腫瘤淋巴結轉移相關MicroRNAs的研究進展

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腫瘤淋巴結轉移相關MicroRNAs的研究進展

張莉向作林

(復旦大學附屬中山醫院放療科，上海200032)

Research Progress of MicroRNAs Associated with Tumor Node Metastasis

ZHANGLiXIANGZuolinDepartmentofRadiotherapy,ZhongshanHospital,FudanUniversity,Shanghai200032,China

1MicroRNAs概述

微小RNA(microRNAs，miRNAs)是一類包含20~24個核苷酸的高度保守的非編碼小分子RNA，可以調節mRNA的翻譯[1]。miRNA結合到多種基因的mRNA的3’-非編碼區，導致靶向mRNA的降解及轉錄的終止[2]。miRNA作為信號通路的樞紐，參與多種生理病理過程，如細胞增殖、凋亡及腫瘤轉移[3-4]。越來越多的研究[5-6]表明，miRNAs可以發揮癌基因或者抑癌基因的作用，它們在多種腫瘤中的異常表達對腫瘤的侵襲和轉移有著重要的影響。因此，異常表達的miRNA有望成分預測腫瘤侵襲及轉移的生物標志物。本文綜述了腫瘤淋巴結轉移相關miRNAs的研究進展。

2miRNA與腫瘤淋巴結轉移

2.1miRNA與頭頸部腫瘤淋巴結轉移Wang等[7]研究表明，EB病毒核抗原1(EBNA1)蛋白在鼻咽癌組織中高表達，并且通過轉化生長因子-β1的介導抑制miR-200a和miR-200b的表達，從而導致鼻咽癌淋巴結轉移的發生。Luo等[8]發現，高表達的miR-18a與晚期鼻咽癌的淋巴結轉移相關。Huang等[9]發現，miR-491-5p 低表達與口腔鱗狀細胞癌淋巴結轉移有關。Lu等[10]研究發現，miR-196a/b在腫瘤組織中高度表達，并且與口腔癌淋巴結轉移密切相關。Yang等[11]研究表明，miR-181可以作為口腔鱗狀細胞癌淋巴結轉移的生物標志物。Abraham 等[12]發現，miR-183 和miR-375的超表達與甲狀腺髓樣癌的對側淋巴結轉移相關(P<0.001、P=0.001)。Chou等[13]研究發現，miR-146b可以顯著增加甲狀腺乳頭狀癌細胞的遷移和侵襲。Wang等[14]發現，miR-2861和miR-451的低表達上調與甲狀腺髓樣癌淋巴結轉移密切相關。

2.2miRNA與胸部腫瘤淋巴結轉移有研究[15-17]表明，高表達的miR-21與食管鱗狀細胞癌的淋巴結轉移顯著相關。Huang等[18]發現，miR-98和 miR-214的表達水平與食管鱗狀細胞癌淋巴結轉移呈負相關。Zhang等[19]研究表明，發生淋巴結轉移的食管鱗狀細胞癌患者中miR-200b表達顯著下降。Wang等[20]發現，miR-196a的高表達與食管鱗狀細胞癌淋巴結轉移相關。Chen等[21]發現，miR-92a高表達的食管鱗狀細胞癌患者較低表達者更容易發生淋巴結轉移。

在非小細胞肺癌的研究中，Meng 等[22]應用全基因組測序證實表達上調的miR-31可以預測肺腺癌患者淋巴結轉移，而且提示預后不良。Yu 等[23]發現，miR-193a-3p/5p低表達與非小細胞肺癌的TNM分期和淋巴結轉移明顯相關。Wang等[24]用基因芯片分析了非小細胞肺癌組織中miRNA的表達譜，發現了40個異常表達的miRNA，其中下調最明顯的miR-451與非小細胞肺癌的分化程度，病理分期和淋巴結轉移顯著相關。Roth 等[25]發現，肺癌患者血清中高表達的miR-10b與淋巴結轉移相關(P<0.03)。Wang等[26]的研究表明，miR-451的低表達水平與非小細胞肺癌的淋巴結轉移相關。Chen等[27]的研究表明，miR-148a的低表達與非小細胞肺癌的淋巴結轉移有關。Li等[28]發現，miR-339-5p可以抑制非小細胞肺癌的淋巴結轉移相關。

Chan等[29]首次發現，低表達的miR-149與乳腺癌患者的淋巴結轉移有密切關系。Yigit 等[30]提出，通過下調miR-10b的表達，可以阻止乳腺癌發生淋巴結轉移。Chen等[31]也發現，miR-10b 和miR-373可作為預測乳腺癌淋巴結轉移的生物標志物。Yang等[32]發現，miR-34可以抑制乳腺癌的侵襲和淋巴結轉移。研究[33-34]發現，發生淋巴結轉移的乳腺癌患者miR-200b表達下調。Gravgaard等[35]運用原位雜交實驗證實miR-200家族和miR-9參與了乳腺癌的遠處轉移。Zhang等[36]研究表明，miR-30a與乳腺癌患者的淋巴結轉移和肺轉移程度呈負相關。Corcoran等[37]發現，miR-21高表達與乳腺癌淋巴結轉移相關。Chu等[38]認為，miR-190a通過多種途徑抑制乳腺癌淋巴結轉移。Li等[39]研究證實，miR-720通過直接靶向下調TWIST1而抑制乳腺癌的轉移。

