Chang Qinzheng, Zhao Shuo, Sun Jiajia, Guo Wei, Yang Lin, Qiu Laiyuan, Zhang Nianzhao, Fan Yidong, Liu Jikai
Department of Urology, Qilu Hospital of Shandong University, Jinan, Shandong, China.
Front Endocrinol (Lausanne). 2025 Mar 3;16:1521940. doi: 10.3389/fendo.2025.1521940. eCollection 2025.
Clear cell renal cell carcinoma is the most predominant type of renal malignancies, characterized by high aggressiveness and probability of distant metastasis. Renin angiotensin system (RAS) plays a crucial role in maintaining fluid balance within the human body, and its involvement in tumorigenesis is increasingly being uncovered, while its role in ccRCC remains unclear.
WGCNA was used to identify RAS related genes. Machine learning was applied to screen hub genes for constructing risk model, E-MTAB-1980 dataset was used for external validation. Transwell and CCK8 assays were used to investigate the impact of SLC6A19 to ccRCC cells.
SLC6A19, SLC16A12 and SMIM24 were eventually screened to construct risk model and the predictive efficiency for prognosis was validated by internal and external cohorts. Moreover, the differences were found in pathway enrichment, immune cell infiltration, mutational landscapes and drug prediction between high and low risk groups. Experimental results indicated that SLC6A19 could inhibit invasion and proliferation of ccRCC cells and GSEA pinpointed that SLC6A19 was intimately correlated with fatty acid metabolism and CPT1A.
The risk model based on the three RAS-related genes have a robust ability to predict the prognosis and drug sensitivity of ccRCC patients, further providing a valid instruction for clinical care.
透明细胞肾细胞癌是最主要的肾脏恶性肿瘤类型，具有高侵袭性和远处转移的可能性。肾素血管紧张素系统（RAS）在维持人体体液平衡中起关键作用，其在肿瘤发生中的作用越来越多地被发现，但其在透明细胞肾细胞癌中的作用仍不清楚。
使用加权基因共表达网络分析（WGCNA）来识别RAS相关基因。应用机器学习筛选枢纽基因以构建风险模型，使用E-MTAB-1980数据集进行外部验证。采用Transwell和CCK8实验研究溶质载体家族6成员19（SLC6A19）对透明细胞肾癌细胞的影响。
最终筛选出SLC6A19、溶质载体家族16成员12（SLC16A12）和小跨膜蛋白24（SMIM24）构建风险模型，并通过内部和外部队列验证了其对预后的预测效率。此外，在高风险组和低风险组之间发现了通路富集、免疫细胞浸润、突变图谱和药物预测方面的差异。实验结果表明，SLC6A19可以抑制透明细胞肾癌细胞的侵袭和增殖，基因集富集分析（GSEA）指出SLC6A19与脂肪酸代谢和肉碱/有机阳离子转运体1A（CPT1A）密切相关。
基于三个RAS相关基因的风险模型具有强大的预测透明细胞肾细胞癌患者预后和药物敏感性的能力，进一步为临床治疗提供了有效的指导。
