Overexpression of Functional SLC6A3 in Clear Cell Renal Cell Carcinoma.
Purpose:Renal cell carcinoma (RCC) is derived from a tissue with a remarkable capacity for vectorial transport. We therefore performed an unbiased exploration of transporter proteins in normal kidney and kidney cancer to discover novel clinical targets.Experimental Design:Using The Cancer Genome Atlas (TCGA) database, we investigated differences in membrane transporter expression in clear cell RCC (ccRCC) and normal kidney. We identified the dopamine transporter SLC6A3 as a specific biomarker for ccRCC. To investigate the functionality of SLC6A3, we used a [3H]-dopamine uptake assay on ccRCC cells. We further explored the effect of hypoxia-inducible factor (HIF) proteins on SLC6A3 expression by introducing siRNA in ccRCC cells and by hypoxic treatment of nonmalignant cells.Results:We show that ccRCC expresses very high transcript levels ofSLC6A3in contrast to normal kidney tissue and other tumor types, which do not express appreciable levels of this transporter. Importantly, we demonstrate that the elevated expression of SLC6A3 in ccRCC cells is associated with specific uptake of dopamine. By targeting the expression of HIF-1α and HIF-2α, we could show thatSLC6A3expression is primarily influenced by HIF-2α and that hypoxia can induceSLC6A3expression in normal renal cells.Conclusions:We conclude that the dopamine transporter SLC6A3 constitutes a novel biomarker that is highly specific for ccRCC. We further postulate that the protein can be exploited for diagnostic or therapeutic purposes for detection or treatment of ccRCC.Clin Cancer Res; 23(8); 2105-15. ©2016 AACR.
Translational Cancer Research, Department of Laboratory Medicine, Lund University, Medicon Village, Lund, Sweden.
Jennifer
J
Hansson
Translational Cancer Research, Department of Laboratory Medicine, Lund University, Medicon Village, Lund, Sweden.
David
D
Lindgren
Center for Molecular Pathology, Department of Translational Medicine, Lund University, Department of Pathology, Skåne University Hospital, Malmö, Sweden.
Helén
H
Nilsson
Translational Cancer Research, Department of Laboratory Medicine, Lund University, Medicon Village, Lund, Sweden.
Elinn
E
Johansson
Center for Molecular Pathology, Department of Translational Medicine, Lund University, Department of Pathology, Skåne University Hospital, Malmö, Sweden.
Martin
M
Johansson
Department of Drug Metabolism, H. Lundbeck A/S, Valby, Denmark.
Lena
L
Gustavsson
Translational Cancer Research, Department of Laboratory Medicine, Lund University, Medicon Village, Lund, Sweden. hakan.axelson@med.lu.se.
Håkan
H
Axelson
D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology*; D016000:Cluster Analysis; D050483:Dopamine Plasma Membrane Transport Proteins / Q000096:biosynthesis*; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D059467:Transcriptome; D015854:Up-Regulation
D014408:Biomarkers, Tumor; D050483:Dopamine Plasma Membrane Transport Proteins; C493214:SLC6A3 protein, human