Zhang Wei, Qiao Xinhua, Xie Ting, Cai Wenbin, Zhang Xu, Chen Chang, Zhang Yaoguang
Department of Urology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China.
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Antioxidants (Basel). 2022 Dec 29;12(1):81. doi: 10.3390/antiox12010081.
Clear cell renal cell carcinoma (ccRCC) is a malignant tumor originating from proximal tubular epithelial cells, and despite extensive research efforts, its redox homeostasis characteristics and protein S-nitrosylation (or S-nitrosation) (SNO) modification remain largely undefined. This serves as a reminder that the aforementioned features demand a comprehensive inspection. We collected tumor samples and paracancerous normal samples from five patients with early-stage ccRCC (T1N0M0) for proteomic, SNO-proteome, and redox-targeted metabolic analyses. The localization and functional properties of SNO proteins in ccRCC tumors and paracancerous normal tissues were elucidated for the first time. Several highly useful ccRCC-associated SNO proteins were further identified. Metabolic reprogramming, redox homeostasis reprogramming, and tumorigenic alterations are the three major characteristics of early-stage ccRCC. Peroxidative damage caused by rapid proliferation coupled with an increased redox buffering capacity and the antioxidant pool is a major mode of redox homeostasis reprogramming. NADPH and NADP, which were identified from redox species, are both effective biomarkers and promising therapeutic targets. According to our findings, SNO protein signatures and redox homeostasis reprogramming are valuable for understanding the pathogenesis of ccRCC and identifying novel topics that should be seriously considered for the diagnosis and precise therapy of ccRCC.
透明细胞肾细胞癌（ccRCC）是一种起源于近端肾小管上皮细胞的恶性肿瘤，尽管进行了广泛的研究，但对其氧化还原稳态特征和蛋白质S-亚硝基化（或S-亚硝化）（SNO）修饰仍知之甚少。这提醒我们需要对上述特征进行全面检查。我们收集了5例早期ccRCC（T1N0M0）患者的肿瘤样本和癌旁正常样本，进行蛋白质组学、SNO蛋白质组学和氧化还原靶向代谢分析。首次阐明了SNO蛋白在ccRCC肿瘤和癌旁正常组织中的定位和功能特性。进一步鉴定了几种高度有用的ccRCC相关SNO蛋白。代谢重编程、氧化还原稳态重编程和致瘤性改变是早期ccRCC的三个主要特征。快速增殖导致的过氧化损伤以及氧化还原缓冲能力和抗氧化池的增加是氧化还原稳态重编程的主要模式。从氧化还原物质中鉴定出的NADPH和NADP既是有效的生物标志物，也是有前景的治疗靶点。根据我们的研究结果，SNO蛋白特征和氧化还原稳态重编程对于理解ccRCC的发病机制以及确定ccRCC诊断和精准治疗中应认真考虑的新课题具有重要价值。
