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Overexpression of Functional SLC6A3 in Clear Cell Renal Cell Carcinoma.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2017 Apr 15; Vol. 23 (8), pp. 2105-2115. Date of Electronic Publication: 2016 Sep 23. - Publication Year :
- 2017
-
Abstract
- 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 [ <superscript>3</superscript> H]-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 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. 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 .<br /> (©2016 American Association for Cancer Research.)
- Subjects :
- Blotting, Western
Carcinoma, Renal Cell metabolism
Cluster Analysis
Humans
Kidney Neoplasms metabolism
Real-Time Polymerase Chain Reaction
Transcriptome
Up-Regulation
Biomarkers, Tumor analysis
Carcinoma, Renal Cell pathology
Dopamine Plasma Membrane Transport Proteins biosynthesis
Kidney Neoplasms pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 23
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 27663598
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-16-0496