miRNA在食管鳞癌发病和治疗中的作用机制

刘艳霞，张璐玉，崔艳艳，刘雯雯，黄团结，李　鹏，杨　璐，许　玲，张彦婷，关方霞

1)郑州大学生命科学学院 郑州 450001　2)郑州大学第一附属医院 郑州 450052

1　引言

食管癌是世界上最常见的上消化道恶性肿瘤，在世界癌症病死率排序中位居第6[1]。根据病理分型，食管癌可分为食管鳞癌和食管腺癌，而中国以食管鳞癌多发。河南、河北和山西三省交界的太行山地区是中国乃至世界上食管鳞癌发病率和病死率最高的地区。在中国北方其发病率超过100/100 000。食管鳞癌的发病机制尚不清楚，只有更好地理解疾病的分子特性，才能选择有效的临床诊断标志物和疾病治疗方式[2]。

miRNA是由18～22个核苷酸组成的单链RNA分子，通过靶向作用于特定mRNA的3’非编码区发挥其对靶基因的负向调控作用，从而参与细胞生长、分化、凋亡等生命活动[3]。研究[3]表明，miRNA作为一类新型的生物分子，在正常细胞和病变细胞中均发挥特定功能，且作为生物标志物具有潜在的临床价值，其异常表达与包括肿瘤在内的多种疾病的发生密切相关。本文就近年来不同miRNA在食管鳞癌发生和治疗中的作用机制进行了简要综述。

2　miRNA在食管鳞癌中的异常表达

miRNA能够调节细胞生长、增殖、分化和凋亡，在食管鳞癌的发展中发挥重要作用。针对食管鳞癌患者组织样本，通过基因芯片和二代测序技术，已发现食管鳞癌中大量miRNA表达异常。Kano等[4]研究发现，与癌旁正常组织相比，食管鳞癌组织中15个miRNA表达下调，且其中4个miRNA能够发挥抑癌作用(miRNA-145、miRNA-30a-3p、miRNA-133a和miRNA-133b)。Yao等[5]在食管鳞癌组织中发现了43个差异表达的miRNA(27个表达上调，16个表达下调)。Yang等[6]研究发现miRNA-338-3p、miRNA-218和hsa-miRNA-139-5p在食管鳞癌组织中表达上调，而miRNA-183、miRNA-574-5p、miRNA-21和miRNA-601表达下调。Hong等[7]研究发现在食管鳞癌组织中有12个miRNA异常表达，其中9个表达上调(miRNA-155、miRNA-100、miRNA-146、miRNA-296、miRNA-10b、miRNA-203、miRNA-483、miRNA-494和miRNA-220)，3个表达下调(miRNA-143、miRNA-375和miRNA-339)。Liu等[8]基于第2代基因测序技术鉴定出食管鳞癌miRNA表达谱中有78个差异表达的miRNA。这些miRNA在食管鳞癌中的异常表达进一步证明了miRNA的异常改变在食管鳞癌的发生发展中发挥了重要作用。

血清miRNA在个体中含量稳定，因此，患者血清miRNA检测有助于食管鳞癌的早期诊断和预测。Wu等[9]利用芯片检测了食管鳞癌患者和正常人血清中的miRNA，发现7个miRNA表达差异(miRNA-25、miRNA-100、miRNA-193-3p、miRNA-194、miRNA-223、miRNA-337-5p和miRNA-483-5p)。Zhang等[10]利用二代测序也识别了7个食管鳞癌患者特异的miRNA，分别为miRNA-10a、miRNA-22、miRNA-100、miRNA-148b、miRNA-223、miRNA-133a和miRNA-127-3p。此外，与正常人相比，食管鳞癌患者血清中miRNA-21表达上调、miRNA-375表达下调，二者与患者复发风险和存活率显著相关[11-12]。miRNA-200c在食管鳞癌患者血清中过表达，并与化疗敏感性相关。

