miRNA在食管鱗癌發病和治療中的作用機制

劉艷霞，張璐玉，崔艷艷，劉雯雯，黃團結，李　鵬，楊　璐，許　玲，張彥婷，關方霞

1)鄭州大學生命科學學院 鄭州 450001　2)鄭州大學第一附屬醫院 鄭州 450052

1　引言

食管癌是世界上最常見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]。根據病理分型，食管癌可分為食管鱗癌和食管腺癌，而中國以食管鱗癌多發。河南、河北和山西三省交界的太行山地區是中國乃至世界上食管鱗癌發病率和病死率最高的地區。在中國北方其發病率超過100/100 000。食管鱗癌的發病機制尚不清楚，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志物和疾病治療方式[2]。

miRNA是由18～22個核苷酸組成的單鏈RNA分子，通過靶向作用于特定mRNA的3’非編碼區發揮其對靶基因的負向調控作用，從而參與細胞生長、分化、凋亡等生命活動[3]。研究[3]表明，miRNA作為一類新型的生物分子，在正常細胞和病變細胞中均發揮特定功能，且作為生物標志物具有潛在的臨床價值，其異常表達與包括腫瘤在內的多種疾病的發生密切相關。本文就近年來不同miRNA在食管鱗癌發生和治療中的作用機制進行了簡要綜述。

2　miRNA在食管鱗癌中的異常表達

miRNA能夠調節細胞生長、增殖、分化和凋亡，在食管鱗癌的發展中發揮重要作用。針對食管鱗癌患者組織樣本，通過基因芯片和二代測序技術，已發現食管鱗癌中大量miRNA表達異常。Kano等[4]研究發現，與癌旁正常組織相比，食管鱗癌組織中15個miRNA表達下調，且其中4個miRNA能夠發揮抑癌作用(miRNA-145、miRNA-30a-3p、miRNA-133a和miRNA-133b)。Yao等[5]在食管鱗癌組織中發現了43個差異表達的miRNA(27個表達上調，16個表達下調)。Yang等[6]研究發現miRNA-338-3p、miRNA-218和hsa-miRNA-139-5p在食管鱗癌組織中表達上調，而miRNA-183、miRNA-574-5p、miRNA-21和miRNA-601表達下調。Hong等[7]研究發現在食管鱗癌組織中有12個miRNA異常表達，其中9個表達上調(miRNA-155、miRNA-100、miRNA-146、miRNA-296、miRNA-10b、miRNA-203、miRNA-483、miRNA-494和miRNA-220)，3個表達下調(miRNA-143、miRNA-375和miRNA-339)。Liu等[8]基于第2代基因測序技術鑒定出食管鱗癌miRNA表達譜中有78個差異表達的miRNA。這些miRNA在食管鱗癌中的異常表達進一步證明了miRNA的異常改變在食管鱗癌的發生發展中發揮了重要作用。

血清miRNA在個體中含量穩定，因此，患者血清miRNA檢測有助于食管鱗癌的早期診斷和預測。Wu等[9]利用芯片檢測了食管鱗癌患者和正常人血清中的miRNA，發現7個miRNA表達差異(miRNA-25、miRNA-100、miRNA-193-3p、miRNA-194、miRNA-223、miRNA-337-5p和miRNA-483-5p)。Zhang等[10]利用二代測序也識別了7個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表達上調、miRNA-375表達下調，二者與患者復發風險和存活率顯著相關[11-12]。miRNA-200c在食管鱗癌患者血清中過表達，并與化療敏感性相關。

