劉艷霞，張璐玉，崔艷艷，劉雯雯，黃團(tuán)結(jié)，李　鵬，楊　璐，許　玲，張彥婷，關(guān)方霞

1)鄭州大學(xué)生命科學(xué)學(xué)院 鄭州 450001　2)鄭州大學(xué)第一附屬醫(yī)院 鄭州 450052

1　引言

食管癌是世界上最常見(jiàn)的上消化道惡性腫瘤，在世界癌癥病死率排序中位居第6[1]。根據(jù)病理分型，食管癌可分為食管鱗癌和食管腺癌，而中國(guó)以食管鱗癌多發(fā)。河南、河北和山西三省交界的太行山地區(qū)是中國(guó)乃至世界上食管鱗癌發(fā)病率和病死率最高的地區(qū)。在中國(guó)北方其發(fā)病率超過(guò)100/100 000。食管鱗癌的發(fā)病機(jī)制尚不清楚，只有更好地理解疾病的分子特性，才能選擇有效的臨床診斷標(biāo)志物和疾病治療方式[2]。

miRNA是由18～22個(gè)核苷酸組成的單鏈RNA分子，通過(guò)靶向作用于特定mRNA的3’非編碼區(qū)發(fā)揮其對(duì)靶基因的負(fù)向調(diào)控作用，從而參與細(xì)胞生長(zhǎng)、分化、凋亡等生命活動(dòng)[3]。研究[3]表明，miRNA作為一類新型的生物分子，在正常細(xì)胞和病變細(xì)胞中均發(fā)揮特定功能，且作為生物標(biāo)志物具有潛在的臨床價(jià)值，其異常表達(dá)與包括腫瘤在內(nèi)的多種疾病的發(fā)生密切相關(guān)。本文就近年來(lái)不同miRNA在食管鱗癌發(fā)生和治療中的作用機(jī)制進(jìn)行了簡(jiǎn)要綜述。

2　miRNA在食管鱗癌中的異常表達(dá)

miRNA能夠調(diào)節(jié)細(xì)胞生長(zhǎng)、增殖、分化和凋亡，在食管鱗癌的發(fā)展中發(fā)揮重要作用。針對(duì)食管鱗癌患者組織樣本，通過(guò)基因芯片和二代測(cè)序技術(shù)，已發(fā)現(xiàn)食管鱗癌中大量miRNA表達(dá)異常。Kano等[4]研究發(fā)現(xiàn)，與癌旁正常組織相比，食管鱗癌組織中15個(gè)miRNA表達(dá)下調(diào)，且其中4個(gè)miRNA能夠發(fā)揮抑癌作用(miRNA-145、miRNA-30a-3p、miRNA-133a和miRNA-133b)。Yao等[5]在食管鱗癌組織中發(fā)現(xiàn)了43個(gè)差異表達(dá)的miRNA(27個(gè)表達(dá)上調(diào)，16個(gè)表達(dá)下調(diào))。Yang等[6]研究發(fā)現(xiàn)miRNA-338-3p、miRNA-218和hsa-miRNA-139-5p在食管鱗癌組織中表達(dá)上調(diào)，而miRNA-183、miRNA-574-5p、miRNA-21和miRNA-601表達(dá)下調(diào)。Hong等[7]研究發(fā)現(xiàn)在食管鱗癌組織中有12個(gè)miRNA異常表達(dá)，其中9個(gè)表達(dá)上調(diào)(miRNA-155、miRNA-100、miRNA-146、miRNA-296、miRNA-10b、miRNA-203、miRNA-483、miRNA-494和miRNA-220)，3個(gè)表達(dá)下調(diào)(miRNA-143、miRNA-375和miRNA-339)。Liu等[8]基于第2代基因測(cè)序技術(shù)鑒定出食管鱗癌miRNA表達(dá)譜中有78個(gè)差異表達(dá)的miRNA。這些miRNA在食管鱗癌中的異常表達(dá)進(jìn)一步證明了miRNA的異常改變?cè)谑彻荀[癌的發(fā)生發(fā)展中發(fā)揮了重要作用。