3　食管鳞癌中致癌性miRNA

3.1miRNA-21miRNA-21在多种肿瘤组织中表达上调，是近年来在食管鳞癌中研究最多的miRNA。miRNA-21通过作用于多个靶基因进而调控细胞的增殖、凋亡、侵袭，如TPM1、PTEN、PDCD4等[13]。研究[11,14-16]发现，miRNA-21在食管鳞癌患者组织、血清、血浆及唾液中均表达上调，与患者预后差、低生存率相关。Tanaka等[17]发现血清miRNA-21主要存在于外泌体中，其含量高于正常人；外泌体穿梭miRNA-21能够影响食管鳞癌细胞增殖、凋亡、迁移能力，与食管鳞癌复发和远端转移密切相关[18]。miRNA-21表达水平与患者对化疗的响应相关，组织和血清中miRNA-21表达量高的患者对化疗的敏感性差[11]，在食管鳞癌细胞中下调miRNA-21能够提高PTEN的表达，进而通过抑制AKT活性提高细胞对化疗药物和放疗的敏感性[19]。此外，miRNA-21能够诱导肿瘤微环境中的细胞交流，从而使成纤维细胞转化成癌相关成纤维细胞[20]。

3.2miRNA-10bmiRNA-10b在食管鳞癌患者血清和唾液中均高表达[21-22]。研究[23]表明，miRNA-10b在食管鳞癌细胞中的表达水平与细胞迁移和侵袭能力有关，KLF4作为抑癌基因能够有效地抑制食管癌细胞的迁移和侵袭，miRNA-10b通过直接作用于KLF4发挥其致癌作用。此外，抑制基因TIP30具有促凋亡和抑制血管生成的作用，其表达量在食管鳞癌中受到启动子甲基化和miRNA-10b的共同调节[24]。

3.3miRNA-17-92基因多顺反子miRNA-17-92基因多顺反子是一个高度保守的基因簇，编码6个成熟的miRNA，包括miRNA-17、miRNA-18a、miRNA-19a、miRNA-19b、miRNA-20a和miRNA-92a，研究[25-26]表明其在食管鳞癌中均呈高表达。miRNA-19b的表达与肿瘤大小、淋巴结转移和临床分期呈正相关；miRNA-18a在食管鳞癌患者组织、血清和血浆中均呈高表达，与肿瘤分型呈正相关；miRNA-17a的过表达与淋巴结转移和临床分期呈正相关；miRNA-92a的表达与肿瘤临床分期和不良预后呈正相关[26-27]。Liu等[25]的研究表明miRNA-17-92基因多顺反子的过表达可从体内外促进细胞的生长，抑制miRNA-19a能够诱导食管鳞癌细胞凋亡，而TNF-α是miRNA-19a的直接靶点。miRNA-92a能够在体外调节食管鳞癌细胞的迁移和侵袭，但不能诱导细胞凋亡或抑制其增殖，并直接抑制靶基因肿瘤转移抑制因子CDH1的表达[27]。

3.4miRNA-25miRNA-25在食管鳞癌患者组织、血清和血浆中均呈高表达，与肿瘤的淋巴结转移和TNM分期高度相关[28-30]。miRNA-25能够通过直接作用于CDH1调节肿瘤细胞增殖，在食管鳞癌细胞中上调miRNA-25表达能显著增加癌细胞转移和侵袭能力，而下调miRNA-25表达能够抑制细胞转移[28]。此外，桥粒钙黏蛋白DSC2同样受到miRNA-25的直接调节，进而调控细胞侵袭[31]。

4　食管鳞癌中抑癌性miRNA

4.1let-7let-7是目前研究最为广泛的miRNA之一，在肿瘤中，let-7具有抑制细胞增殖、促进细胞分化和凋亡等多种生物学功能[32]。研究[33]表明，let-7在食管鳞癌中表达下调，HMGA2被认为是let-7的直接靶点，HMGA2在肿瘤中发挥致癌作用。Liu等[34]的体外实验表明let-7过表达后，HMGA2蛋白表达量下降，但在let-7过表达或抑制表达后，HMGA2 mRNA水平并没有发生明显变化。Sugimura等[35]发现let-7b和let-7c表达与食管鳞癌化疗耐药性相关，let-7c可通过下调IL-6表达进一步使其下游STAT3磷酸化，从而增强食管鳞癌细胞对顺铂的敏感性。此外，RNA结合蛋白Lin28能够在转录后水平选择性地阻断let-7家族的生物合成过程，Lin28在食管鳞癌组织中过表达，且与let-7低表达显著相关[36]。

