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腫瘤淋巴結(jié)轉(zhuǎn)移相關(guān)MicroRNAs的研究進(jìn)展

張莉向作林

(復(fù)旦大學(xué)附屬中山醫(yī)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(gè)核苷酸的高度保守的非編碼小分子RNA，可以調(diào)節(jié)mRNA的翻譯[1]。miRNA結(jié)合到多種基因的mRNA的3’-非編碼區(qū)，導(dǎo)致靶向mRNA的降解及轉(zhuǎn)錄的終止[2]。miRNA作為信號(hào)通路的樞紐，參與多種生理病理過(guò)程，如細(xì)胞增殖、凋亡及腫瘤轉(zhuǎn)移[3-4]。越來(lái)越多的研究[5-6]表明，miRNAs可以發(fā)揮癌基因或者抑癌基因的作用，它們?cè)诙喾N腫瘤中的異常表達(dá)對(duì)腫瘤的侵襲和轉(zhuǎn)移有著重要的影響。因此，異常表達(dá)的miRNA有望成分預(yù)測(cè)腫瘤侵襲及轉(zhuǎn)移的生物標(biāo)志物。本文綜述了腫瘤淋巴結(jié)轉(zhuǎn)移相關(guān)miRNAs的研究進(jìn)展。

2miRNA與腫瘤淋巴結(jié)轉(zhuǎn)移

2.1miRNA與頭頸部腫瘤淋巴結(jié)轉(zhuǎn)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(dá)，并且通過(guò)轉(zhuǎn)化生長(zhǎng)因子-β1的介導(dǎo)抑制miR-200a和miR-200b的表達(dá)，從而導(dǎo)致鼻咽癌淋巴結(jié)轉(zhuǎn)移的發(fā)生。Luo等[8]發(fā)現(xiàn)，高表達(dá)的miR-18a與晚期鼻咽癌的淋巴結(jié)轉(zhuǎn)移相關(guān)。Huang等[9]發(fā)現(xiàn)，miR-491-5p 低表達(dá)與口腔鱗狀細(xì)胞癌淋巴結(jié)轉(zhuǎn)移有關(guān)。Lu等[10]研究發(fā)現(xiàn)，miR-196a/b在腫瘤組織中高度表達(dá)，并且與口腔癌淋巴結(jié)轉(zhuǎn)移密切相關(guān)。Yang等[11]研究表明，miR-181可以作為口腔鱗狀細(xì)胞癌淋巴結(jié)轉(zhuǎn)移的生物標(biāo)志物。Abraham 等[12]發(fā)現(xiàn)，miR-183 和miR-375的超表達(dá)與甲狀腺髓樣癌的對(duì)側(cè)淋巴結(jié)轉(zhuǎn)移相關(guān)(P<0.001、P=0.001)。Chou等[13]研究發(fā)現(xiàn)，miR-146b可以顯著增加甲狀腺乳頭狀癌細(xì)胞的遷移和侵襲。Wang等[14]發(fā)現(xiàn)，miR-2861和miR-451的低表達(dá)上調(diào)與甲狀腺髓樣癌淋巴結(jié)轉(zhuǎn)移密切相關(guān)。

2.2miRNA與胸部腫瘤淋巴結(jié)轉(zhuǎn)移有研究[15-17]表明，高表達(dá)的miR-21與食管鱗狀細(xì)胞癌的淋巴結(jié)轉(zhuǎn)移顯著相關(guān)。Huang等[18]發(fā)現(xiàn)，miR-98和 miR-214的表達(dá)水平與食管鱗狀細(xì)胞癌淋巴結(jié)轉(zhuǎn)移呈負(fù)相關(guān)。Zhang等[19]研究表明，發(fā)生淋巴結(jié)轉(zhuǎn)移的食管鱗狀細(xì)胞癌患者中miR-200b表達(dá)顯著下降。Wang等[20]發(fā)現(xiàn)，miR-196a的高表達(dá)與食管鱗狀細(xì)胞癌淋巴結(jié)轉(zhuǎn)移相關(guān)。Chen等[21]發(fā)現(xiàn)，miR-92a高表達(dá)的食管鱗狀細(xì)胞癌患者較低表達(dá)者更容易發(fā)生淋巴結(jié)轉(zhuǎn)移。