血清miRNA在個(gè)體中含量穩(wěn)定，因此，患者血清miRNA檢測(cè)有助于食管鱗癌的早期診斷和預(yù)測(cè)。Wu等[9]利用芯片檢測(cè)了食管鱗癌患者和正常人血清中的miRNA，發(fā)現(xiàn)7個(gè)miRNA表達(dá)差異(miRNA-25、miRNA-100、miRNA-193-3p、miRNA-194、miRNA-223、miRNA-337-5p和miRNA-483-5p)。Zhang等[10]利用二代測(cè)序也識(shí)別了7個(gè)食管鱗癌患者特異的miRNA，分別為miRNA-10a、miRNA-22、miRNA-100、miRNA-148b、miRNA-223、miRNA-133a和miRNA-127-3p。此外，與正常人相比，食管鱗癌患者血清中miRNA-21表達(dá)上調(diào)、miRNA-375表達(dá)下調(diào)，二者與患者復(fù)發(fā)風(fēng)險(xiǎn)和存活率顯著相關(guān)[11-12]。miRNA-200c在食管鱗癌患者血清中過(guò)表達(dá)，并與化療敏感性相關(guān)。

3　食管鱗癌中致癌性miRNA

3.1miRNA-21miRNA-21在多種腫瘤組織中表達(dá)上調(diào)，是近年來(lái)在食管鱗癌中研究最多的miRNA。miRNA-21通過(guò)作用于多個(gè)靶基因進(jìn)而調(diào)控細(xì)胞的增殖、凋亡、侵襲，如TPM1、PTEN、PDCD4等[13]。研究[11,14-16]發(fā)現(xiàn)，miRNA-21在食管鱗癌患者組織、血清、血漿及唾液中均表達(dá)上調(diào)，與患者預(yù)后差、低生存率相關(guān)。Tanaka等[17]發(fā)現(xiàn)血清miRNA-21主要存在于外泌體中，其含量高于正常人；外泌體穿梭miRNA-21能夠影響食管鱗癌細(xì)胞增殖、凋亡、遷移能力，與食管鱗癌復(fù)發(fā)和遠(yuǎn)端轉(zhuǎn)移密切相關(guān)[18]。miRNA-21表達(dá)水平與患者對(duì)化療的響應(yīng)相關(guān)，組織和血清中miRNA-21表達(dá)量高的患者對(duì)化療的敏感性差[11]，在食管鱗癌細(xì)胞中下調(diào)miRNA-21能夠提高PTEN的表達(dá)，進(jìn)而通過(guò)抑制AKT活性提高細(xì)胞對(duì)化療藥物和放療的敏感性[19]。此外，miRNA-21能夠誘導(dǎo)腫瘤微環(huán)境中的細(xì)胞交流，從而使成纖維細(xì)胞轉(zhuǎn)化成癌相關(guān)成纖維細(xì)胞[20]。

3.2miRNA-10bmiRNA-10b在食管鱗癌患者血清和唾液中均高表達(dá)[21-22]。研究[23]表明，miRNA-10b在食管鱗癌細(xì)胞中的表達(dá)水平與細(xì)胞遷移和侵襲能力有關(guān)，KLF4作為抑癌基因能夠有效地抑制食管癌細(xì)胞的遷移和侵襲，miRNA-10b通過(guò)直接作用于KLF4發(fā)揮其致癌作用。此外，抑制基因TIP30具有促凋亡和抑制血管生成的作用，其表達(dá)量在食管鱗癌中受到啟動(dòng)子甲基化和miRNA-10b的共同調(diào)節(jié)[24]。

