Core Instrument Facility, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005, China.
National Institute of Biological Sciences,7 Science Park Road ZGC Life Science Park, Beijing 102206, China.
J Proteome Res. 2024 Oct 4;23(10):4495-4507. doi: 10.1021/acs.jproteome.4c00431. Epub 2024 Aug 30.
Aromatic caninurine formamase (AFMID) is an enzyme involved in the tryptophan pathway, metabolizing N-formylkynurenine to kynurenine. AFMID had been found significantly downregulated in clear cell renal cell carcinoma (ccRCC) in both tissue and urine samples. Although ccRCC is characterized by a typical Warburg-like phenotype, mitochondrial dysfunction, and elevated fat deposition, it is unknown whether AFMID plays a role in tumorigenesis and the development of ccRCC. In the present study, AFMID overexpression had inhibitory effects for ccRCC cells, decreasing the rate of cell proliferation. Quantitative proteomics showed that AFMID overexpression altered cellular signaling pathways involved in cell growth and cellular metabolism pathways, including lipid metabolism and inositol phosphate metabolism. Further urine proteomic analysis indicated that cellular function dysfunction with AFMID overexpression could be reflected in the urine. The activity of predicted upregulators DDX58, TREX1, TGFB1, SMARCA4, and TNF in ccRCC cells and urine showed opposing change trends. Potential urinary biomarkers were tentatively discovered and further validated using an independent cohort. The protein panel of APOC3, UMOD, and CILP achieved an AUC value of 0.862 for the training cohort and 0.883 for the validation cohort. The present study is of significance in terms of highlighting various aspects of pathway changes associated with AFMID enzymes, discovering potential specific biomarkers for potential patient diagnosis, and therapeutic targeting.
芳香犬尿酸-formamidase (AFMID) 是色氨酸途径中的一种酶，可将 N-甲酰犬尿氨酸代谢为犬尿氨酸。在组织和尿液样本中，均发现透明细胞肾细胞癌 (ccRCC) 中 AFMID 显著下调。尽管 ccRCC 的特征是典型的沃伯格样表型、线粒体功能障碍和脂肪沉积升高，但尚不清楚 AFMID 是否在肿瘤发生和 ccRCC 的发展中起作用。在本研究中，AFMID 的过表达对 ccRCC 细胞具有抑制作用，降低了细胞增殖率。定量蛋白质组学显示，AFMID 的过表达改变了涉及细胞生长和细胞代谢途径的细胞信号通路，包括脂质代谢和肌醇磷酸盐代谢。进一步的尿液蛋白质组分析表明，AFMID 过表达导致的细胞功能障碍可在尿液中反映出来。在 ccRCC 细胞和尿液中，预测上调物 DDX58、TREX1、TGFB1、SMARCA4 和 TNF 的活性显示出相反的变化趋势。使用独立队列初步发现并进一步验证了潜在的尿液生物标志物。APOC3、UMOD 和 CILP 蛋白组在训练队列中的 AUC 值为 0.862，在验证队列中的 AUC 值为 0.883。本研究在强调与 AFMID 酶相关的各种途径变化方面、发现潜在的特定生物标志物用于潜在的患者诊断以及治疗靶点方面具有重要意义。
