title: Identification of the dopamine transporter SLC6A3 as a biomarker for patients with renal cell carcinoma.
abstract: BACKGROUND
  Clear cell renal cell carcinoma (ccRCC) is among the most common human malignancies.
  
  
  METHODS
  In order to provide better understanding of the molecular biology of ccRCC and to identify potential diagnostic/prognostic biomarker and therapeutic targets, we utilized a microarray to profile mRNA expression of corresponding normal and malignant renal tissues. Real-time PCR, Western Blot and immunohistochemistry were applied to study the expression of candidate biomarkers. ccRCC cell lines were treated with sertraline to inhibit the dopamine transporter SLC6A3.
  
  
  RESULTS
  Differential expression of fourteen mRNAs, yet not studied in ccRCC in depth, was confirmed using qPCR (upregulation: SLC6A3, NPTX2, TNFAIP6, NDUFA4L2, ENPP3, FABP6, SPINK13; downregulation: FXYD4, SLC12A1, KNG1, NPHS2, SLC13A3, GCGR, PLG). Up-/downregulation was also confirmed for FXYD4, KNG1, NPTX2 and SLC12A1 by Western Blot on the protein level. In contrast to the mRNA expression, protein expression of the dopamine transporter SLC6A3 was lower in ccRCC compared to normal renal tissue. Immunohistochemistry indicated that this decrease was due to higher concentrations of SLC6A3 in the proximal tubules. Immunohistochemical analyses further demonstrated that high SLC6A3 expression in ccRCC tissue was correlated with a shorter period of recurrence-free survival following surgery. Treatment of ccRCC cells with the SLC6A3 inhibitor sertraline induced dose-dependent cell-death.
  
