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摘要：MiRNA是近年来发现的一类新型基因调节因子，在多种恶性肿瘤中起着重要的作用。近年来的研究显示，在卵巢癌、子宫内膜癌和宫颈癌这三大常见妇科肿瘤中miRNA的表达存在明显异常，提示其与这三大妇科肿瘤的发生、发展密切相关。在此阐述miRNA的分子生物学特点，并分析和总结miRNA与女性生殖系统肿瘤的早期诊断、侵袭和转移、治疗以及预后之间的关系，本文就通过这几方面对miRNA与女性生殖系统肿瘤关系的研究进展作一综述。
关键词：miRNA；卵巢癌；子宫内膜癌；宫颈癌
本文引用格式：郭珍珍,尹瑞雪,田小飞.miRNA与女性生殖系统肿瘤的研究进展[J].世界最新医学信息文摘,2019,19(76):123-125.
Research Progress of miRNA and Tumor of Female Reproductive System
GUO Zhen-zhen1,YIN Rui-xue1,TIAN Xiao-fei2*
（1.Xi’an Medical University,Xi’an Shanxi;2.Oncology Hospital of Shanxi,Xi’an Shanxi）
ABSTRACT:MiRNA is a new type of gene regulatory factor found in recent years,which plays an important role in many malignant tumors.Recent studies have shown that the expression of miRNA is abnormal in ovarian carcinoma,endometrial carcinoma and cervical cancer,suggesting that it is closely related to the occurrence and development of these three gynecological tumors.In this paper,the molecular biological characteristics of miRNA will be reviewed,and the relationship between miRNA and female reproductive systerm tumors in early diagnosis,invasion,metastasis,treatment and prognosis will be analyzed and summarized.This article reviews the research progress of the relationship between miRNA and female reproductive system tumors in these aspects.
KEY WORDS:miRNA;Ovarian cancer;Endometrial cancer;Cervical cancer
1miRNA的分子生物学特点
微小RNAs（microRNAs，mi RNAs）是一类内源性非编码小分子RNA，由Lee等[1]在研究线虫时首次发现。miRNA的合成分为两步，分别在细胞核和细胞质中进行，首先由DNA聚合酶II在细胞核中合成长双链前体，即初级miRNAs。随后在Drosha（RNA内切酶Ⅲ）作用下，生成70个单核苷酸的发夹状茎环结构，即前体miRNA，并通过Expotin 5蛋白转运到细胞质[2]，前体miRNA进入细胞质后，被Dicer酶剪切成大小约22nt的成熟miRNA。成熟的miRNA与AGO蛋白结合形成RISC（RNA沉默复合体）[3]，RISC通过与靶标基因miRNA的3’UTR区域特定位点结合，通过抑制miRNA的翻译和或促进mRNA的降解来下调其靶基因的表达，表达方式取决于miRNA的互补程度，完全互补或近完全互补有利于miRNA的降解，而较小程度的互补仅控制翻译[4]。miRNAs对基因表达的调控是一个复杂的网络，通过与基因调节信号通路的相互作用，从而调节肿瘤的发生、发展、侵袭和转移、治疗以及预后。
2miRNA与三大妇科肿瘤
2.1miRNA与卵巢癌
