Abstract. Clear cell renal cell carcinoma (ccRCC) features a Von Hippel-Lindau mutation, associated with a hypoxia-inducible factor (HIF) imbalance. Copper transporter 1 (CTR1) may also promote tumor progression through the modulation of the HIF

Clear cell renal cell carcinoma (ccRCC) features a Von Hippel-Lindau mutation, associated with a hypoxia-inducible factor (HIF) imbalance. Copper transporter 1 (CTR1) may also promote tumor progression through the modulation of the HIF pathway by copper. Therefore, the present study explored the prognostic effect of tumor CTR1 expression in patients with ccRCC. A total of 293 patients with ccRCC that underwent nephrectomy were retrospectively enrolled. CTR1 expression was assessed by immunohistochemistry, and its association with clinicopathological features and prognosis were evaluated. The present data indicated that high tumor CTR1 expression was independently associated with poor overall survival (OS) [hazard ratio, 2.291; 95% confidence interval (CI), 1.389-3.777; P<0.001] and disease-free survival (DFS) (hazard ratio, 2.210; 95% CI, 1.299-3.759; P=0.003) rates in patients with ccRCC. Furthermore, CTR1 expression was significantly higher for Mayo Clinic stage, size, grade and necrosis score risk groups, and could be incorporated into several existing prognostic models to improve performance. Nomograms incorporating tumor CTR1 expression with other parameters performed well in the 5and 8-year OS and DFS rate predictions of patients (concordance index 0.805 and 0.787, respectively). In conclusion, the present study demonstrated that CTR1 expression is a potential independent biomarker for poor prognosis for the recurrence and survival prediction of patients with ccRCC following nephrectomy. Introduction Renal cell carcinoma (RCC) accounts for 2-3% of all cases of malignancy in adults globally in 2014 (1). Although associated diagnostic techniques and targeted therapies have greatly improved in recent decades, in 2004, 20-30% of RCC patients were diagnosed with metastatic disease, and a further one-third of patients with localized disease that undergo curative surgery subsequently experience recurrence or metastasis in North America (2). The tumor-node-metastasis (TNM) stage (3) and Fuhrman grade (4) systems remain the most used outcome predictors; several integrated models have also been established, including the Mayo Clinic stage, size, grade and necrosis (SSIGN) score (5) and the University of California Integrated Staging System (UISS) (6); however, these parameters are not entirely reliable (7). In the era of precision medicine, it is expected that specific molecular biomarkers will provide supplementary prognostic information that may be incorporated into existing conventional models for the improved prediction of patient prognosis (8). Copper transporter (CTR) 1, encoded by the SLC31A1 gene, has been characterized as a high-affinity copper transporter since its identification in 1997 (9). This membrane-bound molecule is the major driving force in facilitating copper import, and thus may raise the Cu2+ concentration in expressing cells (10). Copper, as an essential trace mineral, serves an important role in the regulation of human physiological functions; its aberrant upregulation may promote tumor angiogenesis and progression in various types of cancer (11-13). This oncogenic potential is partially associated with the stimulation of the hypoxia-inducible factor (HIF) pathway by copper. For example, a previous study has identified that copper serves an essential role in the HIF-1α/hypoxia response element-binding process; high concentrations of Cu2+ may stabilize HIF-1α in the nucleus and activate downstream signals, including the upregulation of vascular endothelial growth factor (VEGF), and induce the epithelial‐mesenchymal transition (EMT) (14). CTR1-knockdown, leading to reduced intracellular copper, has been demonstrated to inhibit angiogenesis and EMT in multiple types of cell, including human breast cancer and endothelial cells (15,16). Clinical trials with copper chelation therapy for metastatic diseases have also generated promising data (17). Prognostic value of copper transporter 1 expression in patients with clear cell renal cell carcinoma YU XIA1*, LI LIU1*, QI BAI1*, QILAI LONG1, JIAJUN WANG1, WEI XI1, JIEJIE XU2 and JIANMING GUO1 1Department of Urology, Zhongshan Hospital; 2Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R. China Received April 18, 2016; Accepted July 5, 2017 DOI: 10.3892/ol.2017. 6942 Correspondence to: Dr Jiejie Xu, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, 138 Yi Xue Yuan Road, Shanghai 200032, P.R. China E-mail: jjxufdu@fudan.edu. cn Dr Jianming Guo, Department of Urology, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai 200032, P.R. China E-mail: guo.jianming@zs-hospital.sh. cn *Contributed equally