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Liuyang GONG
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Jiaxi FENG
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Usausapharmacy A Usa Szh 1 Usa Usa Pharmacy Advances of MicroRNA in Lung Cancer | GONG | Usa Usa Pharmacy Chinese Journal of Lung Cancer
Usausapharmacy A Usa Szh 1 Usa Usa Pharmacy
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search促使其增殖[18]。Hayashita 等[19]用DNA印迹法发现miR-17-92在肺癌尤其小细胞肺癌上表达显著增加，体外细胞转染miR-17-92后，可以促使肿瘤细胞增殖。利用反义单核苷酸肽片段抑制miR-17-5p，可诱导高表达miR-17-92的肺癌细胞凋亡。同时发现，miR-17-92可以通过调节myc/E2F基因家族发挥转录后调节作用，而myc、E2F可以负反馈调节miR-17-92的表达。但关于miR-17-92促肺癌血管生长的作用及机制需进一步研究。
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肿瘤中基因甲基化是较普遍的现象，抑癌基因甲基化沉默促进肿瘤的增殖、转移，并且与某些耐药相关。目前发现miRNA在其中也具有某些作用。Fabbri等[20]研究NSCLC发现miRNA-29家族可以与DNA甲基转移酶（DNMT）-3A、-3B的3'UTR互补结合，而体内外重建miR-29s均使异常甲基化的沉默抑癌基因重新表达，包括FHIT及WWOX。miRNA基因甲基化可使自身功能丧失，研究[21]发现miR-34b/c在淋巴结转移癌细胞中的表达与其超甲基化沉默相关，在转染甲基化miR-34小鼠体内重新引入miR-34后，可以逆转肿瘤运动性、减小瘤体并抑制远处转移，该作用与miR-34下调C-MYC、E2F3、TGIF2等致癌基因水平相关。
4 miRNA的早期诊断价值
目前miRNA相关研究均提示其具有组织特异性，不同的肿瘤甚至肿瘤亚型中有不同的表达水平，故miRNA有望作为一种可靠的诊断指标，并且可以预示某些临床特征。对比正常肺组织，肺鳞癌中15种miRNA表达异常，包括miR-17-92，miRNA-55及let-7，后两者对腺癌同样具有诊断意义，而miR-146b对肺鳞癌诊断具有最高的敏感性[22]。对比环境烟草暴露28天后小鼠及非暴露组小鼠肺中126种miRNA的表达，发现let-7、miR-10、miR-26、miR-30、miR-34、miR-122、miR-123、miR-124、miR-125、miR-140、miR-145下降2倍以上；而miR-294表达上升[23]，说明在肿瘤发生早期，如缺氧等危险因素压力诱导下，miRNA即参与细胞基因调控、信号转化，参与癌前病变的发生，故可以作为早期预测或干预因素进一步研究。另外发现，miRNA的表达与细胞分化水平相关。Mascaux C等[24]利用荧光支气管镜活检正常组织、异常增生、原位癌、浸润性鳞癌等不同病理过程组织，发现miR-32、miR-34c表达呈线性下降，miR-142-3p、miR-9则上升。
5 miRNA相关的治疗前景
多项研究表明miRNA在肿瘤组织中的异常表达与预后相关，Junichi等[25]随访肺癌术后患者，let-7低表达是独立于肿瘤分期的预后因素（hazard ratio=2.17）。肺癌细胞中miR-34显著下降，与NSCLC术后低缓解率相关。另外发现miR-21、miR-182、miR-372、miR-137及miR-221均与肺癌预后相关，而miR-372与肺癌转移相关，与肿瘤发生关系不大[26]。另外，Li等[27]体外研究发现肿瘤细胞miRNA与化疗耐药相关，通过调节microtubule-associated protein kinases 等耐药相关基因蛋白的表达，能改善肿瘤对药物的敏感性，可以作为化疗耐药预测及调节手段进一步研究。
Shin等[28]研究A549细胞分别接受20 Gy、40 Gy放射剂量后，miRNA表达变化情况发现，分别有4种、10种miRNA表达改变；有8种在两者中都有改变。这些变化的miRNA与放射引起的细胞凋亡、细胞周期调控及DNA损失修复相关。提示miRNA与放射治疗有关，其具体疗效或预后相关性需要进一步的临床研究。
鉴于miRNA的特性，通过调节其表达控制肿瘤的生物学行为是目前肿瘤治疗的新策略。包括两方面的研究：①重建miRNA的表达。该方法主要应用在miRNA表达下降或受抑制的情况下。目前研究基本停留在体外细胞阶段，可以通过合成目标miRNA类似物或引入特异miRNA的DNA载体，增加miRNA前体合成，增加miRNA的表达。达到miRNA潜在治疗作用，需要更多的研究，尤其体内研究模型的构建；②抗miRNAs，即利用反义寡核苷酸直接结合miRNA阻断其活性。体外试验表明2，-MOEs（2, -O-methoxyethyl oligonucleotides）是强效的抗miRNA。最早的相关体内试验是Esau等利用2，-MOE抗miRNA-122特异性对抗肝miRNA-122的表达。他们还通过引入多miRNA结合位点的mRNA消耗过表达miRNA的抑制作用，保护内源性mRNA[29]。
总之，miRNA以其独特的转录后调节机制，广泛参与肺癌的发生发展。在肺癌的早期诊断、个体化治疗及预后中有重大意义，但在其临床应用前尚需更多的深入研究。
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