近年来许多研究表明miRNA在卵巢癌中表达谱存在明显异常，张等[5]通过高通量测序研究卵巢癌患者与健康妇女血浆中miRNA的表达，发现卵巢癌患者中miRNA-106a-5p、let7d-5p和miRNA-93-5p的表达水平显著升高，而miRNA-122-5p、miRNA-185-5p和miRNA-99b-5p的表达水平明显降低。Paola等研究[6]发现，与健康人相比，miRNA-1246在诊断为高级别浆液性卵巢癌（HGSOC）的患者血清中明显上调。也有研究[7]表明，miRNA-1290在HGSOC患者血清中显著升高，可用于鉴别可能区分HGSOC患者和非HGSOC患者，miRNA-1290还可以反映瘤负荷。CA125是卵巢癌诊断的常用指标，特异性较差，苏等[8]发现血清miR-375和miRNA-1307表达的上调，而且上调的miRNA-375和miRNA-1307增强了CA 125对卵巢癌的诊断能力。Kim等[9]发现卵巢癌患者血清中miRNA-93、miRNA-145和miRNA-200C的表达明显升高。Zuberi等[10]在70例新诊断的上皮性卵巢癌患者中发现miRNA-125b表达显著上调，并发现DNA过甲基化可能参与了miRNA-125b的失活。
卵巢癌是妇科肿瘤中恶性程度较高的肿瘤，其远处转移是卵巢癌患者预后不良的主要原因之一。刘等[11]等研究表明，高级别浆液性卵巢癌患者中miRNA-301b-3p通过靶向调控CPEB 3/EGFR轴，进而促进卵巢癌细胞的迁移和侵袭。miRNA-616[12]也可以通过促进细胞迁移、侵袭和EMT进而促进卵巢癌的进展。Chu[13]等发现miRNA-205在卵巢癌组织中明显上调，miRNA-205通过抑制其靶基因PTEN和Smad 4在体内的表达，从而促进卵巢癌细胞的增殖和侵袭。miRNA也可以抑制肿瘤的侵袭与转移，过表达miRNA-208A-5p[14]通过miRNA-208-5p/DAAM 1轴抑制卵巢癌细胞的侵袭与转移。
MiRNA对相关靶基因的调控已成为分子靶向癌症治疗的策略之一。已发现[15]miRNA-21在卵巢癌中过度表达，沉默miR-21可对异种移植模型小鼠肿瘤的生长有显著抑制作用。Hua等[16]发现miRNA-145在卵巢癌组织和细胞系中的表达降低，并可通过抑制其靶点D型细胞周期蛋白2(cyclin-2)、细胞周期蛋白D2(CCND 2)和E2F转录因子3(E2F3)，从而抑制EOC细胞的增殖、迁移和侵袭，为宫颈癌的治疗提供新思路。miRNA-542-3p[17]也可以通过直接靶向促进细胞周期蛋白依赖性激酶14(CDK14)的表达，显著减弱了肿瘤生长。miRNA-219-5p[18]通过下调Twist/Wnt/β-catenin信号通路来抑制细胞增殖、迁移和侵袭，miRNA-219-5p有可能成为治疗宫颈癌的新靶点。
卵巢癌的恶性程度高，预后差，研究发现miRNA的表达与卵巢癌患者的预后密切相关。Brouwer J等[19]发现miRNA-145-5p的表达与卵巢癌FIGO分期密切相关，晚期患者miRNA-145-5p的表达低于早期，高表达miRNA-145-5p的预后较好。Cho等[20]的研究表明，miRNA-424-5p表达的降低与高分期癌(Ⅲ、Ⅳ期)、远处转移及其他不良预后指标呈正相关。也有学者[21]通过对肿瘤基因组图谱数据的分析，发现miRNA-147b-5p的表达对卵巢癌患者的中位生存期有积极的影响。
2.2miRNA与子宫内膜癌
分析miRNA表达谱，发现[22]miRNA-15b、miRNA-27a和miRNA-233可以用于子宫内膜腺癌的临床诊断，其各自的ROC-AUC均高于CA-125。Martina等[23]发现子宫内膜癌患者血清中miRNA-186，miRNA-222，miRNA-223上调，miRNA-204下调。Muralidharan等发现[24]子宫内膜癌中8个异常表达的miRNA，其中2个上调，6个下调。Akhil等[25]通过检测子宫内膜癌患者尿中miRNA的表达谱，结果显示miRNA-200C-3P的富集程度最高。
王等[26]发现miRNA-365在子宫内膜癌患者中表达降低，过表达miRNA-365可抑制癌细胞增殖，促进细胞凋亡和衰老。miRNA-152[27]通过下调WNT-1，从而抑制卵巢癌细胞周期的G1/S转换，从而抑制细胞增殖。李美仪等[28]发现miRNA-373-3p可明显抑制HEC-1A细胞的增殖和迁移能力。Chen等[29]发现miRNA-10b在子宫内膜癌组织中表达上调，而miRNA-10b沉默后通过调节其靶基因HOCB3的表达促进细胞凋亡，抑制子宫内膜癌细胞的增殖、迁移和侵袭。
