Association of epigenetic inactivation of the WRN gene with anticancer drug sensitivity in cervical cancer cells.
Association of epigenetic inactivation of the WRN gene with anticancer drug sensitivity in cervical cancer cells.
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DOI：
10.3892/or.2012.1912
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发表时间：
2012-10
期刊：
影响因子：
4.2
通讯作者：
Aoki D
中科院分区：
文献类型：
--
作者：
Masuda K;Banno K;Yanokura M;Tsuji K;Kobayashi Y;Kisu I;Ueki A;Yamagami W;Nomura H;Tominaga E;Susumu N;Aoki D
Werner（WRN）基因编码DNA解旋酶，有助于基因组的稳定性，并已被确定为负责早衰症的基因。最近的研究表明，由于癌细胞中异常的DNA超甲基化，WRN表达减少。此外，WRN表达被认为影响癌症治疗中对DNA拓扑异构酶I抑制剂的敏感性。在这项研究中，我们研究了WRN异常DNA超甲基化与宫颈癌细胞对抗癌药物敏感性之间的关系。从22例原发性宫颈癌患者和6个人宫颈癌衍生细胞系的样品中提取DNA。通过甲基化特异性PCR分析异常DNA超甲基化。使用RT-PCR检测在加入脱甲基剂5-氮杂-2-脱氧胞苷之前和之后培养的细胞中WRN的表达。使用胶原凝胶液滴包埋培养物药物敏感性试验（CD-DST）测定细胞对抗癌药物的敏感性。将针对WRN的siRNA转染到具有高WRN表达的宫颈癌衍生细胞系中。通过CD-DST测定沉默WRN后药物敏感性的变化。在7/21例原发性宫颈癌和两个宫颈癌衍生细胞系中检测到异常DNA高甲基化和WRN表达降低。这两种细胞系对拓扑异构酶I抑制剂CPT-11表现出高敏感性，但在用5-氮杂-2-脱氧胞苷处理后变得对CPT-11耐药。针对WRN的siRNA的转染增加了细胞对CPT-11的敏感性。WRN的异常DNA超甲基化也增加了宫颈癌细胞对CPT-11的敏感性。因此，该基因的表观遗传失活可能是选择治疗宫颈癌药物的生物标志物。这是第一份显示WRN基因甲基化与妇科癌症对CPT-11敏感性之间关系的报告。
The Werner (WRN) gene codes for a DNA helicase that contributes to genomic stability and has been identified as the gene responsible for progeria. Recent studies have shown reduced WRN expression due to aberrant DNA hypermethylation in cancer cells. Furthermore, WRN expression is thought to affect sensitivity to DNA topoisomerase I inhibitors in cancer therapy. In this study, we examined the relationship between aberrant DNA hypermethylation of WRN and the sensitivity of cervical cancer cells to anticancer drugs. DNA was extracted from samples from 22 patients with primary cervical cancer and 6 human cervical cancer-derived cell lines. Aberrant DNA hypermethylation was analyzed by methylation-specific PCR. WRN expression in cultured cells before and after addition of 5-aza-2-deoxycytidine, a demethylating agent, was examined using RT-PCR. The sensitivity of cells to anticancer drugs was determined using a collagen gel droplet embedded culture drug sensitivity test (CD-DST). siRNA against WRN was transfected into a cervical cancer-derived cell line with high WRN expression. Changes in drug sensitivity after silencing WRN were determined by CD-DST. Aberrant DNA hypermethylation and decreased expression of WRN were detected in 7/21 cases of primary cervical cancer and in two cervical cancer-derived cell lines. These two cell lines showed high sensitivity to CPT-11, a topoisomerase I inhibitor, but became resistant to CPT-11 after treatment with 5-aza-2-deoxycytidine. Transfection of siRNA against WRN increased the sensitivity of the cells to CPT-11. Aberrant DNA hypermethylation of WRN also increased the sensitivity of cervical cancer cells to CPT-11. Therefore, epigenetic inactivation of this gene may be a biomarker for selection of drugs for the treatment of cervical cancer. This is the first report to show a relationship between the methylation of the WRN gene and sensitivity to CPT-11 in gynecological cancers.
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