在非小細(xì)胞肺癌的研究中，Meng 等[22]應(yīng)用全基因組測(cè)序證實(shí)表達(dá)上調(diào)的miR-31可以預(yù)測(cè)肺腺癌患者淋巴結(jié)轉(zhuǎn)移，而且提示預(yù)后不良。Yu 等[23]發(fā)現(xiàn)，miR-193a-3p/5p低表達(dá)與非小細(xì)胞肺癌的TNM分期和淋巴結(jié)轉(zhuǎn)移明顯相關(guān)。Wang等[24]用基因芯片分析了非小細(xì)胞肺癌組織中miRNA的表達(dá)譜，發(fā)現(xiàn)了40個(gè)異常表達(dá)的miRNA，其中下調(diào)最明顯的miR-451與非小細(xì)胞肺癌的分化程度，病理分期和淋巴結(jié)轉(zhuǎn)移顯著相關(guān)。Roth 等[25]發(fā)現(xiàn)，肺癌患者血清中高表達(dá)的miR-10b與淋巴結(jié)轉(zhuǎn)移相關(guān)(P<0.03)。Wang等[26]的研究表明，miR-451的低表達(dá)水平與非小細(xì)胞肺癌的淋巴結(jié)轉(zhuǎn)移相關(guān)。Chen等[27]的研究表明，miR-148a的低表達(dá)與非小細(xì)胞肺癌的淋巴結(jié)轉(zhuǎn)移有關(guān)。Li等[28]發(fā)現(xiàn)，miR-339-5p可以抑制非小細(xì)胞肺癌的淋巴結(jié)轉(zhuǎn)移相關(guān)。

Chan等[29]首次發(fā)現(xiàn)，低表達(dá)的miR-149與乳腺癌患者的淋巴結(jié)轉(zhuǎn)移有密切關(guān)系。Yigit 等[30]提出，通過(guò)下調(diào)miR-10b的表達(dá)，可以阻止乳腺癌發(fā)生淋巴結(jié)轉(zhuǎn)移。Chen等[31]也發(fā)現(xiàn)，miR-10b 和miR-373可作為預(yù)測(cè)乳腺癌淋巴結(jié)轉(zhuǎn)移的生物標(biāo)志物。Yang等[32]發(fā)現(xiàn)，miR-34可以抑制乳腺癌的侵襲和淋巴結(jié)轉(zhuǎn)移。研究[33-34]發(fā)現(xiàn)，發(fā)生淋巴結(jié)轉(zhuǎn)移的乳腺癌患者miR-200b表達(dá)下調(diào)。Gravgaard等[35]運(yùn)用原位雜交實(shí)驗(yàn)證實(shí)miR-200家族和miR-9參與了乳腺癌的遠(yuǎn)處轉(zhuǎn)移。Zhang等[36]研究表明，miR-30a與乳腺癌患者的淋巴結(jié)轉(zhuǎn)移和肺轉(zhuǎn)移程度呈負(fù)相關(guān)。Corcoran等[37]發(fā)現(xiàn)，miR-21高表達(dá)與乳腺癌淋巴結(jié)轉(zhuǎn)移相關(guān)。Chu等[38]認(rèn)為，miR-190a通過(guò)多種途徑抑制乳腺癌淋巴結(jié)轉(zhuǎn)移。Li等[39]研究證實(shí)，miR-720通過(guò)直接靶向下調(diào)TWIST1而抑制乳腺癌的轉(zhuǎn)移。

