因3'-UTR的SNP(rs11077) 的A等位基因可预测CRC患者的预后及临床转归, A携带者(AA+AC)与CRC的肿瘤进展时间(time to progression, TTP)和疾病控制率(disease control rate, DCR)的相关性显著高于CC基因型[23]. AGO1、AGO2、TARBP2、TNRC6A、TNRC6C和EXPORTIN5这6个miRNA合成基因的编码序列都存在7个以上的单核苷酸重复, 相关区域在微卫星不稳定性(microsatellite instability, MSI)的肿瘤中易发生框移突变. 除AGO1基因外, 27%的CRC样本中存在这一突变, 而高MSI、低MSI和微卫星稳定(stable microsatellite instability, MSS)样本的突变频率分别为19/58、0/32和0/90, 提示该突变可能为高MSI特异性. 这些基因的框移突变可能影响miRNA的合成并导致CRC患者发展为高MSI表型[29]. 高MSI状态的肿瘤预后较好, 但化疗反应不佳, 运用相关技术检测CRC患者的微卫星稳定状态可能用于指导临床治疗.
位于miRNA 5'-UTR的2-7个核苷酸为miRNA的种子区域, 这一区域主要功能为参与miRNA对靶基因的特异识别, 因此相关区域的SNP可影响miRNA与靶基因的结合[30]. miR-26a-1的预测靶基因smad1是TGF-β/SMAD信号通路成员之一, 可参与调控细胞的增殖、分化和凋亡[31], miR-100的预测靶基因IGF1R在多数恶性肿瘤中都高表达, 是重要的抗凋亡分子及肿瘤治疗耐药的关键调控因子[32], 这两种miRNA的SNP有可能直接影响多个肿瘤生物学行为相关调控信号通路. 相关研究表明接受5-FU和伊立替康联合化疗的高加索人群转移性CRC患者体内pri-miR26a-1的种子区域(rs7372209)存在C-T突变, 且与肿瘤整体反应率(overall response rate, ORR)和TTP相关, pri-miR-100的种子区域(rs1834306)发生C→T突变的患者TTP显著延长[23], 这两种miRNA的多态性突变或可应用于预测转移性CRC患者对联合化疗的临床转归.
pre-miRNA茎环结构的SNP可影响miRNA的加工过程从而影响成熟miRNA的表达水平. 国内学者[33]利用iPLEX平台对408个CRC样本中10个已知的位于pre-miRNA的SNP进行分析, 发现与野生型纯合子相比, pre-miR-423(rs6505162)和pre-miR-608(rs4919510)的突变型都与汉族人群CRC总生存期(overall survival, OS)和无复发生存期(recurrence-free survival, RFS)相关, 突变型患者复发/死亡风险均显著高于野生型患者. 而在接受化疗的CRC患者中, 这种相关性更为显著, 具一定提示意义, 但还需要扩大临床样本量进行证实.
成熟miRNA的SNP也与肿瘤的肿瘤易感性和预后转归密切相关. 既往的研究表明, miRNA-196a2基因C/T多态(rsl1614913)与多种恶性肿瘤患癌风险增加显著相关[34-36]. 在CRC患者中, 该多态的C等位基因是肿瘤风险因子, 相关SNP在韩国人和中国人群中均与CRC肿瘤易感性增加有关, CC基因型的韩国人群患癌风险显著高于TT/CT型人群, 这一相关性在非糖尿病患者和直肠癌患者中尤为显著[37]; 在中国人群中则表现为CT/CC基因型人群的患癌风险显著高于TT基因型人群, 在进展期(Dukes C和D)CRC患者中这一风险因子作用尤为显著[38]; 而在CRC发病率极高的高加索人群中, 这一多态位点并不与该人群的患癌风险具有显著相关性[39]. Lin等[40]针对1 097例CRC患者进行回顾性分析, 发现miR-219-1和miR-608基因多态均与接受过联合化疗的TNM Ⅲ期CRC患者的死亡率显著相关, 其中miR-219-1基因T/C多态(rs213210)和miR-608基因C/G多态(rs4919510)两者任一发生即可使CRC患者死亡率增加2.51倍, 而当两种SNP共存的情况下, CRC患者死亡率增加了5.6倍, 提示多重SNP可能会对接受联合化疗的进展期CRC患者预后产生叠加影响, 相关联系的具体分子机制还有待于功能学实验的进一步探索.
