目的：探讨miR-135a在小细胞肺癌（small cell lung cancer，SCLC）多药耐药中的作用。方法：收集2008年1月至2013年12月本院肿瘤科及呼吸内科就诊的48例SCLC患者外周血液标本，将其分为化疗敏感组（28例）和耐药组（20例），采用QRT-PCR法检测患者血液标本、SCLC敏感细胞株H69及耐药细胞株H69AR中miR-135a的表达，分析其与临床预后的关系，并应用miR-135a模拟物和抑制剂分别上、下调细胞株中miR-135a的表达，采用CCK-8法检测细胞对各种化疗药物（ADM、DDP和VP-16）敏感性的影响。结果：与化疗敏感组相比，miR-135a在化疗耐药患者血液标本中的表达明显增高\[（2.174±3.981） vs （-1.963±3.750）， P <0.001\]；在临床患者血液标本中，miR-135a的表达与患者的性别、年龄无关( P >0.05)，与疾病的分期、化疗敏感性及患者的生存时间相关（均 P <0.01）。miR-135a在H69AR细胞中的表达明显高于H69细胞\[（7.841±0.392） vs （1.047±0.081）， P <0.01\]；通过miR-135a抑制剂下调H69AR中miR-135a的表达能够显著增加细胞对化疗药物的敏感性，H69AR细胞对DDP、ADM及VP-16的 IC 50值明显下降\[(247.09±11.55) vs (76.64±10.00)、（150.83±8.03） vs (40.72±5.06)、（436.63±61.19） vs (163.35±20.00)；H69细胞转染miR-135a mimics后对化疗药物DDP、ADM和VP-16的 IC50值明显增加\[(18.58±1.37) vs (159.27±3.29)、（24.37±2.63） vs (129.19±2.64)，(48.55±2.59) vs (359.87±2.92) μg/ml， P <0.01\]。结论： miR-135a参与调节SCLC的多药耐药，下调miR-135a基因的表达可能增加细胞对化疗药物的敏感性。

Objective: To investigate the role of miR-135a in regulating multi-drug resistance of small cell lung cancer. Methods: The expression of miR-135a was assessed by qRT-PCR in peripheral blood samples collected from 48 patients with SCLC admitted to our department between Janurary 2008 and December 2013, which include both chemotherapy responders (28 patients) and non-responders (20 patients). The relationships between miR-135a expression and treatment response, clinical pathological features, and prognosis of patients were analyzed. We also determined the expression of miR-135a in the drug-sensitive SCLC H69 cells and drug-resistant H69AR cell line by qRT-PCR and examined the effects of miR-135a mimics and inhibitor on the sensitivities of H69 and H69AR to chemotherapy drugs ADM, DDP, VP-16 by CCK-8 assay. Results: The level of miR-135a was significantly increased in SCLC non-responders compared with that in the responders \[(2.174±3.981） vs （-1.963±3.750）， P <0.001\]. While it is not correlated with gender and age of the patients ( P >0.05), miR-135a level is statistically correlated with clinical stage, chemosensitivity and overall survival (all P <0.05). The expression of miR-135a was also markedly increased in H69AR cells compared with that in the H69 cells \[(7.841±0.392) vs (1.047±0.081)， P <0.01\]. The drug-sensitivities H69 cells became more resistant to chemotherapeutics DDP, ADM and VP-16 after transfected with miR-135a mimics, and exhibited significantly increased IC 50 \[(18.58±1.37) vs (159.27±3.29)，（24.37±2.63） vs （129.19±2.64），and（48.55±2.59） vs （359.87±2.92）μg/ml，all P <0.01\]. Furthermore, the drug-resistant H69AR cells became more sensitive to these drugs when miR135a was downregulated, and had markedly decreased IC 50 \[(247.09±11.55) vs (76.64±10.00)，（150.83±8.03） vs （40.72±5.06），（436.63±61.19） vs （163.35±20.00）μg/ml；all P <0.01\]. Conclusion: In small cell lung cancer, miR-135a participates in the regulation of the sensitivities to multi-chemotheraputic drugs, and downregulation of miR-135a may reverses the multidrug resistance.

广东省医学科研基金（No. B2014310）