2.3miRNA與腹部腫瘤淋巴結(jié)轉(zhuǎn)移Zheng等[40]發(fā)現(xiàn)，miR-148a下調(diào)將會(huì)導(dǎo)致胃癌患者發(fā)生淋巴結(jié)轉(zhuǎn)移。Tang 等[41]發(fā)現(xiàn)，miR-200b、 miR-200c下調(diào)與胃癌的淋巴結(jié)轉(zhuǎn)移有關(guān)。有研究[42]表明，miR-146a表達(dá)降低對(duì)胃癌淋巴結(jié)轉(zhuǎn)移的發(fā)生起著重要的作用。Zheng 等[43]運(yùn)用基因芯片和生物信息學(xué)分析證實(shí)，miR-409可以抑制胃癌細(xì)胞發(fā)生淋巴結(jié)轉(zhuǎn)移。Zhao等[44]發(fā)現(xiàn)，miR-7參與了胃癌上皮間質(zhì)轉(zhuǎn)化及淋巴結(jié)轉(zhuǎn)移等生物學(xué)行為。Xu等[45]發(fā)現(xiàn)，miR-335的低表達(dá)和胃癌淋巴結(jié)轉(zhuǎn)移明顯相關(guān)。Feng等[46]發(fā)現(xiàn)，miR-126在胃癌淋巴結(jié)轉(zhuǎn)移中起著腫瘤抑制基因的作用。Shin 等[47]發(fā)現(xiàn)，miR-135a可以抑制胃癌淋巴結(jié)轉(zhuǎn)移。Xu等[48]發(fā)現(xiàn)，miR-21可以作為預(yù)測(cè)胃癌淋巴結(jié)轉(zhuǎn)移的生物標(biāo)志物。Chen等[49]發(fā)現(xiàn)，miR-10a參與了胃癌淋巴結(jié)轉(zhuǎn)移的發(fā)生。

Yuan等[50]研究表明，在結(jié)直腸癌細(xì)胞中，miR-221和miR-224的表達(dá)水平與其淋巴結(jié)轉(zhuǎn)移以及腫瘤分期呈負(fù)相關(guān)。Siemens等[51]發(fā)現(xiàn)，miR-34a啟動(dòng)子甲基化與結(jié)腸癌的遠(yuǎn)處轉(zhuǎn)移有關(guān)。Toiyama等[52]發(fā)現(xiàn)，血清中高表達(dá)的miR-200c是結(jié)直腸癌淋巴結(jié)轉(zhuǎn)移的獨(dú)立預(yù)測(cè)因子(P=0.0005)。此外，Paterson等[53]也發(fā)現(xiàn)，高表達(dá)的miR-200家族參與了結(jié)直腸癌的淋巴結(jié)轉(zhuǎn)移。Chen等[54]研究發(fā)現(xiàn)，miR-103/107可以促進(jìn)結(jié)直腸癌淋巴結(jié)轉(zhuǎn)移及遠(yuǎn)處轉(zhuǎn)移。Yuan等[55]發(fā)現(xiàn)，miR-145表達(dá)上調(diào)在結(jié)直腸癌淋巴結(jié)轉(zhuǎn)移中起著重要的作用。Wang等[56]研究表明，miR-195 表達(dá)下降與結(jié)直腸癌淋巴結(jié)轉(zhuǎn)移及預(yù)后差有關(guān)。

Chen等[57]發(fā)現(xiàn)，發(fā)生淋巴結(jié)轉(zhuǎn)移患者的肝癌組織中，miR-100表達(dá)降低。Guo等[58]發(fā)現(xiàn)，在體外miR-34a的異常表達(dá)可以抑制Hepa1-6和HCa-F細(xì)胞的生長(zhǎng)和侵襲；此外，miR-34a可以引起G1期阻滯，并且下調(diào)Hepa1-6 細(xì)胞中cyclinD1和CDK6的表達(dá)；而且該研究進(jìn)一步發(fā)現(xiàn)miR-34a可以降低Hca-F細(xì)胞黏附到局域淋巴結(jié)的能力，進(jìn)而抑制肝癌淋巴結(jié)轉(zhuǎn)移。