与miRNA生物合成基因SNP和miRNA核酸序列SNP相比, miRNA结合位点SNP更加丰富多变, 这些多态可引起成熟miRNA与靶基因结合障碍, 或产生新的miRNA结合位点, 抑制基因表达, 继而改变细胞内蛋白翻译水平. 由于相关SNP仅影响靶基因及下游效应分子表达, 而miRNA水平并未发生改变, 因此这一效应可用于解释一些miRNA表达无差异而蛋白翻译发生改变的生物学现象.
运用基因分析网站(PicTar, DianaMicroT, miRBase, miRanda, TargetScan和microInspector), Landi等[41]对104个基因的3'-UTR末端的miRNA结合位点进行分析, 共检测出57个miRNA结合位点SNP, 其中cd86(rs17281995)和insr(rs1051690)基因与捷克人群的散发性CRC发生显著相关. 进一步分析发现, CD86可对5个不同的miRNA结合位点产生影响: G→C突变时, miR-337、miR-582和miR-200a*与其3'-UTR亲和力显著降低, 而miR-184和miR-212的亲和力则上调, 这一现象很好阐释了miRNA与靶mRNA之间的多对一调控模式.
let-7是CRC发生发展重要调控因子, 其可通过抑制细胞生长促进细胞凋亡发挥抑癌基因的作用[42]. let-7靶基因KRAS 3'-UTR存在一多态位点KRAS-LCS6(rs61764370), 这一SNP并不会提高人们患CRC的风险, 但他能引起KRAS的过表达, 携带kras-lcs6的CRC患者生存时间明显延长, 且携带不同基因型的CRC患者临床治疗效果也存在差异[43-45].
miRNA在CRC的发生发展及预后治疗中发挥重要作用, 分子机制复杂多变, 而其多基因多通路参与特征使得这方面的研究极具意义. 随着生物学技术发展, miRNA相关SNP的发现进一步补充和丰富了miRNA参与CRC的分子生物学和遗传学机制, 并可能作为CRC早期筛查、诊断及预后监测的分子标志物. 但目前相关研究尚处于起始阶段, 除需继续寻找与CRC miRNA相关的SNP外, 原已发现的SNP的具体功能及临床意义也有待于进一步研究. 相关问题的解决可为阐明CRC的发生发展、临床诊断、治疗和预后监测提供新的切入点.
miRNA是一类可参与多种生命进程的调控分子, 而miRNA相关单核苷酸多态性(SNP)不仅可影响个体的正常发育, 参与多种疾病的形成, 更可影响肿瘤发病的风险, 是miRNA调节多种生命进程的重要决定因素, 对其深入研究将为认识和治疗肿瘤提供新的思路.
王娅兰, 教授, 重庆医科大学基础医学院病理教研室
近年研究发现, miRNA相关SNP既是大肠癌(CRC)患癌风险重要决定因素, 又能影响患者的预后转归, 其与CRC之间的关系错综复杂. 但目前相关研究尚处于起始阶段, 其具体功能和作用机制尚不完全清楚, 需深入研究和探讨.
miR-219-1基因T/C多态(rs213210)和miR-608基因C/G多态(rs4919510)两者任一发生即可使CRC患者死亡率增加2.51倍, 而当两种SNP共存的情况下, CRC患者死亡率增加了5.6倍, 提示多重SNP可能会对接受联合化疗的进展期CRC患者预后产生叠加影响.
本文综述了CRC相关miRNA的SNP, 并探讨了这些miRNA相关SNP在CRC患癌风险及预后转归中的作用及意义, 旨在为阐明CRC的发生发展、临床诊断、治疗和预后监测提供新的切入点.
本文为从事大肠癌相关miRNA的研究者提供了借鉴和指导. 如能深入研究并阐明miRNA本身基因多态性及突变对大肠癌的具体功能及临床意义, 将为大肠癌早期诊断及治疗开拓新的视野.
本文对miRNA的SNP在大肠癌中的研究进展进行了综述, 对于进一步认识miRNA的SNP与肿瘤的关系, 尤其是在大肠癌中的作用, 有一定的参考价值.
