Li Wenhui, Pan Huan, Zhou Bangwei, Cao Yifang, Shen Bin, Li Nan, Zhang Yao, He Yi, Jin Jing, Shi Lili, Gao Jinlai
Department of Pharmacology, College of Medical, Jiaxing University, Jiaxing, China.
College of Life Science, Zhejiang Sci-Tech University, Hangzhou, China.
Transl Androl Urol. 2025 Feb 28;14(2):360-378. doi: 10.21037/tau-24-565. Epub 2025 Feb 25.
Clear cell renal cell carcinoma (ccRCC) is a lethal urological cancer that accounts for a considerable portion of all malignant tumors in adults. Alterations in mitochondrial function and metabolism may influence the onset and progression of ccRCC. This study aims to develop a novel clinical prognostic signature for ccRCC based on mitochondria-associated genes, as well as to identify new potential therapeutic agents for this condition.
A total of 539 ccRCC tumors and 72 normal kidney specimens were analyzed from The Cancer Genome Atlas (TCGA). We created a prognostic signature based on univariate, multivariate Cox, and least absolute shrinkage and selection operator (LASSO) Cox regression. A differential expression analysis, functional enrichment, and assessment of tumor immune cell infiltration were performed. Connectivity Map (CMap) and L1000CDS dataset were utilized for potential therapeutic drug identification. Vorinostat was examined for its effects on ccRCC cell proliferation, cell death, migration, and invasion using Cell Counting Kit-8 (CCK-8), lactate dehydrogenase (LDH) release, wound healing, and transwell assays.
The prognostic signature, comprising 16 mitochondria-related genes, demonstrated marked changes in overall survival between high- and low-risk groups. Functional analysis implicated immune-related pathways, indicating potential for immunotherapy strategies. Vorinostat, identified through drug screening, exhibited inhibitory implications on ccRCC cell proliferation, migration, and invasion and induced cell death.
The constructed prognostic signature provides a valuable tool for patient prognosis prediction. Vorinostat emerges as a promising therapeutic candidate for high-risk ccRCC patients, contributing to a deeper understanding of ccRCC biology and personalized therapeutic interventions.
透明细胞肾细胞癌（ccRCC）是一种致命的泌尿系统癌症，在成人所有恶性肿瘤中占相当大的比例。线粒体功能和代谢的改变可能影响ccRCC的发生和进展。本研究旨在基于线粒体相关基因开发一种新的ccRCC临床预后特征，并确定针对该疾病的新的潜在治疗药物。
从癌症基因组图谱（TCGA）分析了总共539个ccRCC肿瘤和72个正常肾标本。我们基于单变量、多变量Cox回归以及最小绝对收缩和选择算子（LASSO）Cox回归创建了一个预后特征。进行了差异表达分析、功能富集分析以及肿瘤免疫细胞浸润评估。利用连通性图谱（CMap）和L1000CDS数据集进行潜在治疗药物的鉴定。使用细胞计数试剂盒-8（CCK-8）、乳酸脱氢酶（LDH）释放、伤口愈合和Transwell实验检测伏立诺他对ccRCC细胞增殖、细胞死亡、迁移和侵袭的影响。
由16个线粒体相关基因组成的预后特征显示，高风险组和低风险组之间的总生存期有显著差异。功能分析涉及免疫相关途径，表明免疫治疗策略具有潜力。通过药物筛选鉴定出的伏立诺他对ccRCC细胞增殖、迁移和侵袭具有抑制作用，并诱导细胞死亡。
构建的预后特征为患者预后预测提供了有价值的工具。伏立诺他成为高危ccRCC患者有前景的治疗候选药物，有助于更深入地了解ccRCC生物学特性和个性化治疗干预。
