Gene expression profiling of drug-resistant small cell lung cancer cells by combining microRNA and cDNA expression analysis
Gene expression profiling of drug-resistant small cell lung cancer cells by combining microRNA and cDNA expression analysis
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DOI：
10.1016/j.ejca.2010.02.043
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发表时间：
2010-06-01
影响因子：
8.4
通讯作者：
Guo, Ying
中科院分区：
文献类型：
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作者：
Guo, Linlang;Liu, Yongguang;Guo, Ying
目前已知microRNA（miRNAs）在调控发育时序、细胞增殖和凋亡的基因表达中发挥重要作用。因此，它们也可能调节对抗癌药物的敏感性和耐药性。为了更好地了解SCLC多药耐药的分子机制并鉴定新的分子标记物，我们使用miRNA微阵列和cDNA微阵列评估了856个miRNA和22，000个相似基因在SCLC细胞模型中的表达，这些细胞模型被广泛用作对化疗敏感的细胞系（NCI-H69）和耐药的细胞系（NCI-H69 AR）。我们还分析了miRNA和mRNA表达模式之间的相关性。进一步的研究旨在确定差异表达的miRNAs是否参与SCLC的多药耐药。我们的结果显示，61个miRNAs被显著表达（>3倍），其中24个miRNAs表达上调，37个miRNAs表达下调。在61个差异表达的miRNAs中，有48个miRNAs与耐药密切相关，其中37.7%（24/61）的miRNAs基因可分为10个簇。我们还发现69个miRNAs中只有27个与MAS数据库中21，522 70个mRNA转录本中的604个显著相关。分别用miR-134、miR-379和miR-495的模拟物或非模拟物转染耐药H69 AR细胞后，对抗癌药物顺铂、依托泊苷和阿霉素的敏感性大大增加或降低。miR-134通过诱导H69 AR细胞中的G1期阻滞来增加细胞存活。MRP 1/ABCC 1受miR-134负调控，MRP 1/ABCC 1在蛋白水平的下调与H69 AR细胞中miR-134水平的升高在很大程度上相关。我们的研究结果首次支持了miRNAs在SCLC多药耐药中的重要作用。miR-134可能是H69 AR细胞中MRP 1/ABCC 1表达下调的原因之一。这些发现为这些miRNAs作为特异性诊断生物标志物和新的治疗方法用于SCLC耐药提供了有价值的信息。(C)2010爱思唯尔有限公司版权所有。
MicroRNAs (miRNAs) are now known to play important roles in the regulation of gene expression for developmental timing, cell proliferation and apoptosis. Therefore, it is likely that they also modulate sensitivity and resistance to anti-cancer drugs. To better understand the molecular mechanisms of multidrug resistance in SCLC and identify novel molecular markers, we evaluated the expression of 856 miRNAs and similar to 22,000 genes using miRNA microarray and cDNA microarray in cellular models of SCLC which were widely used as sensitive (NCI-H69) and resistant cell lines (NCI-H69AR) to chemotherapy. We also analysed the correlations between miRNA and mRNA expression patterns. Further studies were tested to determine whether the differentially expressed miRNAs were involved in multidrug resistance in SCLC. Our results showed that 61 miRNAs are presented significantly (>3-fold) including up-regulation of 24 miRNAs and down-regulation of 37 miRNAs. Among these miRNAs, 48 of 61 differentially expressed miRNAs were firstly reported to be closely associated with drug resistance and 37.7% (24/61) of miRNA genes were organised as 10 clusters in total 61 significantly expressed miRNAs. We also found that only 27 of 69 miRNAs were significantly correlated with 604 of 21,522 70 mRNA transcripts by MAS database. The sensitivity to anti-cancer drugs Cisplatin, Etoposide and Doxorubicin greatly increased or reduced following transfection of the drug-resistant H69AR cells with the mimics or antagomirs of miR-134, miR-379 and miR-495, respectively. miR-134 increases the cell survival by inducing G1 arrest in H69AR cells. MRP1/ABCC1 is negatively regulated by miR-134 and down-regulation of MRP1/ABCC1 at the protein level largely correlates with elevated levels of miR-134 in H69AR cells. Our results support for the first time a substantial role for miRNAs in multidrug resistance in SCLC. miR-134 could be a causal factor of the down-regulation of MRP1/ABCC1 in H69AR cells. These findings provide valuable information for potential utility of these miRNAs as specific diagnostic biomarkers and novel therapeutic approaches for drug resistance of SCLC. (C) 2010 Elsevier Ltd. All rights reserved.