编辑:田滢 电编:闫晋利
| 1. | Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69-90. [PubMed] [DOI] |
| 2. | Zhang S, Cui Y, Weng Z, Gong X, Chen M, Zhong B. Changes on the disease pattern of primary colorectal cancers in Southern China: a retrospective study of 20 years. Int J Colorectal Dis. 2009;24:943-949. [PubMed] [DOI] |
| 3. | Demant P. The genetic factors in cancer development and their implications for cancer prevention and detection. Radiat Res. 2005;164:462-466. [PubMed] [DOI] |
| 4. | Bushati N, Cohen SM. microRNA functions. Annu Rev Cell Dev Biol. 2007;23:175-205. [PubMed] [DOI] |
| 5. | Landi D, Gemignani F, Landi S. Role of variations within microRNA-binding sites in cancer. Mutagenesis. 2012;27:205-210. [PubMed] [DOI] |
| 6. | Dong Y, Wu WK, Wu CW, Sung JJ, Yu J, Ng SS. MicroRNA dysregulation in colorectal cancer: a clinical perspective. Br J Cancer. 2011;104:893-898. [PubMed] [DOI] |
| 7. | Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet. 2010;11:597-610. [PubMed] [DOI] |
| 9. | Bohnsack MT, Czaplinski K, Gorlich D. Exportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of pre-miRNAs. RNA. 2004;10:185-191. [PubMed] [DOI] |
| 10. | Cullen BR. Transcription and processing of human microRNA precursors. Mol Cell. 2004;16:861-865. [PubMed] [DOI] |
| 11. | Murphy D, Dancis B, Brown JR. The evolution of core proteins involved in microRNA biogenesis. BMC Evol Biol. 2008;8:92. [PubMed] [DOI] |
| 12. | Parker JS, Roe SM, Barford D. Molecular mechanism of target RNA transcript recognition by Argonaute-guide complexes. Cold Spring Harb Symp Quant Biol. 2006;71:45-50. [PubMed] [DOI] |
| 13. | Iorio MV, Croce CM. MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review. EMBO Mol Med. 2012;4:143-159. [PubMed] [DOI] |
| 14. | Pasquinelli AE. MicroRNAs and their targets: recognition, regulation and an emerging reciprocal relationship. Nat Rev Genet. 2012;13:271-282. [PubMed] [DOI] |
| 15. | Iorio MV, Croce CM. MicroRNAs in cancer: small molecules with a huge impact. J. Clin Oncol. 2009;27:5848-5856. [PubMed] [DOI] |
| 16. | Garzon R, Marcucci G, Croce CM. Targeting microRNAs in cancer: rationale, strategies and challenges. Nat Rev Drug Discov. 2010;9:775-789. [PubMed] [DOI] |
| 17. | Kong YW, Ferland-McCollough D, Jackson TJ, Bushell M. microRNAs in cancer management. Lancet Oncol. 2012;13:e249-e258. [PubMed] [DOI] |
| 18. | Osman A. MicroRNAs in health and disease--basic science and clinical applications. Clin Lab. 2012;58:393-402. [PubMed] |
| 19. | Schetter AJ, Harris CC. Alterations of microRNAs contribute to colon carcinogenesis. Semin Oncol. 2011;38:734-742. [PubMed] [DOI] |
| 20. | Carlson CS, Newman TL, Nickerson DA. SNPing in the human genome. Curr Opin Chem Biol. 2001;5:78-85. [PubMed] [DOI] |
| 21. | Kwok PY. Methods for genotyping single nucleotide polymorphisms. Annu Rev Genomics Hum Genet. 2001;2:235-258. [PubMed] [DOI] |
| 22. | Slaby O, Bienertova-Vasku J, Svoboda M, Vyzula R. Genetic polymorphisms and microRNAs: new direction in molecular epidemiology of solid cancer. J Cell Mol Med. 2012;16:8-21. [PubMed] [DOI] |
| 23. | Boni V, Zarate R, Villa JC, Bandrés E, Gomez MA, Maiello E, Garcia-Foncillas J, Aranda E. Role of primary miRNA polymorphic variants in metastatic colon cancer patients treated with 5-fluorouracil and irinotecan. Pharmacogenomics J. 2011;11:429-436. [PubMed] [DOI] |
