1 Beijing Scientific Operation Co., Ltd, Beijing 100121, P.R. China.
*These authors contributed equally to this work.
Exp Biol Med (Maywood). 2018 Apr;243(7):655-662. doi: 10.1177/1535370218760283. Epub 2018 Feb 22.
This study is to investigate transcription factors involved in cisplatin resistance in ovarian cancer cells. The transcriptome of cisplatin resistant and sensitive A2780 epithelial ovarian cancer cells was obtained from GSE15372. Ovarian transcriptome data GSE62944 was downloaded from TCGA and applied for transcription regulatory network analysis. The analysis results were confirmed using quantitative polymerase chain reaction. The roles of SREBP2 in cisplatin-resistant cells were investigated by RNA inference and cell viability analysis. Transcription regulatory network analysis found that 12 transcription factors and their targets were involved in cisplatin resistant in A2780 cells. Among these factors, the targets of EZH2 and SREBP2 revealed by Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining were also enriched in differentially expressed genes between cisplatin resistant and cisplatin sensitive cells. Their targets were enriched mainly in cell cycle and cholesterol metabolic process, respectively. Bioinformatic analysis illustrated three known targets of SREBP2, namely LDLR, FDFT1, and HMGCR were increased in A2780-resistant cell lines. Additionally, the three genes and SREBP2 were also elevated in live cells after cisplatin treatment via quantitative polymerase chain reaction. Importantly, RNA inference of SREBP2 in A2780 cell line resulted in a decrease of cell viability after cisplatin treatment. SREBP2 played important roles in cisplatin resistance and cholesterol metabolic process might be a novel target for cancer therapy. Impact statement Transcriptome of cisplatin resistant and sensitive A2780 epithelial ovarian cancer cells was obtained from GSE15372 and TCGA. Twelve transcription factors and their targets were involved in cisplatin resistant. Among these factors, the targets of EZH2 and SREBP2 revealed by Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining were also enriched in differentially expressed genes. Their targets were enriched mainly in cell cycle and cholesterol metabolic process. Three targets of SREBP2, namely LDLR, FDFT1, and HMGCR were increased in A2780-resistant cell lines and were found elevated in live cells after cisplatin treatment via qPCR. RNAi of SREBP2 in A2780 cell line resulted in a decrease of cell viability after cisplatin treatment. SREBP2 played important roles in cisplatin resistance and might be a novel target for cancer therapy.
本研究旨在探讨顺铂耐药卵巢癌细胞中涉及的转录因子。从 GSE15372 中获得顺铂耐药和敏感 A2780 上皮卵巢癌细胞的转录组。从 TCGA 下载卵巢转录组数据 GSE62944，并应用于转录调控网络分析。使用定量聚合酶链反应（PCR）对分析结果进行验证。通过 RNA 干扰和细胞活力分析研究 SREBP2 在顺铂耐药细胞中的作用。转录调控网络分析发现，12 种转录因子及其靶基因参与 A2780 细胞的顺铂耐药。在这些因子中，通过基于句子的文本挖掘揭示的 EZH2 和 SREBP2 的靶基因也富集在顺铂耐药和敏感细胞之间差异表达的基因中。它们的靶基因主要富集在细胞周期和胆固醇代谢过程中。生物信息学分析表明，SREBP2 的三个已知靶基因 LDLR、FDFT1 和 HMGCR 在 A2780 耐药细胞系中增加。此外，通过定量聚合酶链反应（PCR）还发现，在顺铂处理后的活细胞中，这三个基因和 SREBP2 也升高。重要的是，通过 RNA 干扰 SREBP2 在 A2780 细胞系中导致顺铂处理后细胞活力下降。SREBP2 在顺铂耐药和胆固醇代谢过程中发挥重要作用，可能成为癌症治疗的新靶点。