4.2miRNA-375miRNA-375位于2q2.3，能够作用于多个信号通路，与食管鳞癌的发生发展关系密切[37]。食管鳞癌患者组织、血清和血浆中miRNA-375均呈低表达，食管鳞癌患者肿瘤的进展、转移和生存时间均与miRNA-375密切相关，多篇文献[15,30,38]认为致癌性miRNA-21和抑癌性miRNA-375能够作为有效的食管鳞癌分子标志物。miRNA-375的表达受到甲基化和乙酰化调控，在食管鳞癌组织中miRNA-375启动子高度甲基化，利用组蛋白去乙酰化酶抑制剂处理食管鳞癌细胞后，miRNA-375表达水平提高近千倍，且在临床样本中，LDHB和AEG-1/MTDH在mRNA和蛋白水平表达情况均与miRNA-375密切相关[38-39]。miRNA-375能够直接作用于PDK1，进而降低AKT的磷酸化水平，抑制细胞凋亡[38]。体外实验[40]表明，miRNA-375能够与IGF1R的3’末端非编码区相互作用下调其表达水平，且临床样本检测发现，miRNA-375表达水平与IGF1R的表达呈负相关。

4.3miRNA-145miRNA-145在多种肿瘤组织中呈低表达，在食管鳞癌中同样表达下调，与患者的淋巴结转移、无病生存期密切相关[41-42]。miRNA-145表达受甲基化调控，5-AZA去甲基化作用后miRNA-145表达量显著提高，在食管鳞癌组织中miRNA-145启动子甲基化程度明显高于正常组织[43]。研究[44]发现，P53能够通过与miRNA-145启动子相互作用诱导其转录，进而下调miRNA-145直接靶点c-Myc的表达，miRNA-145可能通过P53-c-Myc信号通路发挥其抑制肿瘤发生的作用。Wang等[45]证实在食管鳞癌细胞中过表达miRNA-145能够降低c-Myc的表达水平。Kano等[4]发现FSCN1是miRNA-145的另一个直接靶点，体外实验表明FSCN1表达下调能够抑制食管鳞癌细胞增殖和迁移。但针对食管鳞癌的组织样本检测发现，miRNA-145和FSCN1的表达水平并无线性相关[46]。此外，miRNA-145能直接作用于PLCE1的3’非编码区，敲除PLCE1能够在体外促进细胞凋亡，抑制细胞增殖及转移，且在食管鳞癌组织中miRNA-145与PLCE1表达呈负相关[47]。

4.4miRNA-34amiRNA-34a最近被证明是一个关键的肿瘤抑癌基因，能够调控参与细胞周期和凋亡的多种基因，包括CDK4、CDK6、细胞周期蛋白D1、E2F3、MYCN、SIRT1和bcl-2[48]。在食管鳞癌中，NF-κB能够直接与miRNA-34a启动子区结合，抑癌基因p53在NF-κB介导的miRNA-34a转录激活中是必不可少的[49]，而miRNA-34a的抗肿瘤活性主要依赖于SIRT1和P53/P21蛋白，与凋亡相关蛋白并不相关[50]。另一方面，miRNA-34a的转录受到甲基化调控，在食管鳞癌组织中，miRNA-34a的启动子CpG岛有明显甲基化，用甲基化抑制剂DAC处理细胞后，miRNA-34a的表达量明显提高[51]。此外，体外实验[52]表明在食管鳞癌中转录因子YY1是miRNA-34a的直接靶点，miRNA-34a能够通过YY1调节癌细胞侵袭和迁移。