3　食管鱗癌中致癌性miRNA

3.1miRNA-21miRNA-21在多種腫瘤組織中表達上調，是近年來在食管鱗癌中研究最多的miRNA。miRNA-21通過作用于多個靶基因進而調控細胞的增殖、凋亡、侵襲，如TPM1、PTEN、PDCD4等[13]。研究[11,14-16]發現，miRNA-21在食管鱗癌患者組織、血清、血漿及唾液中均表達上調，與患者預后差、低生存率相關。Tanaka等[17]發現血清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胞增殖、凋亡、遷移能力，與食管鱗癌復發和遠端轉移密切相關[18]。miRNA-21表達水平與患者對化療的響應相關，組織和血清中miRNA-21表達量高的患者對化療的敏感性差[11]，在食管鱗癌細胞中下調miRNA-21能夠提高PTEN的表達，進而通過抑制AKT活性提高細胞對化療藥物和放療的敏感性[19]。此外，miRNA-21能夠誘導腫瘤微環境中的細胞交流，從而使成纖維細胞轉化成癌相關成纖維細胞[20]。

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

3.3miRNA-17-92基因多順反子miRNA-17-92基因多順反子是一個高度保守的基因簇，編碼6個成熟的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。miRNA-19b的表達與腫瘤大小、淋巴結轉移和臨床分期呈正相關；miRNA-18a在食管鱗癌患者組織、血清和血漿中均呈高表達，與腫瘤分型呈正相關；miRNA-17a的過表達與淋巴結轉移和臨床分期呈正相關；miRNA-92a的表達與腫瘤臨床分期和不良預后呈正相關[26-27]。Liu等[25]的研究表明miRNA-17-92基因多順反子的過表達可從體內外促進細胞的生長，抑制miRNA-19a能夠誘導食管鱗癌細胞凋亡，而TNF-α是miRNA-19a的直接靶點。miRNA-92a能夠在體外調節食管鱗癌細胞的遷移和侵襲，但不能誘導細胞凋亡或抑制其增殖，并直接抑制靶基因腫瘤轉移抑制因子CDH1的表達[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，與腫瘤的淋巴結轉移和TNM分期高度相關[28-30]。miRNA-25能夠通過直接作用于CDH1調節腫瘤細胞增殖，在食管鱗癌細胞中上調miRNA-25表達能顯著增加癌細胞轉移和侵襲能力，而下調miRNA-25表達能夠抑制細胞轉移[28]。此外，橋粒鈣黏蛋白DSC2同樣受到miRNA-25的直接調節，進而調控細胞侵襲[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具有抑制細胞增殖、促進細胞分化和凋亡等多種生物學功能[32]。研究[33]表明，let-7在食管鱗癌中表達下調，HMGA2被認為是let-7的直接靶點，HMGA2在腫瘤中發揮致癌作用。Liu等[34]的體外實驗表明let-7過表達后，HMGA2蛋白表達量下降，但在let-7過表達或抑制表達后，HMGA2 mRNA水平并沒有發生明顯變化。Sugimura等[35]發現let-7b和let-7c表達與食管鱗癌化療耐藥性相關，let-7c可通過下調IL-6表達進一步使其下游STAT3磷酸化，從而增強食管鱗癌細胞對順鉑的敏感性。此外，RNA結合蛋白Lin28能夠在轉錄后水平選擇性地阻斷let-7家族的生物合成過程，Lin28在食管鱗癌組織中過表達，且與let-7低表達顯著相關[36]。

4.2miRNA-375miRNA-375位于2q2.3，能夠作用于多個信號通路，與食管鱗癌的發生發展關系密切[37]。食管鱗癌患者組織、血清和血漿中miRNA-375均呈低表達，食管鱗癌患者腫瘤的進展、轉移和生存時間均與miRNA-375密切相關，多篇文獻[15,30,38]認為致癌性miRNA-21和抑癌性miRNA-375能夠作為有效的食管鱗癌分子標志物。miRNA-375的表達受到甲基化和乙酰化調控，在食管鱗癌組織中miRNA-375啟動子高度甲基化，利用組蛋白去乙酰化酶抑制劑處理食管鱗癌細胞后，miRNA-375表達水平提高近千倍，且在臨床樣本中，LDHB和AEG-1/MTDH在mRNA和蛋白水平表達情況均與miRNA-375密切相關[38-39]。miRNA-375能夠直接作用于PDK1，進而降低AKT的磷酸化水平，抑制細胞凋亡[38]。體外實驗[40]表明，miRNA-375能夠與IGF1R的3’末端非編碼區相互作用下調其表達水平，且臨床樣本檢測發現，miRNA-375表達水平與IGF1R的表達呈負相關。

