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 in order to discover novel clinical targets.
Using the TCGA database we investigated differences in membrane transporter expression in 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 HIF proteins on SLC6A3 expression by introducing siRNA in ccRCC cells and by hypoxic treatment of non-malignant cells.
We show that ccRCC express very high transcript levels of SLC6A3 in 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 that SLC6A3 expression is primarily influenced by HIF-2α, and that hypoxia can induce SLC6A3 expression in normal renal cells.
We conclude that the dopamine transporter SLC6A3 constitute 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.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2016 Sep 23 [Epub ahead of print]
Jennifer Hansson, David Lindgren, Helén Nilsson, Elinn Johansson, Martin Johansson, Lena Gustavsson, Hakan Axelson
Laboratory Medicine, Lund, Lund University., Oncology, Clinical sciences., Center for Molecular Pathology, Lund University., Laboratory Medicine, Lund University., Pathology, Lund University., Department of Drug Metabolism, Lundbeck A/S., Laboratory Medicine, Lund, Lund University .