4.5miRNA-143miRNA-143在多种肿瘤中表达降低，多项研究[53-55]证实在食管鳞癌组织中miRNA-143表达显著下降，与肿瘤复发、淋巴结转移、浸润和TNM分期相关。过表达miRNA-143能够在体内外水平抑制食管鳞癌细胞凋亡、转移和侵袭，促进细胞增殖，将细胞周期阻滞在G1/S期；荧光素酶实验[41,55-57]显示miRNA-143在食管鳞癌中的直接作用靶点包括STAT3、FAM83F、FSCN1和QKI-5，miRNA-143通过调节STAT3和FAM83F的表达抑制细胞周期和EMT信号通路，而过表达QKI-5能够消除miRNA-143引起的细胞增殖抑制作用。食管鳞癌组织样本检测结果表明，miRNA-143表达与FAM83F、QKI-5表达呈负相关，但与FSCN1表达无线性相关[41,56-57]。

5　食管鳞癌化疗中耐药相关miRNA

5.1miRNA-141miRNA-141位于人12号染色体上，在人上皮细胞类型的肿瘤中具有特定的表达模式。在食管鳞癌中，miRNA-141呈高表达，且与肿瘤分化程度和TNM分期相关，能够调节细胞对化疗药物的耐受性[58]。Imanaka等[59]研究发现，miRNA-141在顺铂耐药的食管鳞癌细胞株中高表达，能够通过直接作用于YAP1基因的3’非编码区下调其表达，增强细胞对顺铂的耐受性，而YAP1在造成DNA损伤的抗肿瘤药物引起的细胞凋亡中起关键作用。Jin等[58]研究发现在5-FU和奥沙利铂耐受性食管鳞癌细胞株中miRNA-141高表达，在体内外抑制其表达均能逆转肿瘤细胞对化疗药物的耐受性，且PTEN是miRNA-141的直接靶点，在组织中二者表达呈负相关。因此，miRNA-141可能在食管鳞癌细胞的顺铂耐药性中起着重要的调节作用。

5.2miRNA-27amiRNA-27a作为一种致癌基因，可调控细胞存活和血管的生成。在食管鳞癌组织和细胞中，miRNA-27a均高表达，能够与KRAS的3’非编码区结合而下调其表达，二者在组织中的表达呈负相关[60]。Tanaka等[61]检测了对化疗敏感与不敏感食管鳞癌患者血清中的miRNA，发现miRNA-27a表达量高的患者对化疗响应差，在食管鳞癌细胞中过表达miRNA-27a并不影响细胞的化疗敏感性，而将食管鳞癌细胞与过表达miRNA-27a的正常成纤维细胞上清液共培养，能够增强癌细胞对顺铂的耐受性。这是由于过表达miRNA-27a的正常成纤维细胞分泌α-SMA，增强了TGF-β的表达，从而影响食管鳞癌细胞对化疗药物的敏感性。Zhang等[62]的研究表明在食管鳞癌中下调miRNA-27a表达，能够增加细胞对化疗药物敏感性，显著抑制P-糖蛋白、Bcl-2的表达和多药耐药基因1的转录。

5.3miRNA-296miRNA-296与许多生理和病理过程有关，如癌变、胎儿乙醇综合征和胰岛素分泌[63]。在食管炎、食管原位癌和食管鳞癌组织中，miRNA-296的表达逐渐升高[7]。Ko等[46]针对伊立替康/顺铂和放疗前后的食管鳞癌组织进行miRNA检测，发现miRNA-296表达量变化2倍以上。下调miRNA-296可以在体内外通过调节细胞周期蛋白D1和P27来抑制食管鳞癌细胞的生长，通过增加胞内阿霉素含量促进细胞凋亡，进而提高癌细胞对化疗药物敏感性[7]。

5.4miRNA-200cmiRNA-200c作为致癌性miRNA，在肿瘤的诊断、上皮-间质转化和耐药等方面发挥重要作用，在食管鳞癌组织中发现miRNA-200c异常高表达[64]。Tanaka等[65]检测了接受新辅助疗法的食管鳞癌患者血清中的miRNA，发现miRNA-200c表达量明显高于正常人，并与生存期短和化疗响应差有关。Hamano等[66]对经过化疗的食管鳞癌患者癌组织进行检测后发现，miRNA-200c高表达与化疗不敏感相关，且顺铂抗性食管鳞癌细胞中miRNA-200c表达高于亲本细胞，抑制miRNA-200c表达能够提高细胞对顺铂的敏感性。因此，miRNA-200c在食管鳞癌中可以有效地预测化疗反应。

