Department of Molecular Biology and Genetics, Koc University, Istanbul, Turkey.
Department of Pathology, Koc University School of Medicine, Istanbul, Turkey.
Mol Cancer Res. 2021 Aug;19(8):1322-1337. doi: 10.1158/1541-7786.MCR-21-0004. Epub 2021 May 11.
Clear cell renal cell carcinoma (ccRCC) is the third most common and most malignant urological cancer, with a 5-year survival rate of 10% for patients with advanced tumors. Here, we identified 10,160 unique proteins by in-depth quantitative proteomics, of which 955 proteins were significantly regulated between tumor and normal adjacent tissues. We verified four putatively secreted biomarker candidates, namely, PLOD2, FERMT3, SPARC, and SIRPα, as highly expressed proteins that are not affected by intratumor and intertumor heterogeneity. Moreover, SPARC displayed a significant increase in urine samples of patients with ccRCC, making it a promising marker for the detection of the disease in body fluids. Furthermore, based on molecular expression profiles, we propose a biomarker panel for the robust classification of ccRCC tumors into two main clusters, which significantly differed in patient outcome with an almost three times higher risk of death for cluster 1 tumors compared with cluster 2 tumors. Moreover, among the most significant clustering proteins, 13 were targets of repurposed inhibitory FDA-approved drugs. Our rigorous proteomics approach identified promising diagnostic and tumor-discriminative biomarker candidates which can serve as therapeutic targets for the treatment of ccRCC. IMPLICATIONS: Our in-depth quantitative proteomics analysis of ccRCC tissues identifies the putatively secreted protein SPARC as a promising urine biomarker and reveals two molecular tumor phenotypes.
透明细胞肾细胞癌（ccRCC）是第三大常见且最恶性的泌尿系统癌症，晚期肿瘤患者的 5 年生存率为 10%。在这里，我们通过深入的定量蛋白质组学鉴定了 10160 种独特的蛋白质，其中 955 种蛋白质在肿瘤和正常相邻组织之间存在显著调节。我们验证了四个推定的分泌生物标志物候选物，即 PLOD2、FERMT3、SPARC 和 SIRPα，它们作为高度表达的蛋白质不受肿瘤内和肿瘤间异质性的影响。此外，SPARC 在 ccRCC 患者的尿液样本中表达显著增加，使其成为体液疾病检测的有前途的标志物。此外，基于分子表达谱，我们提出了一个用于 ccRCC 肿瘤的稳健分类的生物标志物面板，该面板将肿瘤分为两个主要簇，簇 1 肿瘤的患者预后明显不同，与簇 2 肿瘤相比，死亡风险高近三倍。此外，在最显著的聚类蛋白中，有 13 个是重新利用的 FDA 批准的抑制性药物的靶点。我们严格的蛋白质组学方法鉴定了有前途的诊断和肿瘤鉴别生物标志物候选物，它们可以作为治疗 ccRCC 的治疗靶点。意义：我们对 ccRCC 组织的深入定量蛋白质组学分析确定了推定的分泌蛋白 SPARC 作为一种很有前途的尿液生物标志物，并揭示了两种分子肿瘤表型。