| 24. | Mishra PJ, Bertino JR. MicroRNA polymorphisms: the future of pharmacogenomics, molecular epidemiology and individualized medicine. Pharmacogenomics. 2009;10:399-416. [PubMed] [DOI] |
| 25. | Ryan BM, Robles AI, Harris CC. Genetic variation in microRNA networks: the implications for cancer research. Nat Rev Cancer. 2010;10:389-402. [PubMed] [DOI] |
| 26. | Bandiera S, Hatem E, Lyonnet S, Henrion-Caude A. microRNAs in diseases: from candidate to modifier genes. Clin Genet. 2010;77:306-313. [PubMed] [DOI] |
| 27. | Kasinski AL, Slack FJ. Epigenetics and genetics. MicroRNAs en route to the clinic: progress in validating and targeting microRNAs for cancer therapy. Nat Rev Cancer. 2011;11:849-864. [PubMed] [DOI] |
| 28. | Treiber T, Treiber N, Meister G. Regulation of microRNA biogenesis and function. Thromb Haemost. 2012;107:605-610. [PubMed] [DOI] |
| 29. | Kim MS, Oh JE, Kim YR, Park SW, Kang MR, Kim SS, Ahn CH, Yoo NJ, Lee SH. Somatic mutations and losses of expression of microRNA regulation-related genes AGO2 and TNRC6A in gastric and colorectal cancers. J Pathol. 2010;221:139-146. [PubMed] [DOI] |
| 30. | Filipowicz W, Bhattacharyya SN, Sonenberg N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet. 2008;9:102-114. [PubMed] [DOI] |
| 31. | Korchynskyi O, Landström M, Stoika R, Funa K, Heldin CH, ten Dijke P, Souchelnytskyi S. Expression of Smad proteins in human colorectal cancer. Int J Cancer. 1999;82:197-202. [PubMed] [DOI] |
| 32. | Casa AJ, Dearth RK, Litzenburger BC, Lee AV, Cui X. The type I insulin-like growth factor receptor pathway: a key player in cancer therapeutic resistance. Front Biosci. 2008;13:3273-3287. [PubMed] [DOI] |
| 33. | Xing J, Wan S, Zhou F, Qu F, Li B, Myers RE, Fu X, Palazzo JP, He X, Chen Z. Genetic polymorphisms in pre-microRNA genes as prognostic markers of colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2012;21:217-227. [PubMed] [DOI] |
| 34. | Li XD, Li ZG, Song XX, Liu CF. A variant in microRNA-196a2 is associated with susceptibility to hepatocellular carcinoma in Chinese patients with cirrhosis. Pathology. 2010;42:669-673. [PubMed] [DOI] |
| 35. | Dou T, Wu Q, Chen X, Ribas J, Ni X, Tang C, Huang F, Zhou L, Lu D. A polymorphism of microRNA196a genome region was associated with decreased risk of glioma in Chinese population. J Cancer Res Clin Oncol. 2010;136:1853-1859. [PubMed] [DOI] |
| 36. | Tian T, Shu Y, Chen J, Hu Z, Xu L, Jin G, Liang J, Liu P, Zhou X, Miao R. A functional genetic variant in microRNA-196a2 is associated with increased susceptibility of lung cancer in Chinese. Cancer Epidemiol Biomarkers Prev. 2009;18:1183-1187. [PubMed] [DOI] |
| 37. | Min KT, Kim JW, Jeon YJ, Jang MJ, Chong SY, Oh D, Kim NK. Association of the miR-146aC& gt; G, 149C& gt; T, 196a2C& gt; T, and 499A& gt; G polymorphisms with colorectal cancer in the Korean population. Mol Carcinog. 2012;51 Suppl 1:E65-E73. [PubMed] [DOI] |
| 38. | Zhu L, Chu H, Gu D, Ma L, Shi D, Zhong D, Tong N, Zhang Z, Wang M. A functional polymorphism in miRNA-196a2 is associated with colorectal cancer risk in a Chinese population. DNA Cell Biol. 2012;31:350-354. [PubMed] [DOI] |
| 39. | Hezova R, Kovarikova A, Bienertova-Vasku J, Sachlova M, Redova M, Vasku A, Svoboda M, Radova L, Kiss I, Vyzula R. Evaluation of SNPs in miR-196-a2, miR-27a and miR-146a as risk factors of colorectal cancer. World J Gastroenterol. 2012;18:2827-2831. [PubMed] [DOI] |
