Alteration of gene expression and DNA methylation in drug-resistant gastric cancer
Alteration of gene expression and DNA methylation in drug-resistant gastric cancer
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DOI：
10.3892/or.2014.3014
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发表时间：
2014-04-01
期刊：
影响因子：
4.2
通讯作者：
Goto, Hidemi
中科院分区：
文献类型：
--
作者：
Maeda, Osamu;Ando, Takafumi;Goto, Hidemi
癌症的耐药机制尚未完全阐明。为了研究胃癌的耐药性，我们分析了5-氟尿嘧啶（5-FU）和顺铂（CDDP）耐药胃癌细胞和活检标本的基因表达和DNA甲基化谱。在含5-FU或CDDP的培养基中培养100 ~ 10个月建立耐药胃癌细胞。内镜活检标本来自于口服氟嘧啶S-1和CDDP化疗的胃癌患者。基因表达和DNA甲基化分析使用微阵列进行，并分别使用实时PCR和焦磷酸测序进行验证。在17933个基因中，541个基因在5-FU-和cdp -耐药AGS细胞中普遍升高，569个基因普遍降低。在5-FU和cddp处理的细胞中，药物改变表达的基因与氧化石墨烯术语“细胞外区域”和“p53信号通路”有关。2例患者化疗后耐药细胞和活检标本中，KLK13等15个基因表达升高，ETV7等12个基因表达降低。在表达微阵列和甲基化微阵列评估的10,365个基因中，74个基因在5- fu耐药或cdp耐药细胞中被高甲基化和下调，或低甲基化和上调。在这些基因中，21个基因的表达，包括FSCN1， CPT1C和NOTCH3，在使用去甲基化剂后增加。耐药胃癌中基因表达和DNA甲基化的改变；它们可能与耐药机制有关，并可能作为胃癌药物敏感性的生物标志物。
The mechanisms of drug resistance in cancer are not fully elucidated. To study the drug resistance of gastric cancer, we analyzed gene expression and DNA methylation profiles of 5-fluorouracil (5-FU)- and cisplatin (CDDP)-resistant gastric cancer cells and biopsy specimens. Drug-resistant gastric cancer cells were established with culture for >10 months in a medium containing 5-FU or CDDP. Endoscopic biopsy specimens were obtained from gastric cancer patients who underwent chemotherapy with oral fluoropyrimidine S-1 and CDDP. Gene expression and DNA methylation analyses were performed using microarray, and validated using real-time PCR and pyrosequencing, respectively. Out of 17,933 genes, 541 genes commonly increased and 569 genes decreased in both 5-FU- and CDDP-resistant AGS cells. Genes with expression changed by drugs were related to GO term 'extracellular region' and 'p53 signaling pathway' in both 5-FU- and CDDP-treated cells. Expression of 15 genes including KLK13 increased and 12 genes including ETV7 decreased, in both drug-resistant cells and biopsy specimens of two patients after chemotherapy. Out of 10,365 genes evaluated with both expression microarray and methylation microarray, 74 genes were hypermethylated and downregulated, or hypomethylated and upregulated in either 5-FU-resistant or CDDP-resistant cells. Of these genes, expression of 21 genes including FSCN1, CPT1C and NOTCH3, increased from treatment with a demethylating agent. There are alterations of gene expression and DNA methylation in drug-resistant gastric cancer; they may be related to mechanisms of drug resistance and may be useful as biomarkers of gastric cancer drug sensitivity.