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Overexpression of functional SLC6A3 in clear cell renal cell carcinoma

Hansson, Jennifer LU ; Lindgren, David LU ; Nilsson, Helén LU ; Johansson, Elinn LU ; Johansson, Martin LU ; Gustavsson, Lena LU and Axelson, Håkan LU (2017) In Clinical Cancer Research 23(8). p.2105-2115
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 in order to discover novel clinical targets.

EXPERIMENTAL DESIGN: 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... (More)

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 in order to discover novel clinical targets.

EXPERIMENTAL DESIGN: 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.

RESULTS: 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.

CONCLUSIONS: 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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Clinical Cancer Research
volume
23
issue
8
pages
2105 - 2115
publisher
American Association for Cancer Research
external identifiers
  • scopus:85018839887
  • wos:000399188300026
ISSN
1078-0432
DOI
10.1158/1078-0432.CCR-16-0496
language
English
LU publication?
yes
id
da7aaacb-904a-4e16-af8d-063f0e350343
date added to LUP
2016-11-30 08:58:51
date last changed
2018-01-07 11:37:37
@article{da7aaacb-904a-4e16-af8d-063f0e350343,
  abstract     = {<p>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 in order to discover novel clinical targets.</p><p>EXPERIMENTAL DESIGN: 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.</p><p>RESULTS: 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.</p><p>CONCLUSIONS: 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.</p>},
  author       = {Hansson, Jennifer and Lindgren, David and Nilsson, Helén and Johansson, Elinn and Johansson, Martin and Gustavsson, Lena and Axelson, Håkan},
  issn         = {1078-0432},
  language     = {eng},
  number       = {8},
  pages        = {2105--2115},
  publisher    = {American Association for Cancer Research},
  series       = {Clinical Cancer Research},
  title        = {Overexpression of functional SLC6A3 in clear cell renal cell carcinoma},
  url          = {http://dx.doi.org/10.1158/1078-0432.CCR-16-0496},
  volume       = {23},
  year         = {2017},
}