Transferrin receptor 1 upregulation in primary tumor and downregulation in benign kidney is associated with progression and mortality in renal cell carcinoma patients

Abstract

// Christopher J. Greene 1 , Kristopher Attwood 2 , Nitika J. Sharma 1 , Kenneth W. Gross 3 , Gary J. Smith 1 , Bo Xu 4 and Eric C. Kauffman 1, 5, 6 1 Department of Urology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA 2 Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA 3 Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA 4 Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA 5 Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA 6 Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214, USA Correspondence to: Eric C. Kauffman, email: eric.kauffman@roswellpark.org Keywords: transferrin receptor; iron; renal cell carcinoma; clear cell; immunohistochemistry Received: May 19, 2017 Accepted: August 31, 2017 Published: November 06, 2017 ABSTRACT The central dysregulated pathway of clear cell (cc) renal cell carcinoma (RCC), the von Hippel Lindau/hypoxia inducible factor-α axis, is a key regulator of intracellular iron levels, however the role of iron uptake in human RCC tumorigenesis and progression remains unknown. We conducted a thorough, large-scale investigation of the expression and prognostic significance of the primary iron uptake protein, transferrin receptor 1 (TfR1/CD71/TFRC), in RCC patients. TfR1 immunohistochemistry was performed in over 1500 cores from 574 renal cell tumor patient tissues (primary tumors, matched benign kidneys, metastases) and non-neoplastic tissues from 36 different body sites. TfR1 levels in RCC tumors, particularly ccRCC, were significantly associated with adverse clinical prognostic features (anemia, lower body mass index, smoking), worse tumor pathology (size, stage, grade, multifocality, sarcomatoid dedifferentiation) and worse survival outcomes, including after adjustments for tumor pathology. Highest TfR1 tissue levels in the non-gravid body were detected in benign renal tubule epithelium. Opposite to TfR1 changes in the primary tumor, TfR1 levels in benign kidney dropped during tumor progression and were inversely associated with worse survival outcomes, independent of tumor pathology. Quantitative measurement of TfR1 subcellular localization in cell lines demonstrated mixed cytoplasmic and membranous expression with increased TfR1 in clusters in ccRCC versus benign renal cell lines. Results of this study support an important role for TfR1 in RCC progression and identify TfR1 as a novel RCC biomarker and therapeutic target.