高表达TK1与卵巢癌耐药性有关

Association of TK1 up-regulation with drug resistance of ovarian cancer

摘要:

目的：研究胸苷激酶１（thymidine kinase 1，TK1）与卵巢癌耐药性之间的关系。方法：运用GEPIA在线工具分析TK1在正常卵巢组织与卵巢癌组织中的表达差异，运用kaplan-meier plotter分析卵巢癌患者关于TK1的总生存曲线；基于GEO数据库分析TK1在顺铂敏感性与顺铂耐药性的卵巢癌细胞株中的表达差异。综合运用基因互作分析、基因通路富集和文本挖掘、miRNA-mRNA相互作用分析等生物信息学方法进一步证明TK1调节卵巢癌耐药性及探索其内在机制。结果：卵巢癌组织中的TK1表达明显高于正常卵巢组织，高表达TK1与卵巢癌患者低生存率有关，顺铂耐药的卵巢癌细胞株TK1表达明显高于顺铂敏感的卵巢癌细胞株，与TK1具有高度关联性的基因大部分与卵巢癌耐药性有关；利用基因通路富集对与TK1相关联的基因分析发现，代谢相关通路程度最高；文本挖掘显示，细胞周期、细胞增殖、S期、入胞、磷酸化等生物过程与TK1蛋白、卵巢癌、肿瘤耐药性具有明显的关联性；miRNA-mRNA互作分析发现，靶向于TK1的11个miRNA皆与卵巢癌耐药性或其他肿瘤耐药性相关。结论：高表达TK1与卵巢癌的耐药性相关。

Abstract:

Objective：To analyze the association of thymidine kinase 1（TK1） with drug resistance of ovarian cancer. Methods：GEPI－A online tool was used to detect the mRNA expression of TK1 in normal ovary tissue and ovarian cancer tissue. KM-Plot was used to perform OS survival rate. GEO profiles database was used to analyze the mRNA expression of TK1 in cisplatin sensitive and cisplatin resistant A2780 cell lines. Comprehensive bioinformatic analyses，protein interaction analysis，genetic pathway enrichment analysis，text mining and miRNA-mRNA interaction analysis were performed to further demonstrate TK1 regulated ovarian cancer drug resis－tance and investigate its potential mechanism. Results：The TK1 expression in the cancer tissue was significantly higher than that in the normal tissue. The high TK1 expression was related with patients’ low survival rates. The TK1 expression in cisplatin resistant A2780 was higher when compared with cisplatin sensitive A2780. Most genes that were closely interacted with TK1 were associated with drug resistance of ovarian cancer. By using genetic pathway enrichment to analyze genes interacted with TK1，it was found that most enriched pathways were related with metabolism. Text mining showed that cell cycle，cell proliferation，S phase，endocytosis and phosphorylation were significantly associated with TK1 protein，ovarian cancer and drug resistance. According to the miRNA-mRNA interaction analysis，it was showed that 11 TK1-targeted microRNAs were related to drug resistance of ovarian cancer or other cancers. Conclusion：Up-regulation of TK1 is associated with drug resistance of ovarian cancer.