Yang Bikang, Yang Juan, Zhang Keqiang
Department of Gynecologic Oncology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Yuelu District, Changsha, 410013, Hunan, People's Republic of China.
Discov Oncol. 2024 May 2;15(1):141. doi: 10.1007/s12672-024-00981-7.
Cuproptosis, programmed cell death by intracellular copper-mediated lipoylated protein aggregation, is involved in various tumorigenesis and drug resistance abilities by mediating the tumor microenvironment. Previous studies have demonstrated that serum copper levels are higher in OC patients than in normal subjects. However, the exact relationship between cuproptosis and ovarian cancer progression remains to be further elucidated.
The Cancer Genome Atlas (TCGA) and gene expression omnibus (GEO) datasets were utilized to establish a cuproptosis-related prognostic signature in ovarian cancer. Subsequently, the bulk RNA-seq analysis and single-cell RNA-seq analysis were used to identify the relationship between signature with immune cell infiltration, chemotherapy, and cuproptosis-related scoring (CuRS) system. Finally, the potential biological functional roles of target genes in cuproptosis were validated in vitro.
By using LASSO-Cox regression analysis to establish the cuproptosis-related prognostic model, our works demonstrated the accuracy and efficiency of our model in the TCGA (583 OC patients) and GEO (260 OC patients) OC cohorts, and the high-scoring groups showed worse survival outcomes. Notably, there were substantial differences between the high and low-risk groups in extensive respects, such as the activating transcription factors, cell pseudotime features, cell intercommunication patterns, immunocytes infiltration, chemotherapy response, and potential drug resistance. KIF26B was selected to construct a prognostic model from the identified 33 prognosis-related genes, and high expression of KIF26B predicted poorer prognosis in ovarian cancer. Ultimately, further in vitro experiments demonstrated that KIF26B participated in the proliferation and cisplatin resistance of OC cells. Knockdown of KIF26B increased the sensitivity of OC cells to elesclomol, a cuproptosis agonists.
This study constructed a new cuproptosis-related gene signature that has a good prognostic capacity in assessing the outcome of OC patients. This study enhances our understanding of cuproptosis associated with ovarian cancer aggressiveness, cross-talk with immunocytes, and serves as a novel chemotherapy strategy.
铜死亡是由细胞内铜介导的脂酰化蛋白聚集引发的程序性细胞死亡，通过介导肿瘤微环境参与多种肿瘤的发生和耐药能力。先前的研究表明，卵巢癌患者血清铜水平高于正常受试者。然而，铜死亡与卵巢癌进展的确切关系仍有待进一步阐明。
利用癌症基因组图谱（TCGA）和基因表达综合数据库（GEO）数据集建立卵巢癌中与铜死亡相关的预后特征。随后，采用批量RNA测序分析和单细胞RNA测序分析来确定该特征与免疫细胞浸润、化疗以及铜死亡相关评分（CuRS）系统之间的关系。最后，在体外验证靶基因在铜死亡中的潜在生物学功能作用。
通过使用LASSO - Cox回归分析建立与铜死亡相关的预后模型，我们的研究证明了该模型在TCGA（583例卵巢癌患者）和GEO（260例卵巢癌患者）卵巢癌队列中的准确性和有效性，高分值组显示出更差的生存结果。值得注意的是，高风险组和低风险组在广泛的方面存在显著差异，如激活转录因子、细胞伪时间特征、细胞间通讯模式、免疫细胞浸润、化疗反应和潜在耐药性。从鉴定出的33个与预后相关的基因中选择KIF26B构建预后模型，KIF26B的高表达预示卵巢癌预后较差。最终，进一步的体外实验表明KIF26B参与卵巢癌细胞的增殖和顺铂耐药。敲低KIF26B增加了卵巢癌细胞对铜死亡激动剂依斯氯铵的敏感性。
本研究构建了一种新的与铜死亡相关的基因特征，在评估卵巢癌患者预后方面具有良好的预后能力。本研究加深了我们对与卵巢癌侵袭性相关的铜死亡、与免疫细胞的相互作用的理解，并作为一种新的化疗策略。
