Yang San-Duk, Ahn So Hee, Kim Jong-Il
Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea.
Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 110-799, Republic of Korea.
Oncol Lett. 2018 Feb;15(2):2611-2618. doi: 10.3892/ol.2017.7560. Epub 2017 Dec 8.
Ovarian cancer (OC) is the second leading cause of mortality from gynecological malignancies and has the highest mortality rate worldwide. As it is commonly asymptomatic during the early stages of the disease, >70% of patients with OC are diagnosed at advanced stages with metastasis. Despite treatment methods, including optimal debulking surgery and chemotherapy with the platinum-based drug cisplatin, OC recurrence is often inevitable, with an overall 5-year survival rate of 45%, mostly due to the steady development of cisplatin resistance. To identify genes involved in cisplatin resistance, the present study determined the half-maximal inhibitory concentrations of eight different OC cell lines and classified them into two groups (sensitive and resistant). mRNA expression was analyzed with GeneChip Human Gene 1.0 ST Arrays, and DNA methylation profiles were evaluated with the HumanMethylation450 BeadChip. Using an integrated approach of analyzing gene expression levels and DNA methylation profiles simultaneously, 26 genes were selected that were differentially expressed and methylated between the resistant and sensitive groups. Among these 26 genes, 3-oxoacid CoA transferase 1 (), which was demonstrated to be downregulated and hypermethylated at promoter CpGs in the cisplatin-resistant group compared with the cisplatin-sensitive group, was selected for further investigation. Treatment with a DNA methyltransferase inhibitor restored hypermethylation-mediated gene silencing of in the cisplatin-resistant group, but not in the cisplatin-sensitive group. Furthermore, overexpression of conferred sensitivity to cisplatin in OC cells. The results of the present study suggest that serves an important role in conferring cisplatin sensitivity, and may provide a potential therapeutic target for cisplatin chemotherapy in patients with recurrent OC.
卵巢癌（OC）是妇科恶性肿瘤致死的第二大原因，在全球范围内死亡率最高。由于该病在早期通常没有症状，超过70%的OC患者在出现转移的晚期阶段才被诊断出来。尽管有包括最佳肿瘤细胞减灭术和使用铂类药物顺铂进行化疗等治疗方法，但OC复发往往不可避免，总体5年生存率为45%，这主要是由于顺铂耐药性的不断发展。为了鉴定与顺铂耐药相关的基因，本研究测定了八种不同OC细胞系的半数最大抑制浓度，并将它们分为两组（敏感组和耐药组）。使用基因芯片人类基因1.0 ST阵列分析mRNA表达，并用人甲基化450芯片评估DNA甲基化谱。通过同时分析基因表达水平和DNA甲基化谱的综合方法，选择了26个在耐药组和敏感组之间差异表达和甲基化的基因。在这26个基因中，选择了3-氧代酸辅酶A转移酶1（），与顺铂敏感组相比，该基因在顺铂耐药组的启动子CpG处被证明下调且高度甲基化，以进行进一步研究。用DNA甲基转移酶抑制剂处理可恢复顺铂耐药组中由高甲基化介导的该基因沉默，但在顺铂敏感组中则不能。此外，该基因的过表达赋予OC细胞对顺铂的敏感性。本研究结果表明，该基因在赋予顺铂敏感性方面发挥重要作用，并可能为复发性OC患者的顺铂化疗提供潜在的治疗靶点。