| 40. | Lin M, Gu J, Eng C, Ellis LM, Hildebrandt MA, Lin J, Huang M, Calin GA, Wang D, Dubois RN. Genetic polymorphisms in MicroRNA-related genes as predictors of clinical outcomes in colorectal adenocarcinoma patients. Clin Cancer Res. 2012;18:3982-3991. [PubMed] [DOI] |
| 41. | Landi D, Gemignani F, Naccarati A, Pardini B, Vodicka P, Vodickova L, Novotny J, Försti A, Hemminki K, Canzian F. Polymorphisms within micro-RNA-binding sites and risk of sporadic colorectal cancer. Carcinogenesis. 2008;29:579-584. [PubMed] [DOI] |
| 42. | Boyerinas B, Park SM, Hau A, Murmann AE, Peter ME. The role of let-7 in cell differentiation and cancer. Endocr Relat Cancer. 2010;17:F19-F36. [PubMed] [DOI] |
| 43. | Chin LJ, Ratner E, Leng S, Zhai R, Nallur S, Babar I, Muller RU, Straka E, Su L, Burki EA. A SNP in a let-7 microRNA complementary site in the KRAS 3' untranslated region increases non-small cell lung cancer risk. Cancer Res. 2008;68:8535-8540. [PubMed] [DOI] |
| 44. | Zhang W, Winder T, Ning Y, Pohl A, Yang D, Kahn M, Lurje G, Labonte MJ, Wilson PM, Gordon MA. A let-7 microRNA-binding site polymorphism in 3'-untranslated region of KRAS gene predicts response in wild-type KRAS patients with metastatic colorectal cancer treated with cetuximab monotherapy. Ann Oncol. 2011;22:104-109. [PubMed] [DOI] |
| 45. | Ruzzo A, Graziano F, Vincenzi B, Canestrari E, Perrone G, Galluccio N, Catalano V, Loupakis F, Rabitti C, Santini D. High let-7a microRNA levels in KRAS-mutated colorectal carcinomas may rescue anti-EGFR therapy effects in patients with chemotherapy-refractory metastatic disease. Oncologist. 2012;17:823-829. [PubMed] [DOI] |
| 46. | Naccarati A, Pardini B, Stefano L, Landi D, Slyskova J, Novotny J, Levy M, Polakova V, Lipska L, Vodicka P. Polymorphisms in miRNA-binding sites of nucleotide excision repair genes and colorectal cancer risk. Carcinogenesis. 2012;33:1346-1351. [PubMed] [DOI] |
| 47. | Zanetti KA, Haznadar M, Welsh JA, Robles AI, Ryan BM, McClary AC, Bowman ED, Goodman JE, Bernig T, Chanock SJ. 3'-UTR and functional secretor haplotypes in mannose-binding lectin 2 are associated with increased colon cancer risk in African Americans. Cancer Res. 2012;72:1467-1477. [PubMed] [DOI] |
| 48. | Landi D, Gemignani F, Pardini B, Naccarati A, Garritano S, Vodicka P, Vodickova L, Canzian F, Novotny J, Barale R. Identification of candidate genes carrying polymorphisms associated with the risk of colorectal cancer by analyzing the colorectal mutome and microRNAome. Cancer. 2012;118:4670-4680. [PubMed] [DOI] |
| 49. | Chen J, Shi Y, Li Z, Yu H, Han Y, Wang X, Sun K, Yang T, Lou K, Song Y. A functional variant of IC53 correlates with the late onset of colorectal cancer. Mol Med. 2011;17:607-618. [PubMed] [DOI] |
| 50. | Mishra PJ, Song B, Mishra PJ, Wang Y, Humeniuk R, Banerjee D, Merlino G, Ju J, Bertino JR. MiR-24 tumor suppressor activity is regulated independent of p53 and through a target site polymorphism. PLoS One. 2009;4:e8445. [PubMed] [DOI] |
| 51. | Mw Z, Mj J, Yx Y, Sc Z, B L, X J, Yf P, Ql L, Xy M, K C. Associations of lifestyle-related factors, hsa-miR-149 and hsa-miR-605 gene polymorphisms with gastrointestinal cancer risk. Mol Carcinog. 2012;51 Suppl 1:E21-E31. [PubMed] [DOI] |
| 52. | Lee HC, Kim JG, Chae YS, Sohn SK, Kang BW, Moon JH, Jeon SW, Lee MH, Lim KH, Park JY. Prognostic impact of microRNA-related gene polymorphisms on survival of patients with colorectal cancer. J Cancer Res Clin Oncol. 2010;136:1073-1078. [PubMed] [DOI] |