3.3miRNA-17-92基因多順?lè)醋觤iRNA-17-92基因多順?lè)醋邮且粋€(gè)高度保守的基因簇，編碼6個(gè)成熟的miRNA，包括miRNA-17、miRNA-18a、miRNA-19a、miRNA-19b、miRNA-20a和miRNA-92a，研究[25-26]表明其在食管鱗癌中均呈高表達(dá)。miRNA-19b的表達(dá)與腫瘤大小、淋巴結(jié)轉(zhuǎn)移和臨床分期呈正相關(guān)；miRNA-18a在食管鱗癌患者組織、血清和血漿中均呈高表達(dá)，與腫瘤分型呈正相關(guān)；miRNA-17a的過(guò)表達(dá)與淋巴結(jié)轉(zhuǎn)移和臨床分期呈正相關(guān)；miRNA-92a的表達(dá)與腫瘤臨床分期和不良預(yù)后呈正相關(guān)[26-27]。Liu等[25]的研究表明miRNA-17-92基因多順?lè)醋拥倪^(guò)表達(dá)可從體內(nèi)外促進(jìn)細(xì)胞的生長(zhǎng)，抑制miRNA-19a能夠誘導(dǎo)食管鱗癌細(xì)胞凋亡，而TNF-α是miRNA-19a的直接靶點(diǎn)。miRNA-92a能夠在體外調(diào)節(jié)食管鱗癌細(xì)胞的遷移和侵襲，但不能誘導(dǎo)細(xì)胞凋亡或抑制其增殖，并直接抑制靶基因腫瘤轉(zhuǎn)移抑制因子CDH1的表達(dá)[27]。

3.4miRNA-25miRNA-25在食管鱗癌患者組織、血清和血漿中均呈高表達(dá)，與腫瘤的淋巴結(jié)轉(zhuǎn)移和TNM分期高度相關(guān)[28-30]。miRNA-25能夠通過(guò)直接作用于CDH1調(diào)節(jié)腫瘤細(xì)胞增殖，在食管鱗癌細(xì)胞中上調(diào)miRNA-25表達(dá)能顯著增加癌細(xì)胞轉(zhuǎn)移和侵襲能力，而下調(diào)miRNA-25表達(dá)能夠抑制細(xì)胞轉(zhuǎn)移[28]。此外，橋粒鈣黏蛋白DSC2同樣受到miRNA-25的直接調(diào)節(jié)，進(jìn)而調(diào)控細(xì)胞侵襲[31]。

4　食管鱗癌中抑癌性miRNA

4.1let-7let-7是目前研究最為廣泛的miRNA之一，在腫瘤中，let-7具有抑制細(xì)胞增殖、促進(jìn)細(xì)胞分化和凋亡等多種生物學(xué)功能[32]。研究[33]表明，let-7在食管鱗癌中表達(dá)下調(diào)，HMGA2被認(rèn)為是let-7的直接靶點(diǎn)，HMGA2在腫瘤中發(fā)揮致癌作用。Liu等[34]的體外實(shí)驗(yàn)表明let-7過(guò)表達(dá)后，HMGA2蛋白表達(dá)量下降，但在let-7過(guò)表達(dá)或抑制表達(dá)后，HMGA2 mRNA水平并沒(méi)有發(fā)生明顯變化。Sugimura等[35]發(fā)現(xiàn)let-7b和let-7c表達(dá)與食管鱗癌化療耐藥性相關(guān)，let-7c可通過(guò)下調(diào)IL-6表達(dá)進(jìn)一步使其下游STAT3磷酸化，從而增強(qiáng)食管鱗癌細(xì)胞對(duì)順鉑的敏感性。此外，RNA結(jié)合蛋白Lin28能夠在轉(zhuǎn)錄后水平選擇性地阻斷l(xiāng)et-7家族的生物合成過(guò)程，Lin28在食管鱗癌組織中過(guò)表達(dá)，且與let-7低表達(dá)顯著相關(guān)[36]。