Ｗｕ等[30]研究发现miRNA-200b／200c／429在子宫内膜癌中高表达，其过度表达与顺铂耐药有关，miR-200b/200C/429可识别AP-2a基因39 UTR中的MRE，并负调控内源性AP-2a蛋白的表达。突变型39 UTR(C等位基因)的AP-2a在子宫内膜癌细胞株HEC-1A中过表达，降低顺铂敏感性，抑制HEC-1A的表达可降低顺铂耐药，有利于宫颈癌的治疗。miRNA-381[31]在子宫内膜癌组织和细胞系中表达下调，发现胰岛素样生长因子受体1(IGF-1R)是miRNA-381的新靶点，高表达miRNA-381可降低IGF-1R的表达，起抑癌作用，miRNA-381有望成为治疗子宫内膜癌新的治疗靶点。
Wang等[32]的研究表明，子宫内膜癌患者外周血miRNA-29b相对表达低于子宫内膜良性肿瘤患者和正常人，III期和IV期子宫内膜癌患者miRNA-29b的表达低于I期和II期患者，表明miRNA-29b在子宫内膜癌患者外周血中的表达与其FIGO分期有关。此外还发现miRNA-29b在原发性或转移性子宫内膜癌患者中表达水平较低，低表达的患者术后生存时间较短，预后差。Wilczynski等[33]在较早分期子宫内膜癌中发现较高的miRNA-205表达水平，高miRNA-205的表达可能与较好的预后相关。
2.3miRNA与宫颈癌
早期诊断是提高宫颈癌患者生存率的重要因素，MiRNA在宫颈癌患者与正常妇女中有差异性表达。Malihe等[34]发现6种循环种异常表达的miRNAs，以及6种组织特异性miRNAs。刘等[35]也发现了6种miRNAs在宫颈癌组织中明显上调。王等[36]在宫颈癌组织的研究种发现4个miRNAs上调，4个miRNAs下调。
许多miRNAs在宫颈癌中异常表达，在其发生发展过程中调节着癌基因和抑癌基因的表达。miRNA-125b[37]通过调节HMGA 1促进宫颈癌的增殖。发现[38]宫颈癌中miRNA-148A下调，RRS1上调，下调的miRNA-148A可通过促进其靶基因RRS1的表达，促进细胞增殖、迁移和侵袭，抑制宫颈癌细胞凋亡。还证明[39]miRNA-381-3p在宫颈癌细胞中低表达，miRNA-381-3p可下调其靶基因Fgf 7的表达，抑制细胞增殖和转移，诱导细胞周期阻滞和凋亡。锌指E盒结合同源盒2(ZEB 2)[40]是宫颈癌miRNA-377的直接靶基因，其在宫颈癌组织中高表达，与miRNA-377水平呈负相关，miRNA-377通过直接靶向ZEB 2降低宫颈癌细胞的增殖和侵袭。
宫颈癌中越来越多的通过miRNA调节的靶轴被发现，这为其治疗方法的发展提供新的思路。吴等[41]发现miR-144-3p在宫颈癌细胞和组织中明显下调，过表达miRNA-144-3p可抑制癌细胞的生长和转移，可作为宫颈癌治疗的新靶点。也有研究[42]表明miRNA-505-5p是一种抑制肿瘤的miRNA，通过直接靶向ETS基因，抑制肿瘤细胞的增殖、迁移和侵袭，过表达miRNA-505-5p有望成为宫颈癌的治疗靶点。miRNA-874[43]通过直接靶向ETS 1在宫颈癌中发挥抑癌作用。
miRNA在宫颈癌的预后预测方面具有一定优势。发现[44]c-Met在宫颈癌组织中高表达，而E-cadherin表达水平低于癌旁组织。24个月的随访结果显示，低水平的c-Met表达水平与E-cadherin的高表达水平和较长的生存率有关，miRNA-1通过下调c-Met来抑制宫颈癌细胞的增殖和迁移，从而提高患者的生存率。Anja的研究[45]显示miRNA-210-3p与宫颈癌患者的不良结局有关。也发现miRNA-665表达下调，与肿瘤大小、远处转移、晚期TNM分期和不良预后呈负相关。
3展望
尽管我们在了解妇科恶性肿瘤的分子基础方面取得了一定的进展，但妇科恶性肿瘤患者的生存率仍较低。在过去的几年的研究中，已经确定miRNAs是妇科肿瘤中很重要的分子，对妇科肿瘤的诊断及预后意义非凡，很可能会影响宫颈癌、子宫内膜癌和卵巢癌的未来治疗策略。然而，在这成为现实之前，我们对miRNAs多样化功能的理解还需要进一步成熟，miRNAs可以针对多个基因进行调节，单个基因可以被多个miRNAs靶向，miRNA对基因的调控网络复杂，需要我们进一步探索。相信在不久的将来，miRNA能在临床中发挥作用，给妇科肿瘤患者带来最大收益。
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