  
  CONCLUSIONS
  Our study identified several novel biomarkers with diagnostic potential and further investigations on sertraline as therapeutic agent in ccRCC patients are warranted.
authors.affiliation: Department of Urology, University Hospital Bonn, Bonn, Germany. sarah.schroedter@hotmail.de.
authors.forename: Sarah
authors.initials: S
authors.lastname: Schrödter
authors.affiliation: Section for Prostate Cancer Research, Institute of Pathology, Center for Integrated Oncology, University Hospital Bonn, Cologne/Bonn, Germany. martin.braun85@googlemail.com.
authors.forename: Martin
authors.initials: M
authors.lastname: Braun
authors.affiliation: Department of Urology, University Hospital Bonn, Bonn, Germany. isabella.syring@ukb.uni-bonn.de.|Section for Prostate Cancer Research, Institute of Pathology, Center for Integrated Oncology, University Hospital Bonn, Cologne/Bonn, Germany. isabella.syring@ukb.uni-bonn.de.
authors.forename: Isabella
authors.initials: I
authors.lastname: Syring
authors.affiliation: Section for Prostate Cancer Research, Institute of Pathology, Center for Integrated Oncology, University Hospital Bonn, Cologne/Bonn, Germany. niklaskluemper1992@gmail.com.
authors.forename: Niklas
authors.initials: N
authors.lastname: Klümper
authors.affiliation: Section for Prostate Cancer Research, Institute of Pathology, Center for Integrated Oncology, University Hospital Bonn, Cologne/Bonn, Germany. mariodeng@googlemail.com.|Klinik und Poliklinik für Urologie und Kinderurologie, Universitätsklinikum Bonn, Sigmund-Freud-Strasse 25, 53105, Bonn, Germany. mariodeng@googlemail.com.
authors.forename: Mario
authors.initials: M
authors.lastname: Deng
authors.affiliation: Department of Urology, University Hospital Bonn, Bonn, Germany. Doris.Schmidt@ukb.uni-bonn.de.
authors.forename: Doris
authors.initials: D
authors.lastname: Schmidt
authors.affiliation: Section for Prostate Cancer Research, Institute of Pathology, Center for Integrated Oncology, University Hospital Bonn, Cologne/Bonn, Germany. sven.perner1972@googlemail.com.
authors.forename: Sven
authors.initials: S
authors.lastname: Perner
authors.affiliation: Department of Urology, University Hospital Bonn, Bonn, Germany. Stefan.Mueller@ukb.uni-bonn.de.
authors.forename: Stefan C
authors.initials: SC
authors.lastname: Müller
authors.affiliation: Department of Urology, University Hospital Bonn, Bonn, Germany. joerg.ellinger@ukb.uni-bonn.de.|Klinik und Poliklinik für Urologie und Kinderurologie, Universitätsklinikum Bonn, Sigmund-Freud-Strasse 25, 53105, Bonn, Germany. joerg.ellinger@ukb.uni-bonn.de.
authors.forename: Jörg
authors.initials: J
authors.lastname: Ellinger
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D050483:Dopamine Plasma Membrane Transport Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015203:Reproducibility of Results; D020280:Sertraline / Q000494:pharmacology
chemical_list: D014408:Biomarkers, Tumor; D050483:Dopamine Plasma Membrane Transport Proteins; D012333:RNA, Messenger; C493214:SLC6A3 protein, human; D020280:Sertraline
references.citation: Nat Med. 2009 Mar;15(3):319-24
references.pmid: 19252501
references.citation: Clin Epigenetics. 2015 Feb 08;7:10
references.pmid: 25685243
references.citation: Nucleic Acids Res. 2016 Jan 8;44(1):e1
references.pmid: 26264667
references.citation: PLoS One. 2010;5(9). pii: e13066. doi: 10.1371/journal.pone.0013066
references.pmid: 20927376
references.citation: Eur J Cancer. 2013 Apr;49(6):1374-403
references.pmid: 23485231
references.citation: Nucleic Acids Res. 2014 Jan;42(Database issue):D472-7
references.pmid: 24243840
references.citation: Nat Genet. 2012 Jul;44(7):751-9
references.pmid: 22683710
references.citation: BMC Syst Biol. 2010;4:51
references.pmid: 20420713
references.citation: Blood. 2004 Oct 1;104(7):2065-72
references.pmid: 15161672
references.citation: Cancer Cell. 2011 Oct 18;20(4):511-23
references.pmid: 22014576
references.citation: Kidney Int. 2008 May;73(10):1114-9
references.pmid: 18272958
references.citation: J Urol. 2014 Jun;191(6):1665-70
references.pmid: 24423441
references.citation: Nature. 2013 Jul 4;499(7456):43-9
references.pmid: 23792563
references.citation: Nat Genet. 2013 Aug;45(8):860-7
references.pmid: 23797736
references.citation: Biomed Pharmacother. 2013 Apr;67(3):240-5
references.pmid: 23462296
references.citation: Histol Histopathol. 2013 May;28(5):605-10
references.pmid: 23361561
references.citation: Int J Cancer. 2010 Nov 15;127(10):2360-6
references.pmid: 20162570
references.citation: BMC Mol Biol. 2007;8:47
references.pmid: 17559644
references.citation: Semin Oncol. 2013 Aug;40(4):429-35
references.pmid: 23972706
references.citation: Cancer Res. 2014 Sep 1;74(17):4796-810
references.pmid: 24962026
references.citation: Eur J Pharmacol. 1997 Dec 11;340(2-3):249-58
references.pmid: 9537821
references.citation: Nat Genet. 2014 Mar;46(3):225-33
references.pmid: 24487277
references.citation: Cancer Discov. 2012 May;2(5):401-4
references.pmid: 22588877
references.citation: BMC Genomics. 2008;9:246
references.pmid: 18501003
references.citation: Mol Cell Proteomics. 2004 Oct;3(10):960-9
references.pmid: 15238602
references.citation: Ann N Y Acad Sci. 2003 Apr;986:382-7
references.pmid: 12763854
references.citation: Genom Data. 2015 Jun 14;5:173-5
references.pmid: 26484251
references.citation: Toxicol Sci. 2014 Feb;137(2):404-15
references.pmid: 24194395
references.citation: Eur Urol. 2015 Jan;67(1):100-10
references.pmid: 24841777
references.citation: Expert Rev Neurother. 2008 Apr;8(4):611-25
references.pmid: 18416663
references.citation: Dig Dis Sci. 2012 Oct;57(10):2608-14
references.pmid: 22806544
references.citation: Neoplasma. 2014;61(1):17-26
references.pmid: 24195504