背景:子宫内膜癌(EC)的耐药性是一个严重的问题,也是改善预后的障碍。PI3K/AKT/mTOR途径在EC中高度激活,并且可以作为潜在的治疗靶标。已经开发了针对AKT的抑制剂,但是对这些抑制剂的抗性是一个问题。本研究旨在建立AKT抑制剂耐药细胞系,并鉴定亲本和AKT抑制剂耐药细胞系之间的差异表达基因(DEGs),以了解EC对AKT抑制剂的耐药机制。
方法:分析8种EC细胞系对AKT抑制剂的敏感性。其中之一用于建立耐药细胞系。使用RNA测序(RNA-seq)检查DEGs。此外,对DEGs进行综合分析以鉴定hub基因。使用定量实时聚合酶链反应评估Hub基因。
结果:RNA-seq鉴定出617个DEG。使用生物信息学分析选择Hub基因。前10个hub基因是TNF,CDH1、CCND1、COL1A1、CDH2、ICAM1、CAV1、THBS1、NCAM1和CDKN2A。TNF的相对mRNA表达显著上调,CDH1,CCND1,THBS1,p16INK4a,和p14ARF,并在耐borussertib的EC细胞系中显著下调CDH2、ICAM1和NCAM1。
结论:对AKT抑制剂的耐药性可能取决于与细胞粘附介导的耐药性和转化生长因子β信号相关的基因。
BACKGROUND: Drug resistance in endometrial cancer (EC) is a serious problem and a barrier to improving prognosis. The PI3K/AKT/mTOR pathway is highly activated in EC and can serve as a potential therapeutic target. Inhibitors against AKT have been developed, but resistance to these inhibitors is a concern. This study aimed to establish AKT inhibitor resistant cell lines and identify differentially expressed genes (DEGs) between parental and AKT inhibitor resistant cell lines to understand the mechanism of drug resistance to AKT inhibitors in EC.
METHODS: The sensitivity of eight EC cell lines to AKT inhibitor was analyzed. One of them was used to establish a drug-resistant cell line. DEGs were examined using RNA sequencing (RNA-seq). Furthermore, DEGs were comprehensively analyzed to identify hub genes. Hub genes were evaluated using quantitative real-time polymerase chain reaction.
RESULTS: RNA-seq identified 617 DEGs. Hub genes were selected using bioinformatics analysis. The top 10 hub genes were TNF, CDH1, CCND1, COL1A1, CDH2, ICAM1, CAV1, THBS1, NCAM1, and CDKN2A. Relative mRNA expression was significantly upregulated for TNF, CDH1, CCND1, THBS1, p16INK4a, and p14ARF and significantly downregulated for CDH2, ICAM1, and NCAM1 in borussertib-resistant EC cell line.
CONCLUSIONS: Drug resistance to AKT inhibitors may depend on genes related to cell adhesion-mediated resistance and transforming growth factor β signaling.