6　展望

目前针对食管鳞癌已发现许多综合性的miRNA表达谱，已经证实一些持续异常表达的miRNA，如miRNA-21、miRNA-10b和miRNA-200c等表达上调，miRNA-375、miRNA-203、let-7等表达下调，组织和血清中miRNA的表达有望成为食管鳞癌诊断的有效标志物。miRNA表达模式的改变对肿瘤抑癌基因和癌基因之间的平衡具有显著的影响，在食管鳞癌发生发展中发挥着关键作用，而miRNA在食管鳞癌多药耐药方面的作用同样不容忽视。因此，miRNA在癌症研究和治疗领域具有广泛的应用前景，基于miRNA的肿瘤治疗研究也在不断深入。然而，miRNA通过复杂的网络调控在肿瘤中发挥作用，虽然目前已取得了一些进展，但二者的关系仍远未完全揭示，miRNA在肿瘤临床治疗中的应用有待于进一步的研究。

[1] HONGO M,NAGASAKI Y,SHOJI T.Epidemiology of esophageal cancer: orient to occident.Effects of chronology, geography and ethnicity[J].J Gastroenterol Hepatol,2009,24(5):729

[2] OHASHI S,MIYAMOTO S,KIKUCHI O,et al.Recent advances from basic and clinical studies of esophageal squamous cell carcinoma[J].Gastroenterology,2015,149(7):1700

[3] ANGLICHEAU D,MUTHUKUMAR T,SUTHANTHIRAN M.MicroRNAs:small RNAs with big effects[J].Transplantation,2010,90(2):105

[4] KANO M,SEKI N,KIKKAWA N,et al.miR-145, miR-133a and miR-133b: tumor-suppressive miRNAs target FSCN1 in esophageal squamous cell carcinoma[J].Int J Cancer,2010,127(12):2804

[5] YAO L,ZHANG Y,ZHU Q,et al.Downregulation of microRNA-1 in esophageal squamous cell carcinoma correlates with an advanced clinical stage and its overexpression inhibits cell migration and invasion[J].Int J Mol Med,2015,35(4):1033

[6] YANG M,LIU R,SHENG J,et al.Differential expression profiles of microRNAs as potential biomarkers for the early diagnosis of esophageal squamous cell carcinoma[J].Oncol Rep,2013,29(1):169

[7] HONG L,HAN Y,ZHANG H,et al.The prognostic and chemotherapeutic value of miR-296 in esophageal squamous cell carcinoma[J].Ann Surg,2010,251(6):1056

[8] LIU R,GU J,JIANG P,et al.DNMT1-microRNA126 epigenetic circuit contributes to esophageal squamous cell carcinoma growth via ADAM9-EGFR-AKT signaling[J].Clin Cancer Res,2015,21(4):854

[9] WU C,WANG C,GUAN X,et al.Diagnostic and prognostic implications of a serum miRNA panel in oesophageal squamous cell carcinoma[J].PLoS One,2014,9(3):e92292

[10]ZHANG CN,WANG C,CHEN X,et al.Expression profile of microRNAs in serum: a fingerprint for esophageal squamous cell carcinoma[J].Clin Chem,2010,56(12):1871

[11]KURASHIGE J,KAMOHARA H,WATANABE M,et al.Serum microRNA-21 is a novel biomarker in patients with esophageal squamous cell carcinoma[J].J Surg Oncol,2012,106(2):188

[12]WINTHER M,ALSNER J,TRAMM T,et al.Evaluation of miR-21 and miR-375 as prognostic biomarkers in esophageal cancer[J].Acta Oncol (Madr),2015,54(9):1582

