Du Haiyang, Si Gao, Si Jiqing, Song Xuejie, Si Fuchun
Traditional Chinese Medicine (Zhong Jing) School, Henan University of Chinese Medicine, Zhengzhou, 450046, China.
Henan Key Laboratory of TCM Syndrome and Prescription Signaling, Henan International Joint Laboratory of TCM Syndrome and Prescription Signaling, Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China.
J Ovarian Res. 2025 May 29;18(1):114. doi: 10.1186/s13048-025-01686-3.
Ovarian cancer is one of the most common malignancies of the female reproductive system and is associated with poor prognosis. This study aimed to utilize single-cell RNA sequencing to investigate the heterogeneity of malignant epithelial cells in ovarian cancer, focusing on their potential functions and the implications for treatment and prognosis.
Single-cell RNA sequencing data were clustered using a single-cell transcriptome clustering method, and malignant epithelial cells were identified through copy number variation analysis. The interaction patterns between different malignant subpopulations and immune/stromal cells were analyzed using cell-to-cell communication analysis. A risk score (URS) model based on the UBE2C + epithelial subpopulation was then constructed through LASSO and multivariable Cox regression. High and low URS groups were compared in terms of tumor mutational burden (TMB), survival outcomes, and drug sensitivity. Finally, the role of GTF2F2 in ovarian cancer progression was validated through gene knockdown experiments in an ovarian cancer cell line (ES-2).
Three major malignant epithelial cell subpopulations were identified (TMSB4X + Epi, TSC22D1 + Epi, and UBE2C + Epi). The UBE2C + Epi subpopulation exhibited higher stemness and greater invasive potential. The constructed URS model effectively stratified patients into high- and low-risk groups, with the high-risk group displaying a higher TMB level (p = 0.00011). Drug sensitivity predictions indicated that osimertinib, rapamycin, and dihydrorotenone might have stronger inhibitory effects in the high-risk group, whereas ERK inhibitors were more effective in the low-risk group. Functional assays demonstrated that GTF2F2 knockdown significantly suppressed ovarian cancer cell migration and invasion. Western blot analyses further showed elevated E-cadherin and reduced N-cadherin expression, suggesting that GTF2F2 may promote epithelial-mesenchymal transition (EMT).
The risk score model established in this study offers a novel framework for patient stratification and personalized therapy. Notably, the identification of the UBE2C + Epi subpopulation and key genes such as GTF2F2 highlights potential diagnostic and therapeutic targets, shedding light on the pathogenesis of ovarian cancer and paving the way for precision medicine approaches.
卵巢癌是女性生殖系统最常见的恶性肿瘤之一，预后较差。本研究旨在利用单细胞RNA测序来研究卵巢癌中恶性上皮细胞的异质性，重点关注其潜在功能以及对治疗和预后的影响。
使用单细胞转录组聚类方法对单细胞RNA测序数据进行聚类，并通过拷贝数变异分析鉴定恶性上皮细胞。使用细胞间通讯分析来分析不同恶性亚群与免疫/基质细胞之间的相互作用模式。然后通过LASSO和多变量Cox回归构建基于UBE2C+上皮亚群的风险评分（URS）模型。对高URS组和低URS组在肿瘤突变负荷（TMB）、生存结果和药物敏感性方面进行比较。最后，通过在卵巢癌细胞系（ES-2）中进行基因敲低实验验证了GTF2F2在卵巢癌进展中的作用。
鉴定出三个主要的恶性上皮细胞亚群（TMSB4X+Epi、TSC22D1+Epi和UBE2C+Epi）。UBE2C+Epi亚群表现出更高的干性和更强的侵袭潜力。构建的URS模型有效地将患者分为高风险组和低风险组，高风险组显示出更高的TMB水平（p=0.00011）。药物敏感性预测表明，奥希替尼、雷帕霉素和二氢鱼藤酮在高风险组可能具有更强的抑制作用，而ERK抑制剂在低风险组更有效。功能分析表明，GTF2F2敲低显著抑制卵巢癌细胞的迁移和侵袭。蛋白质免疫印迹分析进一步显示E-钙黏蛋白表达升高，N-钙黏蛋白表达降低，表明GTF2F2可能促进上皮-间质转化（EMT）。
本研究建立的风险评分模型为患者分层和个性化治疗提供了一个新的框架。值得注意的是，UBE2C+Epi亚群和GTF2F2等关键基因的鉴定突出了潜在的诊断和治疗靶点，为卵巢癌的发病机制提供了线索，并为精准医学方法铺平了道路。
