PDF(Pubmed)
Abstract：
Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer characterized by metabolic reprogramming. Glutamine metabolism is pivotal in metabolic reprogramming, contributing to the significant heterogeneity observed in ccRCC. Consequently, developing prognostic markers associated with glutamine metabolism could enhance personalized treatment strategies for ccRCC patients. This study obtained RNA sequencing and clinical data from 763 ccRCC cases sourced from multiple databases. Consensus clustering of 74 glutamine metabolism related genes (GMRGs)- profiles stratified the patients into three clusters, each of which exhibited distinct prognosis, tumor microenvironment, and biological characteristics. Then, six genes (SMTNL2, MIOX, TMEM27, SLC16A12, HRH2, and SAA1) were identified by machine-learning algorithms to develop a predictive signature related to glutamine metabolism, termed as GMRScore. The GMRScore showed significant differences in clinical prognosis, expression profile of immune checkpoints, abundance of immune cells, and immunotherapy response of ccRCC patients. Besides, the nomogram incorporating the GMRScore and clinical features showed strong predictive performance in prognosis of ccRCC patients. ALDH18A1, one of the GRMGs, exhibited elevated expression level in ccRCC and was related to markedly poorer prognosis in the integrated cohort, validated by proteomic profiling of 232 ccRCC samples from Fudan University Shanghai Cancer Center (FUSCC). Conducting western blotting, CCK-8, transwell, and flow cytometry assays, we found the knockdown of ALDH18A1 in ccRCC significantly promoted apoptosis and inhibited proliferation, invasion, and epithelial-mesenchymal transition (EMT) in two human ccRCC cell lines (786-O and 769-P). In conclusion, we developed a glutamine metabolism-related prognostic signature in ccRCC, which is tightly linked to the tumor immune microenvironment and immunotherapy response, potentially facilitating precision therapy for ccRCC patients. Additionally, this study revealed the key role of ALDH18A1 in promoting ccRCC progression for the first time.
摘要：
透明细胞肾细胞癌（ccRCC）是以代谢重编程为特征的最常见的肾癌亚型。谷氨酰胺代谢在代谢重编程中至关重要，导致ccRCC中观察到的显著异质性。因此,开发与谷氨酰胺代谢相关的预后标志物可以增强ccRCC患者的个性化治疗策略.本研究获得了来自多个数据库的763例ccRCC病例的RNA测序和临床数据。74个谷氨酰胺代谢相关基因（GMRGs）的共识聚类-将患者分为三个聚类，每个都表现出不同的预后，肿瘤微环境,和生物学特征。然后，六个基因(SMTNL2，MIOX，TMEM27，SLC16A12，HRH2和SAA1）通过机器学习算法鉴定，以开发与谷氨酰胺代谢相关的预测特征，称为GMRScore。GMRScore在临床预后方面有显著差异,免疫检查点的表达谱，丰富的免疫细胞，和ccRCC患者的免疫治疗反应。此外,纳入GMRScore和临床特征的列线图对ccRCC患者的预后具有很强的预测作用.ALDH18A1，GRMGs之一，在ccRCC中表现出表达水平升高，并且与整合队列中的预后明显较差有关，通过复旦大学上海癌症中心（FUSCC）232个ccRCC样本的蛋白质组学分析验证。进行西方印迹,CCK-8Transwell,和流式细胞术检测，我们发现ccRCC中ALDH18A1的敲除显著促进细胞凋亡和抑制细胞增殖,入侵,两种人ccRCC细胞系（786-O和769-P）中的上皮-间质转化（EMT）。总之,我们在ccRCC中开发了与谷氨酰胺代谢相关的预后标志，这与肿瘤免疫微环境和免疫疗法反应密切相关，可能促进ccRCC患者的精确治疗。此外,这项研究首次揭示了ALDH18A1在促进ccRCC进展中的关键作用。