[13]SELCUKLU SD,DONOGHUE MT,SPILLANE C.miR-21 as a key regulator of oncogenic processes[J].Biochem Soc Trans,2009,37(Pt 4):918

[14]LI P,MAO WM,ZHENG ZG,et al.Down-regulation of PTEN expression modulated by dysregulated miR-21 contributes to the progression of esophageal cancer[J].Dig Dis Sci,2013,58(12):3483

[15]KOMATSU S,ICHIKAWA D,TAKESHITA H,et al.Prognostic impact of circulating miR-21 and miR-375 in plasma of patients with esophageal squamous cell carcinoma[J].Expert Opin Biol Ther,2012,12(1):S53

[16]XIE ZJ,CHEN G,ZHANG XC,et al.Saliva supernatant miR-21: a novel potential biomarker for esophageal cancer detection[J].Asian Pac J Cancer Prev,2012,13(12):6145

[17]TANAKA Y,KAMOHARA H,KINOSHITA KA,et al.Clinical impact of serum exosomal microRNA-21 as a clinical biomarker in human esophageal squamous cell carcinoma[J].Cancer,2013,119(6):1159

[18]LIAO J,LIU R,SHI YJ,et al.Exosome-shuttling microRNA-21 promotes cell migration and invasion-targeting PDCD4 in esophageal cancer[J].Int J Oncol,2016,48(6):2567

[19]HUANG S,LI XQ,CHEN X,et al.Inhibition of microRNA-21 increases radiosensitivity of esophageal cancer cells through phosphatase and tensin homolog deleted on chromosome 10 activation[J].Dis Esophagus,2013,26(8):823

[20]NOURAEE N,VAN ROOSBROECK K,VASEI M,et al.Expression, tissue distribution and function of miR-21 in esophageal squamous cell carcinoma[J].PLoS One,2013,8(9):e73009

[21]XIE ZJ,CHEN G,ZHANG XC,et al.Salivary microRNAs as promising biomarkers for detection of esophageal cancer[J].PLoS One,2013,8(4):e57502

[22]XU H,YAO YF,MENG FY,et al.Predictive value of serum miR-10b, miR-29c, and miR-205 as promising biomarkers in esophageal squamous cell carcinoma screening[J].Medicine,2015,94(44):e1558

[23]TIAN YY,LUO AP,CAI YR,et al.MicroRNA-10b promotes migration and invasion through KLF4 in human esophageal cancer cell lines[J].J Biol Chem,2010,285(11):7986

[24]DONG W,SHEN R,CHENG S.Reduction of TIP30 in esophageal squamous cell carcinoma cells involves promoter methylation and microRNA-10b[J].Biochem Biophys Res Commun,2014,453(4):772

[25]LIU M,WANG Z,YANG S,et al.TNF-α is a novel target of miR-19a[J].Int J Oncol,2011,38(4):1013

[26]XU XL,JIANG YH,FENG JG,et al.MicroRNA-17, microRNA-18a, and microRNA-19a are prognostic indicators in esophageal squamous cell carcinoma[J].Ann Thorac Surg,2014,97(3):1037

[27]CHEN ZL,ZHAO XH,WANG JW,et al.microRNA-92a promotes lymph node metastasis of human esophageal squamous cell carcinoma via E-cadherin[J].J Biol Chem,2011,286(12):10725

[28]XU X,CHEN Z,ZHAO X,et al.MicroRNA-25 promotes cell migration and invasion in esophageal squamous cell carcinoma[J].Biochem Biophys Res Commun,2012,421(4):640

[29]KOMATSU S,ICHIKAWA D,HIRAJIMA S,et al.Plasma microRNA profiles: identification of miR-25 as a novel diagnostic and monitoring biomarker in oesophageal squamous cell carcinoma[J].Br J Cancer,2014,111(8):1614

[30]WU C,LI M,HU C,et al.Clinical significance of serum miR-223, miR-25 and miR-375 in patients with esophageal squamous cell carcinoma[J].Mol Biol Rep,2014,41(3):1257

