Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
Biomolecules. 2023 Nov 30;13(12):1724. doi: 10.3390/biom13121724.
Ovarian cancer (OV) is associated with high mortality and poses challenges in diagnosis and prognosis prediction. Ubiquitin-related genes (UbRGs) are involved in the initiation and progression of cancers, but have still not been utilized for diagnosis and prognosis of OV.
K48-linked ubiquitination in ovarian tissues from our OV and control cohort was assessed using immunohistochemistry. UbRGs, including ubiquitin and ubiquitin-like regulators, were screened based on the TCGA-OV and GTEx database. Univariate Cox regression analysis identified survival-associated UbRGs. A risk model was established using the LASSO regression and multivariate Cox regression analysis. The relationship between UbRGs and immune cell infiltration, tumor mutational burden, drug sensitivity, and immune checkpoint was determined using the CIBERSORT, ESTIMATE, and Maftools algorithms, based on the Genomics of Drug Sensitivity in Cancer and TCGA-OV databases. GEPIA2.0 was used to analyze the correlation between / and DNA damage repair-related genes. Finally, and were accessed in tissues or cells using immunohistochemistry, qPCR, and Western blot.
We confirmed the crucial role for ubiquitination in OV as a significant decrease of K48-linked ubiquitination was observed in primary OV lesions. We identified a prognostic signature utilizing two specific UbRGs, and . The risk score obtained from this signature accurately predicted the overall survival of TCGA-OV training dataset and GSE32062 validation dataset. Furthermore, this risk score also showed association with immunocyte infiltration and drug sensitivity, revealing potential mechanisms for ubiquitination mediated OV risk. In addition, , but not , was found to be downregulated in OV and positively correlated with DNA damage repair pathways, suggesting as a potential cancer suppressor, likely via facilitating DNA damage repair.
We identified and validated a signature of UbRGs that accurately predicts the prognosis, offers valuable guidance for optimizing chemotherapy and targeted therapies, and suggests a potential role for in OV.
卵巢癌（OV）死亡率高，诊断和预后预测存在挑战。泛素相关基因（UbRGs）参与癌症的发生和进展，但尚未用于 OV 的诊断和预后。
采用免疫组织化学法检测卵巢组织中 K48 连接泛素化。基于 TCGA-OV 和 GTEx 数据库筛选 UbRGs，包括泛素和泛素样调节剂。单因素 Cox 回归分析鉴定与生存相关的 UbRGs。采用 LASSO 回归和多因素 Cox 回归分析建立风险模型。基于癌症基因组药物敏感性和 TCGA-OV 数据库，采用 CIBERSORT、ESTIMATE 和 Maftools 算法确定 UbRGs 与免疫细胞浸润、肿瘤突变负荷、药物敏感性和免疫检查点的关系。利用 GEPIA2.0 分析与 DNA 损伤修复相关基因的相关性。最后，采用免疫组织化学、qPCR 和 Western blot 检测组织或细胞中的和。
我们证实泛素化在 OV 中起关键作用，因为在原发性 OV 病变中观察到 K48 连接泛素化显著减少。我们利用两个特定的 UbRGs 和鉴定出一个预后标志。该标志物获得的风险评分可准确预测 TCGA-OV 训练数据集和 GSE32062 验证数据集的总生存期。此外，该风险评分还与免疫细胞浸润和药物敏感性相关，揭示了泛素介导的 OV 风险的潜在机制。此外，在 OV 中发现下调，与 DNA 损伤修复途径呈正相关，表明可能作为一种潜在的癌症抑制因子，通过促进 DNA 损伤修复发挥作用。
我们鉴定并验证了一个 UbRGs 标志，可准确预测预后，为优化化疗和靶向治疗提供有价值的指导，并提示在 OV 中可能发挥作用。