4.2miRNA-375miRNA-375位于2q2.3，能夠作用于多個(gè)信號(hào)通路，與食管鱗癌的發(fā)生發(fā)展關(guān)系密切[37]。食管鱗癌患者組織、血清和血漿中miRNA-375均呈低表達(dá)，食管鱗癌患者腫瘤的進(jìn)展、轉(zhuǎn)移和生存時(shí)間均與miRNA-375密切相關(guān)，多篇文獻(xiàn)[15,30,38]認(rèn)為致癌性miRNA-21和抑癌性miRNA-375能夠作為有效的食管鱗癌分子標(biāo)志物。miRNA-375的表達(dá)受到甲基化和乙?；{(diào)控，在食管鱗癌組織中miRNA-375啟動(dòng)子高度甲基化，利用組蛋白去乙?；敢种苿┨幚硎彻荀[癌細(xì)胞后，miRNA-375表達(dá)水平提高近千倍，且在臨床樣本中，LDHB和AEG-1/MTDH在mRNA和蛋白水平表達(dá)情況均與miRNA-375密切相關(guān)[38-39]。miRNA-375能夠直接作用于PDK1，進(jìn)而降低AKT的磷酸化水平，抑制細(xì)胞凋亡[38]。體外實(shí)驗(yàn)[40]表明，miRNA-375能夠與IGF1R的3’末端非編碼區(qū)相互作用下調(diào)其表達(dá)水平，且臨床樣本檢測(cè)發(fā)現(xiàn)，miRNA-375表達(dá)水平與IGF1R的表達(dá)呈負(fù)相關(guān)。

4.3miRNA-145miRNA-145在多種腫瘤組織中呈低表達(dá)，在食管鱗癌中同樣表達(dá)下調(diào)，與患者的淋巴結(jié)轉(zhuǎn)移、無(wú)病生存期密切相關(guān)[41-42]。miRNA-145表達(dá)受甲基化調(diào)控，5-AZA去甲基化作用后miRNA-145表達(dá)量顯著提高，在食管鱗癌組織中miRNA-145啟動(dòng)子甲基化程度明顯高于正常組織[43]。研究[44]發(fā)現(xiàn)，P53能夠通過(guò)與miRNA-145啟動(dòng)子相互作用誘導(dǎo)其轉(zhuǎn)錄，進(jìn)而下調(diào)miRNA-145直接靶點(diǎn)c-Myc的表達(dá)，miRNA-145可能通過(guò)P53-c-Myc信號(hào)通路發(fā)揮其抑制腫瘤發(fā)生的作用。Wang等[45]證實(shí)在食管鱗癌細(xì)胞中過(guò)表達(dá)miRNA-145能夠降低c-Myc的表達(dá)水平。Kano等[4]發(fā)現(xiàn)FSCN1是miRNA-145的另一個(gè)直接靶點(diǎn)，體外實(shí)驗(yàn)表明FSCN1表達(dá)下調(diào)能夠抑制食管鱗癌細(xì)胞增殖和遷移。但針對(duì)食管鱗癌的組織樣本檢測(cè)發(fā)現(xiàn)，miRNA-145和FSCN1的表達(dá)水平并無(wú)線性相關(guān)[46]。此外，miRNA-145能直接作用于PLCE1的3’非編碼區(qū)，敲除PLCE1能夠在體外促進(jìn)細(xì)胞凋亡，抑制細(xì)胞增殖及轉(zhuǎn)移，且在食管鱗癌組織中miRNA-145與PLCE1表達(dá)呈負(fù)相關(guān)[47]。

4.4miRNA-34amiRNA-34a最近被證明是一個(gè)關(guān)鍵的腫瘤抑癌基因，能夠調(diào)控參與細(xì)胞周期和凋亡的多種基因，包括CDK4、CDK6、細(xì)胞周期蛋白D1、E2F3、MYCN、SIRT1和bcl-2[48]。在食管鱗癌中，NF-κB能夠直接與miRNA-34a啟動(dòng)子區(qū)結(jié)合，抑癌基因p53在NF-κB介導(dǎo)的miRNA-34a轉(zhuǎn)錄激活中是必不可少的[49]，而miRNA-34a的抗腫瘤活性主要依賴于SIRT1和P53/P21蛋白，與凋亡相關(guān)蛋白并不相關(guān)[50]。另一方面，miRNA-34a的轉(zhuǎn)錄受到甲基化調(diào)控，在食管鱗癌組織中，miRNA-34a的啟動(dòng)子CpG島有明顯甲基化，用甲基化抑制劑DAC處理細(xì)胞后，miRNA-34a的表達(dá)量明顯提高[51]。此外，體外實(shí)驗(yàn)[52]表明在食管鱗癌中轉(zhuǎn)錄因子YY1是miRNA-34a的直接靶點(diǎn)，miRNA-34a能夠通過(guò)YY1調(diào)節(jié)癌細(xì)胞侵襲和遷移。