2.3miRNA與腹部腫瘤淋巴結轉移Zheng等[40]發現，miR-148a下調將會導致胃癌患者發生淋巴結轉移。Tang 等[41]發現，miR-200b、 miR-200c下調與胃癌的淋巴結轉移有關。有研究[42]表明，miR-146a表達降低對胃癌淋巴結轉移的發生起著重要的作用。Zheng 等[43]運用基因芯片和生物信息學分析證實，miR-409可以抑制胃癌細胞發生淋巴結轉移。Zhao等[44]發現，miR-7參與了胃癌上皮間質轉化及淋巴結轉移等生物學行為。Xu等[45]發現，miR-335的低表達和胃癌淋巴結轉移明顯相關。Feng等[46]發現，miR-126在胃癌淋巴結轉移中起著腫瘤抑制基因的作用。Shin 等[47]發現，miR-135a可以抑制胃癌淋巴結轉移。Xu等[48]發現，miR-21可以作為預測胃癌淋巴結轉移的生物標志物。Chen等[49]發現，miR-10a參與了胃癌淋巴結轉移的發生。

Yuan等[50]研究表明，在結直腸癌細胞中，miR-221和miR-224的表達水平與其淋巴結轉移以及腫瘤分期呈負相關。Siemens等[51]發現，miR-34a啟動子甲基化與結腸癌的遠處轉移有關。Toiyama等[52]發現，血清中高表達的miR-200c是結直腸癌淋巴結轉移的獨立預測因子(P=0.0005)。此外，Paterson等[53]也發現，高表達的miR-200家族參與了結直腸癌的淋巴結轉移。Chen等[54]研究發現，miR-103/107可以促進結直腸癌淋巴結轉移及遠處轉移。Yuan等[55]發現，miR-145表達上調在結直腸癌淋巴結轉移中起著重要的作用。Wang等[56]研究表明，miR-195 表達下降與結直腸癌淋巴結轉移及預后差有關。

Chen等[57]發現，發生淋巴結轉移患者的肝癌組織中，miR-100表達降低。Guo等[58]發現，在體外miR-34a的異常表達可以抑制Hepa1-6和HCa-F細胞的生長和侵襲；此外，miR-34a可以引起G1期阻滯，并且下調Hepa1-6 細胞中cyclinD1和CDK6的表達；而且該研究進一步發現miR-34a可以降低Hca-F細胞黏附到局域淋巴結的能力，進而抑制肝癌淋巴結轉移。

Caponi等[59]研究發現，高表達的miR-21與胰腺導管乳頭狀瘤淋巴結陽性相關(P=0.03)。He等[60]發現，miR-218和 ROBO-1 信號通路參與胰腺癌淋巴結轉移。

2.4miRNA與泌尿生殖系統腫瘤淋巴結轉移Brase等[61]發現，在前列腺癌淋巴結陽性患者的血清中，miR-375和miR-141水平升高。Spahn等[62]研究表明，低表達的miR-221有望成為預測前列腺癌淋巴結轉移的生物標志物。Chen等[63]發現，血清中的6個microRNAs ：miR-1246、miR-20a、miR-2392、miR-3147、miR-3162-5p、miR-4484，可預測早期宮頸癌的淋巴結轉移。Zhao 等[64]發現，可以根據血清中高表達的miR-20a和低表達的miR-203篩選出發生淋巴結轉移的早期宮頸癌患者。Yeh等[65]研究表明，miR-138低表達和SOX4高表達的卵巢癌患者更容易發生淋巴結轉移，且腫瘤分級較高，也更易出現腹水。de Melo等研究[66]發現，miR-223-5p和miR-19-b1-5p的下調與外陰腫瘤的淋巴結轉移相關，miR-100-3p 和miR-19-b1-5p的下調與外陰腫瘤的侵襲有關，miR-519b和miR-133a與其FIGO晚期有關。

3小結

近年來，miRNA與腫瘤淋巴結轉移的研究取得了較大進展，為腫瘤的基因診斷、治療提供了新靶點。然而，腫瘤淋巴結轉移的機制還不完全明了。如果能通過建立腫瘤淋巴結轉移的預測模型來預測淋巴結轉移的發生，篩選出腫瘤淋巴結轉移的高危人群，就能早期對其淋巴引流區進行預防性治療，降低淋巴結轉移，提高患者的生活質量，延長無瘤生存期。這將從根本上改變腫瘤淋巴結轉移的治療，即由出現淋巴結轉移后的姑息性被動治療轉變為積極預防淋巴結轉移的主動治療。因此，篩選腫瘤淋巴結轉移相關的miRNA、建立腫瘤淋巴結轉移的預測模型具有非常重要的意義，有助于指導個體化治療策略的制定。

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通訊作者向作林，E-mail: Xiangzuolinmd@hotmail.com

基金項目：上海市衛生局面上項目(編號：20124208)

中圖分類號R73-37

文獻標識碼A