[31]FANG WK,LIAO LD,LI LY,et al.Down-regulated desmocollin-2 promotes cell aggressiveness through redistributing adherens junctions and activating beta-catenin signalling in oesophageal squamous cell carcinoma[J].J Pathol,2013,231(2):257

[32]REINHART BJ,SLACK FJ,BASSON M,et al.The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans[J].Nature,2000,403(6772):901

[33]LIU Q,LIU T,ZHENG S,et al.HMGA2 is down-regulated by microRNA let-7 and associated with epithelial-mesenchymal transition in oesophageal squamous cell carcinomas of Kazakhs[J].Histopathology,2014,65(3):408

[34]LIU Q,LV GD,QIN X,et al.Role of microRNA let-7 and effect to HMGA2 in esophageal squamous cell carcinoma[J].Mol Biol Rep,2012,39(2):1239

[35]SUGIMURA K,MIYATA H,TANAKA K,et al.Let-7 expression is a significant determinant of response to chemotherapy through the regulation of IL-6/STAT3 pathway in esophageal squamous cell carcinoma[J].Clin Cancer Res,2012,18(18):5144

[36]HAMANO R,MIYATA H,YAMASAKI M,et al.High expression of Lin28 is associated with tumour aggressiveness and poor prognosis of patients in oesophagus cancer[J].Br J Cancer,2012,106(8):1415

[37]KINOSHITA T,HANAZAWA T,NOHATA NA,et al.The functional significance of microRNA-375 in human squamous cell carcinoma: aberrant expression and effects on cancer pathways[J].J Hum Genet,2012,57(9):556

[38]LI X,LIN R,LI J.Epigenetic silencing of microRNA-375 regulates PDK1 expression in esophageal cancer[J].Dig Dis Sci,2011,56(10):2849

[39]ISOZAKI Y,HOSHINO I,NOHATA N,et al.Identification of novel molecular targets regulated by tumor suppressive miR-375 induced by histone acetylation in esophageal squamous cell carcinoma[J].Int J Oncol,2012,41(3):985

[40]KONG KL,KWONG DL,CHAN TH,et al.MicroRNA-375 inhibits tumour growth and metastasis in oesophageal squamous cell carcinoma through repressing insulin-like growth factor 1 receptor[J].Gut,2012,61(1):33

[41]LIU R,LIAO J,YANG M,et al.The cluster of miR-143 and miR-145 affects the risk for esophageal squamous cell carcinoma through co-regulating fascin homolog1[J].PLoS One,2012,7(3):e33987

[42]MAYNE GC,HUSSEY DJ,WATSON DI.Can miRNA profiling allow us to determine which patients with esophageal cancer will respond to chemoradiotherapy?[J].Expert Rev Anticancer Ther,2013,13(3):271

[43]HARADA K,BABA YS,KOSUMI K,et al.Suppressor microRNA-145 is epigenetically regulated by promoter hypermethylation in esophageal squamous cell carcinoma[J].Cancer Res,2015,75(15):4617

[44]MATSUSHIMA K,ISOMOTO H,YAMAGUCHI N,et al.MiRNA-205 modulates cellular invasion and migration via regulating zinc finger E-box binding homeobox 2 expression in esophageal squamous cell carcinoma cells[J].J Transl Med,2011,9:30

[45]WANG F,XIA J,WANG NC,et al.miR-145 inhibits proliferation and invasion of esophageal squamous cell carcinoma in part by targeting c-Myc[J].Onkologie,2013,36(12):754

[46]KO MA,ZEHONG G,VIRTANEN C,et al.MicroRNA expression profiling of esophageal cancer before and after induction chemoradiotherapy[J].Ann Thorac Surg,2012,94(4):1094

[47]CUI XB,LI S,LI TT,et al.Targeting oncogenic PLCE1 by miR-145 impairs tumor proliferation and metastasis of esophageal squamous cell carcinoma[J].Oncotarget,2016,7(2):1777

[48]LI L.Regulatory mechanisms and clinical perspectives of miR-34a in cancer[J].J Cancer Res Ther,2014,10(4):805