4.3miRNA-145miRNA-145在多種腫瘤組織中呈低表達，在食管鱗癌中同樣表達下調，與患者的淋巴結轉移、無病生存期密切相關[41-42]。miRNA-145表達受甲基化調控，5-AZA去甲基化作用后miRNA-145表達量顯著提高，在食管鱗癌組織中miRNA-145啟動子甲基化程度明顯高于正常組織[43]。研究[44]發現，P53能夠通過與miRNA-145啟動子相互作用誘導其轉錄，進而下調miRNA-145直接靶點c-Myc的表達，miRNA-145可能通過P53-c-Myc信號通路發揮其抑制腫瘤發生的作用。Wang等[45]證實在食管鱗癌細胞中過表達miRNA-145能夠降低c-Myc的表達水平。Kano等[4]發現FSCN1是miRNA-145的另一個直接靶點，體外實驗表明FSCN1表達下調能夠抑制食管鱗癌細胞增殖和遷移。但針對食管鱗癌的組織樣本檢測發現，miRNA-145和FSCN1的表達水平并無線性相關[46]。此外，miRNA-145能直接作用于PLCE1的3’非編碼區，敲除PLCE1能夠在體外促進細胞凋亡，抑制細胞增殖及轉移，且在食管鱗癌組織中miRNA-145與PLCE1表達呈負相關[47]。

4.4miRNA-34amiRNA-34a最近被證明是一個關鍵的腫瘤抑癌基因，能夠調控參與細胞周期和凋亡的多種基因，包括CDK4、CDK6、細胞周期蛋白D1、E2F3、MYCN、SIRT1和bcl-2[48]。在食管鱗癌中，NF-κB能夠直接與miRNA-34a啟動子區結合，抑癌基因p53在NF-κB介導的miRNA-34a轉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，與凋亡相關蛋白并不相關[50]。另一方面，miRNA-34a的轉錄受到甲基化調控，在食管鱗癌組織中，miRNA-34a的啟動子CpG島有明顯甲基化，用甲基化抑制劑DAC處理細胞后，miRNA-34a的表達量明顯提高[51]。此外，體外實驗[52]表明在食管鱗癌中轉錄因子YY1是miRNA-34a的直接靶點，miRNA-34a能夠通過YY1調節癌細胞侵襲和遷移。

4.5miRNA-143miRNA-143在多種腫瘤中表達降低，多項研究[53-55]證實在食管鱗癌組織中miRNA-143表達顯著下降，與腫瘤復發、淋巴結轉移、浸潤和TNM分期相關。過表達miRNA-143能夠在體內外水平抑制食管鱗癌細胞凋亡、轉移和侵襲，促進細胞增殖，將細胞周期阻滯在G1/S期；熒光素酶實驗[41,55-57]顯示miRNA-143在食管鱗癌中的直接作用靶點包括STAT3、FAM83F、FSCN1和QKI-5，miRNA-143通過調節STAT3和FAM83F的表達抑制細胞周期和EMT信號通路，而過表達QKI-5能夠消除miRNA-143引起的細胞增殖抑制作用。食管鱗癌組織樣本檢測結果表明，miRNA-143表達與FAM83F、QKI-5表達呈負相關，但與FSCN1表達無線性相關[41,56-57]。