4.5miRNA-143miRNA-143在多種腫瘤中表達(dá)降低，多項(xiàng)研究[53-55]證實(shí)在食管鱗癌組織中miRNA-143表達(dá)顯著下降，與腫瘤復(fù)發(fā)、淋巴結(jié)轉(zhuǎn)移、浸潤(rùn)和TNM分期相關(guān)。過(guò)表達(dá)miRNA-143能夠在體內(nèi)外水平抑制食管鱗癌細(xì)胞凋亡、轉(zhuǎn)移和侵襲，促進(jìn)細(xì)胞增殖，將細(xì)胞周期阻滯在G1/S期；熒光素酶實(shí)驗(yàn)[41,55-57]顯示miRNA-143在食管鱗癌中的直接作用靶點(diǎn)包括STAT3、FAM83F、FSCN1和QKI-5，miRNA-143通過(guò)調(diào)節(jié)STAT3和FAM83F的表達(dá)抑制細(xì)胞周期和EMT信號(hào)通路，而過(guò)表達(dá)QKI-5能夠消除miRNA-143引起的細(xì)胞增殖抑制作用。食管鱗癌組織樣本檢測(cè)結(jié)果表明，miRNA-143表達(dá)與FAM83F、QKI-5表達(dá)呈負(fù)相關(guān)，但與FSCN1表達(dá)無(wú)線性相關(guān)[41,56-57]。

5　食管鱗癌化療中耐藥相關(guān)miRNA

5.1miRNA-141miRNA-141位于人12號(hào)染色體上，在人上皮細(xì)胞類型的腫瘤中具有特定的表達(dá)模式。在食管鱗癌中，miRNA-141呈高表達(dá)，且與腫瘤分化程度和TNM分期相關(guān)，能夠調(diào)節(jié)細(xì)胞對(duì)化療藥物的耐受性[58]。Imanaka等[59]研究發(fā)現(xiàn)，miRNA-141在順鉑耐藥的食管鱗癌細(xì)胞株中高表達(dá)，能夠通過(guò)直接作用于YAP1基因的3’非編碼區(qū)下調(diào)其表達(dá)，增強(qiáng)細(xì)胞對(duì)順鉑的耐受性，而YAP1在造成DNA損傷的抗腫瘤藥物引起的細(xì)胞凋亡中起關(guān)鍵作用。Jin等[58]研究發(fā)現(xiàn)在5-FU和奧沙利鉑耐受性食管鱗癌細(xì)胞株中miRNA-141高表達(dá)，在體內(nèi)外抑制其表達(dá)均能逆轉(zhuǎn)腫瘤細(xì)胞對(duì)化療藥物的耐受性，且PTEN是miRNA-141的直接靶點(diǎn)，在組織中二者表達(dá)呈負(fù)相關(guān)。因此，miRNA-141可能在食管鱗癌細(xì)胞的順鉑耐藥性中起著重要的調(diào)節(jié)作用。

5.2miRNA-27amiRNA-27a作為一種致癌基因，可調(diào)控細(xì)胞存活和血管的生成。在食管鱗癌組織和細(xì)胞中，miRNA-27a均高表達(dá)，能夠與KRAS的3’非編碼區(qū)結(jié)合而下調(diào)其表達(dá)，二者在組織中的表達(dá)呈負(fù)相關(guān)[60]。Tanaka等[61]檢測(cè)了對(duì)化療敏感與不敏感食管鱗癌患者血清中的miRNA，發(fā)現(xiàn)miRNA-27a表達(dá)量高的患者對(duì)化療響應(yīng)差，在食管鱗癌細(xì)胞中過(guò)表達(dá)miRNA-27a并不影響細(xì)胞的化療敏感性，而將食管鱗癌細(xì)胞與過(guò)表達(dá)miRNA-27a的正常成纖維細(xì)胞上清液共培養(yǎng)，能夠增強(qiáng)癌細(xì)胞對(duì)順鉑的耐受性。這是由于過(guò)表達(dá)miRNA-27a的正常成纖維細(xì)胞分泌α-SMA，增強(qiáng)了TGF-β的表達(dá)，從而影響食管鱗癌細(xì)胞對(duì)化療藥物的敏感性。Zhang等[62]的研究表明在食管鱗癌中下調(diào)miRNA-27a表達(dá)，能夠增加細(xì)胞對(duì)化療藥物敏感性，顯著抑制P-糖蛋白、Bcl-2的表達(dá)和多藥耐藥基因1的轉(zhuǎn)錄。

