Lei Han, Guo Ke, Shu Guang, Wang Maonan, Li Yu, Tan Zhihui, Pan Qiong, Yin Gang
Department of Pathology, Xiangya Hospital, School of Basic Medical Sciences, Central South University, Changsha, China.
Department of Neurology, The Third Xiangya Hospital of Central South University, Changsha, China.
Apoptosis. 2025 May 15. doi: 10.1007/s10495-025-02119-8.
Cuproptosis, a recently identified copper-dependent cell death mechanism, remains poorly unexplored in ovarian cancer (OC). This study systematically evaluates clinically significant cuproptosis-related genes (CRGs) as potential prognostic biomarkers in OC. Cox regression analysis and LASSO algorithms were used to develop a prognostic risk model incorporating 5 CRGs (CD8B2, GJB2, GRIP2, MELK, and PLA2G2D) within the TCGA cohort. This model stratified OC patients into high-risk and low-risk groups, with the high-risk group exhibiting significantly shorter overall survival compared to the low-risk group. The model's predictive accuracy for prognosis in OC patients was validated in the TCGA training cohort, TCGA testing cohort, and ICGC external validation cohorts. Among these 5 signature genes, the number of cuproptosis genes associated with GJB2 is the largest, so we selected GJB2 for further validation. qPCR revealed that GJB2 was highly expressed in OC cells and tumor tissues. The high expression of GJB2 was closely associated with poor prognosis in OC patients. Functionally, GJB2 silencing suppressed OC cell proliferation and migration while its overexpression promoted malignant progression and EMT. Furthermore, GJB2 regulated copper homeostasis and reduced cuproptosis sensitivity, while also facilitating immune escape by inhibiting CD8 T cell infiltration and cytokine secretion, revealing its multiple roles in OC progression. In conclusion, we established a novel prognostic model incorporating 5 CRGs that effectively predicts clinical outcomes and characterizes the immune microenvironment in OC. Our findings particularly highlight GJB2 as a key regulator of cuproptosis with significant potential as both a prognostic biomarker and therapeutic target for OC management.
铜死亡是一种最近发现的依赖铜的细胞死亡机制，在卵巢癌（OC）中的研究仍很少。本研究系统评估了具有临床意义的铜死亡相关基因（CRGs）作为OC潜在的预后生物标志物。使用Cox回归分析和LASSO算法在TCGA队列中建立了一个包含5个CRGs（CD8B2、GJB2、GRIP2、MELK和PLA2G2D）的预后风险模型。该模型将OC患者分为高风险和低风险组，高风险组的总生存期明显短于低风险组。该模型对OC患者预后的预测准确性在TCGA训练队列、TCGA测试队列和ICGC外部验证队列中得到了验证。在这5个特征基因中，与GJB2相关的铜死亡基因数量最多，因此我们选择GJB2进行进一步验证。qPCR显示GJB2在OC细胞和肿瘤组织中高表达。GJB2的高表达与OC患者的不良预后密切相关。在功能上，GJB2沉默抑制了OC细胞的增殖和迁移，而其过表达促进了恶性进展和EMT。此外，GJB2调节铜稳态并降低铜死亡敏感性，同时还通过抑制CD8 T细胞浸润和细胞因子分泌促进免疫逃逸，揭示了其在OC进展中的多重作用。总之，我们建立了一个包含5个CRGs的新型预后模型，该模型能有效预测临床结果并描绘OC中的免疫微环境。我们的研究结果特别强调GJB2是铜死亡的关键调节因子，作为OC管理的预后生物标志物和治疗靶点具有巨大潜力。