5　食管鱗癌化療中耐藥相關miRNA

5.1miRNA-141miRNA-141位于人12號染色體上，在人上皮細胞類型的腫瘤中具有特定的表達模式。在食管鱗癌中，miRNA-141呈高表達，且與腫瘤分化程度和TNM分期相關，能夠調節細胞對化療藥物的耐受性[58]。Imanaka等[59]研究發現，miRNA-141在順鉑耐藥的食管鱗癌細胞株中高表達，能夠通過直接作用于YAP1基因的3’非編碼區下調其表達，增強細胞對順鉑的耐受性，而YAP1在造成DNA損傷的抗腫瘤藥物引起的細胞凋亡中起關鍵作用。Jin等[58]研究發現在5-FU和奧沙利鉑耐受性食管鱗癌細胞株中miRNA-141高表達，在體內外抑制其表達均能逆轉腫瘤細胞對化療藥物的耐受性，且PTEN是miRNA-141的直接靶點，在組織中二者表達呈負相關。因此，miRNA-141可能在食管鱗癌細胞的順鉑耐藥性中起著重要的調節作用。

5.2miRNA-27amiRNA-27a作為一種致癌基因，可調控細胞存活和血管的生成。在食管鱗癌組織和細胞中，miRNA-27a均高表達，能夠與KRAS的3’非編碼區結合而下調其表達，二者在組織中的表達呈負相關[60]。Tanaka等[61]檢測了對化療敏感與不敏感食管鱗癌患者血清中的miRNA，發現miRNA-27a表達量高的患者對化療響應差，在食管鱗癌細胞中過表達miRNA-27a并不影響細胞的化療敏感性，而將食管鱗癌細胞與過表達miRNA-27a的正常成纖維細胞上清液共培養，能夠增強癌細胞對順鉑的耐受性。這是由于過表達miRNA-27a的正常成纖維細胞分泌α-SMA，增強了TGF-β的表達，從而影響食管鱗癌細胞對化療藥物的敏感性。Zhang等[62]的研究表明在食管鱗癌中下調miRNA-27a表達，能夠增加細胞對化療藥物敏感性，顯著抑制P-糖蛋白、Bcl-2的表達和多藥耐藥基因1的轉錄。

5.3miRNA-296miRNA-296與許多生理和病理過程有關，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的表達逐漸升高[7]。Ko等[46]針對伊立替康/順鉑和放療前后的食管鱗癌組織進行miRNA檢測，發現miRNA-296表達量變化2倍以上。下調miRNA-296可以在體內外通過調節細胞周期蛋白D1和P27來抑制食管鱗癌細胞的生長，通過增加胞內阿霉素含量促進細胞凋亡，進而提高癌細胞對化療藥物敏感性[7]。

5.4miRNA-200cmiRNA-200c作為致癌性miRNA，在腫瘤的診斷、上皮-間質轉化和耐藥等方面發揮重要作用，在食管鱗癌組織中發現miRNA-200c異常高表達[64]。Tanaka等[65]檢測了接受新輔助療法的食管鱗癌患者血清中的miRNA，發現miRNA-200c表達量明顯高于正常人，并與生存期短和化療響應差有關。Hamano等[66]對經過化療的食管鱗癌患者癌組織進行檢測后發現，miRNA-200c高表達與化療不敏感相關，且順鉑抗性食管鱗癌細胞中miRNA-200c表達高于親本細胞，抑制miRNA-200c表達能夠提高細胞對順鉑的敏感性。因此，miRNA-200c在食管鱗癌中可以有效地預測化療反應。

6　展望

目前針對食管鱗癌已發現許多綜合性的miRNA表達譜，已經證實一些持續異常表達的miRNA，如miRNA-21、miRNA-10b和miRNA-200c等表達上調，miRNA-375、miRNA-203、let-7等表達下調，組織和血清中miRNA的表達有望成為食管鱗癌診斷的有效標志物。miRNA表達模式的改變對腫瘤抑癌基因和癌基因之間的平衡具有顯著的影響，在食管鱗癌發生發展中發揮著關鍵作用，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域具有廣泛的應用前景，基于miRNA的腫瘤治療研究也在不斷深入。然而，miRNA通過復雜的網絡調控在腫瘤中發揮作用，雖然目前已取得了一些進展，但二者的關系仍遠未完全揭示，miRNA在腫瘤臨床治療中的應用有待于進一步的研究。

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