[49]LI J,WANG K,CHEN X,et al.Transcriptional activation of microRNA-34a by NF-kappa B in human esophageal cancer cells[J].BMC Mol Biol,2012,13:4

[50]YE Z,FANG J,DAI S,et al.MicroRNA-34a induces a senescence-like change via the down-regulation of SIRT1 and up-regulation of p53 protein in human esophageal squamous cancer cells with a wild-type p53 gene background[J].Cancer Lett,2016,370(2):216

[51]CHEN X,HU H,GUAN X,et al.CpG island methylation status of miRNAs in esophageal squamous cell carcinoma[J].Int J Cancer,2012,130(7):1607

[52]NIE J,GE X,GENG Y,et al.miR-34a inhibits the migration and invasion of esophageal squamous cell carcinoma by targeting Yin Yang-1[J].Oncol Rep,2015,34(1):311

[53]MAYNE GC,HUSSEY DJ,WATSON DI.MicroRNAs and esophageal cancer: implications for pathogenesis and therapy[J].Curr Pharm Des,2013,19(7):1211

[54]NI Y,MENG L,WANG L,et al.MicroRNA-143 functions as a tumor suppressor in human esophageal squamous cell carcinoma[J].Gene,2013,517(2):197

[55]LIU J,MAO Y,ZHANG D,et al.MiR-143 inhibits tumor cell proliferation and invasion by targeting STAT3 in esophageal squamous cell carcinoma[J].Cancer Lett,2016,373(1):97

[56]MAO Y,LIU J,ZHANG D,et al.miR-143 inhibits tumor progression by targeting FAM83F in esophageal squamous cell carcinoma[J].Tumor Biol,2016,37(7):9009

[57]HE ZY,YI J,LIU XL,et al.MiR-143-3p functions as a tumor suppressor by regulating cell proliferation, invasion and epithelial-mesenchymal transition by targeting QKI-5 in esophageal squamous cell carcinoma[J].Mol Cancer,2016,15(1):51

[58]JIN YY,CHEN QJ,XU K,et al.Involvement of microRNA-141-3p in 5-fluorouracil and oxaliplatin chemo-resistance in esophageal cancer cells via regulation of PTEN[J].Mol Cell Biochem,2016,422(1/2):161

[59]IMANAKA Y,TSUCHIYA S,SATO F,et al.MicroRNA-141 confers resistance to cisplatin-induced apoptosis by targeting YAP1 in human esophageal squamous cell carcinoma[J].J Hum Genet,2011,56(4):270

[60]ZHU LA,WANG ZJ,FAN QX,et al.microRNA-27a functions as a tumor suppressor in esophageal squamous cell carcinoma by targeting KRAS[J].Oncol Rep,2014,31(1):280

[61]TANAKA K,MIYATA H,SUGIMURA K,et al.miR-27 is associated with chemoresistance in esophageal cancer through transformation of normal fibroblasts to cancer-associated fibroblasts[J].Carcinogenesis,2015,36(8):894

[62]ZHANG H,LI M,HAN Y,et al.Down-regulation of miR-27a might reverse multidrug resistance of esophageal squamous cell carcinoma[J].Dig Dis Sci,2010,55(9):2545

[63]KAPOOR S.miR-296 and modulation of tumor growth in systemic malignancies[J].Ann Thorac Surg,2013,96(1):378

[64]ZHAO BS,LIU SG,WANG TY,et al.Screening of microRNA in patients with esophageal cancer at same tumor node metastasis stage with different prognoses[J].Asian Pac J Cancer Prev,2013,14(1):139

[65]TANAKA K,MIYATA H,YAMASAKI M,et al.Circulating miR-200c levels significantly predict response to chemotherapy and prognosis of patients undergoing neoadjuvant chemotherapy for esophageal cancer[J].Ann Surg Oncol,2013,20(Suppl 3):S607

[66]HAMANO R,MIYATA H,YAMASAKI M,et al.Overexpression of miR-200c induces chemoresistance in esophageal cancers mediated through activation of the Akt signaling pathway[J].Clin Cancer Res,2011,17(9):3029