5.3miRNA-296miRNA-296與許多生理和病理過(guò)程有關(guān)，如癌變、胎兒乙醇綜合征和胰島素分泌[63]。在食管炎、食管原位癌和食管鱗癌組織中，miRNA-296的表達(dá)逐漸升高[7]。Ko等[46]針對(duì)伊立替康/順鉑和放療前后的食管鱗癌組織進(jìn)行miRNA檢測(cè)，發(fā)現(xiàn)miRNA-296表達(dá)量變化2倍以上。下調(diào)miRNA-296可以在體內(nèi)外通過(guò)調(diào)節(jié)細(xì)胞周期蛋白D1和P27來(lái)抑制食管鱗癌細(xì)胞的生長(zhǎng)，通過(guò)增加胞內(nèi)阿霉素含量促進(jìn)細(xì)胞凋亡，進(jìn)而提高癌細(xì)胞對(duì)化療藥物敏感性[7]。

5.4miRNA-200cmiRNA-200c作為致癌性miRNA，在腫瘤的診斷、上皮-間質(zhì)轉(zhuǎn)化和耐藥等方面發(fā)揮重要作用，在食管鱗癌組織中發(fā)現(xiàn)miRNA-200c異常高表達(dá)[64]。Tanaka等[65]檢測(cè)了接受新輔助療法的食管鱗癌患者血清中的miRNA，發(fā)現(xiàn)miRNA-200c表達(dá)量明顯高于正常人，并與生存期短和化療響應(yīng)差有關(guān)。Hamano等[66]對(duì)經(jīng)過(guò)化療的食管鱗癌患者癌組織進(jìn)行檢測(cè)后發(fā)現(xiàn)，miRNA-200c高表達(dá)與化療不敏感相關(guān)，且順鉑抗性食管鱗癌細(xì)胞中miRNA-200c表達(dá)高于親本細(xì)胞，抑制miRNA-200c表達(dá)能夠提高細(xì)胞對(duì)順鉑的敏感性。因此，miRNA-200c在食管鱗癌中可以有效地預(yù)測(cè)化療反應(yīng)。

6　展望

目前針對(duì)食管鱗癌已發(fā)現(xiàn)許多綜合性的miRNA表達(dá)譜，已經(jīng)證實(shí)一些持續(xù)異常表達(dá)的miRNA，如miRNA-21、miRNA-10b和miRNA-200c等表達(dá)上調(diào)，miRNA-375、miRNA-203、let-7等表達(dá)下調(diào)，組織和血清中miRNA的表達(dá)有望成為食管鱗癌診斷的有效標(biāo)志物。miRNA表達(dá)模式的改變對(duì)腫瘤抑癌基因和癌基因之間的平衡具有顯著的影響，在食管鱗癌發(fā)生發(fā)展中發(fā)揮著關(guān)鍵作用，而miRNA在食管鱗癌多藥耐藥方面的作用同樣不容忽視。因此，miRNA在癌癥研究和治療領(lǐng)域具有廣泛的應(yīng)用前景，基于miRNA的腫瘤治療研究也在不斷深入。然而，miRNA通過(guò)復(fù)雜的網(wǎng)絡(luò)調(diào)控在腫瘤中發(fā)揮作用，雖然目前已取得了一些進(jìn)展，但二者的關(guān)系仍遠(yuǎn)未完全揭示，miRNA在腫瘤臨床治療中的應(yīng)用有待于進(jìn)一步的研究。

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