Caponi等[59]研究發(fā)現(xiàn)，高表達(dá)的miR-21與胰腺導(dǎo)管乳頭狀瘤淋巴結(jié)陽(yáng)性相關(guān)(P=0.03)。He等[60]發(fā)現(xiàn)，miR-218和 ROBO-1 信號(hào)通路參與胰腺癌淋巴結(jié)轉(zhuǎn)移。

2.4miRNA與泌尿生殖系統(tǒng)腫瘤淋巴結(jié)轉(zhuǎn)移Brase等[61]發(fā)現(xiàn)，在前列腺癌淋巴結(jié)陽(yáng)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(dá)的miR-221有望成為預(yù)測(cè)前列腺癌淋巴結(jié)轉(zhuǎn)移的生物標(biāo)志物。Chen等[63]發(fā)現(xiàn)，血清中的6個(gè)microRNAs ：miR-1246、miR-20a、miR-2392、miR-3147、miR-3162-5p、miR-4484，可預(yù)測(cè)早期宮頸癌的淋巴結(jié)轉(zhuǎn)移。Zhao 等[64]發(fā)現(xiàn)，可以根據(jù)血清中高表達(dá)的miR-20a和低表達(dá)的miR-203篩選出發(fā)生淋巴結(jié)轉(zhuǎn)移的早期宮頸癌患者。Yeh等[65]研究表明，miR-138低表達(dá)和SOX4高表達(dá)的卵巢癌患者更容易發(fā)生淋巴結(jié)轉(zhuǎn)移，且腫瘤分級(jí)較高，也更易出現(xiàn)腹水。de Melo等研究[66]發(fā)現(xiàn)，miR-223-5p和miR-19-b1-5p的下調(diào)與外陰腫瘤的淋巴結(jié)轉(zhuǎn)移相關(guān)，miR-100-3p 和miR-19-b1-5p的下調(diào)與外陰腫瘤的侵襲有關(guān)，miR-519b和miR-133a與其FIGO晚期有關(guān)。

3小結(jié)

近年來(lái)，miRNA與腫瘤淋巴結(jié)轉(zhuǎn)移的研究取得了較大進(jìn)展，為腫瘤的基因診斷、治療提供了新靶點(diǎn)。然而，腫瘤淋巴結(jié)轉(zhuǎn)移的機(jī)制還不完全明了。如果能通過(guò)建立腫瘤淋巴結(jié)轉(zhuǎn)移的預(yù)測(cè)模型來(lái)預(yù)測(cè)淋巴結(jié)轉(zhuǎn)移的發(fā)生，篩選出腫瘤淋巴結(jié)轉(zhuǎn)移的高危人群，就能早期對(duì)其淋巴引流區(qū)進(jìn)行預(yù)防性治療，降低淋巴結(jié)轉(zhuǎn)移，提高患者的生活質(zhì)量，延長(zhǎng)無(wú)瘤生存期。這將從根本上改變腫瘤淋巴結(jié)轉(zhuǎn)移的治療，即由出現(xiàn)淋巴結(jié)轉(zhuǎn)移后的姑息性被動(dòng)治療轉(zhuǎn)變?yōu)榉e極預(yù)防淋巴結(jié)轉(zhuǎn)移的主動(dòng)治療。因此，篩選腫瘤淋巴結(jié)轉(zhuǎn)移相關(guān)的miRNA、建立腫瘤淋巴結(jié)轉(zhuǎn)移的預(yù)測(cè)模型具有非常重要的意義，有助于指導(dǎo)個(gè)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(xiàng)目：上海市衛(wèi)生局面上項(xiàng)目(編號(hào)：20124208)

中圖分類號(hào)R73-37

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