Wang Ruixue, Deng Jiaxing, Zhang Meng, Wang Zhihui, Wu Shangjie, Liu Shilong, Qi Lishuang
Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
Oncol Lett. 2024 Nov 26;29(2):77. doi: 10.3892/ol.2024.14823. eCollection 2025 Feb.
Cervical cancer (CC) is the fourth leading cause of cancer-associated mortalities among women worldwide. The chemotherapeutical platinum-based agent cisplatin (DDP) is the standard therapy for locally advanced or recurrent CC; however, platinum resistance limits its clinical benefit. Therefore, the present study aimed to identify key genes associated with DDP resistance in patients with CC and investigate the underlying molecular mechanisms. Firstly, using the CRISPR-Cas9 dataset of CC cells derived from DepMap portal, 699 genes associated with CC cell survival were identified. Subsequently, using the gene expression profiles of normal and CC samples with a response status to DDP, derived from The Cancer Genome Atlas (TCGA), hypoxia upregulated 1 () was further identified as significantly upregulated in CC samples and patients that did not respond to DDP (non-responders) when compared with healthy controls and patients that did respond to DDP (responders), respectively, using unpaired student's t-tests. Additionally, the log-rank test revealed that the high expression of was significantly associated with the poor survival of patients receiving DDP. The association between the high expression levels and the poor survival of patients receiving DDP was validated in the remaining TCGA dataset of patients with CC. expression levels were positively associated with the half-maximal inhibitory concentration value of DDP in CC cells using data derived from the Genomics of Drug Sensitivity in Cancer database. , western blotting experiments revealed high HYOU1 protein expression levels in DDP-resistant HeLa cells compared with their parental HeLa cells. Furthermore, the knockdown of resulted in an increased sensitivity of HeLa cells to DDP. Finally, using the sequence-based RNA adenosine methylation site predictor program, it was found that N-methyladenosine (mA) was highly enriched in HYOU1. The expression levels of the mA reader, , was positively correlated with the expression levels of and was upregulated in the non-response group compared with the response group in a dataset from TCGA database. Additionally, had the highest probability of binding to the mA motifs of compared with other genes. In GSE56363 obtained from the Gene Expression Omnibus, the non-responders had significantly increased expression levels of compared with the responders. In conclusion, high expression levels of , which may be regulated by due to mA modifications, was associated with DDP resistance in patients with CC and could potentially be used as an indicator of DDP treatment resistance.
宫颈癌（CC）是全球女性癌症相关死亡的第四大主要原因。化疗用铂类药物顺铂（DDP）是局部晚期或复发性CC的标准治疗方法；然而，铂耐药性限制了其临床疗效。因此，本研究旨在确定CC患者中与DDP耐药相关的关键基因，并研究其潜在的分子机制。首先，利用来自DepMap数据库的CC细胞的CRISPR-Cas9数据集，鉴定出699个与CC细胞存活相关的基因。随后，利用来自癌症基因组图谱（TCGA）的正常和CC样本对DDP反应状态的基因表达谱，通过非配对学生t检验，进一步确定缺氧上调1（HYOU1）在CC样本和对DDP无反应的患者（无反应者）中相对于健康对照和对DDP有反应的患者（有反应者）显著上调。此外，对数秩检验显示HYOU1的高表达与接受DDP治疗患者的不良生存显著相关。在CC患者的其余TCGA数据集中验证了HYOU1高表达水平与接受DDP治疗患者不良生存之间的关联。利用来自癌症药物敏感性基因组学数据库的数据，HYOU1表达水平与CC细胞中DDP的半数最大抑制浓度值呈正相关。此外，蛋白质免疫印迹实验显示，与亲本HeLa细胞相比，DDP耐药的HeLa细胞中HYOU1蛋白表达水平较高。此外，敲低HYOU1导致HeLa细胞对DDP的敏感性增加。最后，使用基于序列的RNA腺苷甲基化位点预测程序，发现N-甲基腺苷（m⁶A）在HYOU1中高度富集。m⁶A阅读器YTHDF1的表达水平与HYOU1的表达水平呈正相关，并且在TCGA数据库的数据集中，与反应组相比，非反应组中YTHDF1上调。此外，与其他基因相比，YTHDF1与HYOU1的m⁶A基序结合的概率最高。在从基因表达综合数据库获得的GSE56363中，与有反应者相比，无反应者的YTHDF1表达水平显著增加。总之，HYOU1的高表达水平可能由于m⁶A修饰而受YTHDF1调控，与CC患者的DDP耐药相关，并可能潜在地用作DDP治疗耐药的指标。
