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首页> 外文期刊>Epigenetics: official journal of the DNA Methylation Society >Integrated analysis of DNA methylation and mRNA expression profiling reveals candidate genes associated with cisplatin resistance in non-small cell lung cancer
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Integrated analysis of DNA methylation and mRNA expression profiling reveals candidate genes associated with cisplatin resistance in non-small cell lung cancer

机译：DNA甲基化和mRNA表达谱的综合分析显示非小细胞肺癌中与顺铂耐药相关的候选基因

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摘要

DNA methylation plays a critical role during the development of acquired chemoresistance. The aim of this study was to identify candidate DNA methylation drivers of cisplatin (DDP) resistance in non-small cell lung cancer (NSC LC). The A549/DDP cell line was established by continuous exposure of A549 cells to increasing concentrations of DDP. Gene expression and methylation profiling were determined by high-throughput microarrays. Relationship of methylation status and DDP response was validated in primary tumor cell culture and the Cancer Genome Atlas (TCGA) samples. Cell proliferation, apoptosis, cell cycle, and response to DDP were determined in vitro and in vivo. A total of 372 genes showed hypermethylation and downregulation in A549/DDP cells, and these genes were involved in most fundamental biological processes. Ten candidate genes (S100P, GDA, WISP2, LOXL1, TIMP4, ICAM1, CLMP, HSP8, GAS1, BMP2) were selected, and exhibited varying degrees of association with DDP resistance. Low dose combination of 5-aza-2′-deoxycytidine (5-AzadC) and trichostatin A (TSA) reversed drug resistance of A549/DDP cells in vitro and in vivo, along with demethylation and restoration of expression of candidate genes (GAS1, TIMP4, ICAM1 and WISP2). Forced expression of GAS 1 in A549/ DDP cells by gene transfection contributed to increased sensitivity to DDP, proliferation inhibition, cell cycle arrest, apoptosis enhancement, and in vivo growth retardation. Together, our study demonstrated that a panel of candidate genes downregulated by DNA methylation induced DDP resistance in NSC LC, and showed that epigenetic therapy resensitized cells to DDP.
机译：DNA甲基化在获得性化学抗性的发展过程中起着至关重要的作用。这项研究的目的是确定非小细胞肺癌（NSC LC）中顺铂（DDP）耐药性的候选DNA甲基化驱动程序。通过将A549细胞连续暴露于不断增加的DDP浓度来建立A549 / DDP细胞系。基因表达和甲基化分析由高通量微阵列确定。在原发肿瘤细胞培养和癌症基因组图谱（TCGA）样品中验证了甲基化状态与DDP反应的关系。在体外和体内测定细胞增殖，凋亡，细胞周期和对DDP的反应。共有372个基因在A549 / DDP细胞中显示出高度甲基化和下调，这些基因参与了最基本的生物学过程。选择了十个候选基因（S100P，GDA，WISP2，LOXL1，TIMP4，ICAM1，CLMP，HSP8，GAS1，BMP2），并显示出与DDP抗性相关的不同程度。 5-氮杂2'-脱氧胞苷（5-AzadC）和曲古抑菌素A（TSA）的低剂量组合可在体内和体外逆转A549 / DDP细胞的耐药性，以及脱甲基作用和候选基因表达的恢复（GAS1， TIMP4，ICAM1和WISP2）。基因转染在A549 / DDP细胞中强迫表达GAS 1有助于增加对DDP的敏感性，增殖抑制，细胞周期停滞，细胞凋亡增强和体内生长迟缓。在一起，我们的研究表明，一组被DNA甲基化下调的候选基因在NSC LC中诱导了DDP抗性，并表明表观遗传学疗法使细胞对DDP敏感。

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