title: Down-Regulation of SLC8A1 as a Putative Apoptosis Evasion Mechanism by Modulation of Calcium Levels in Penile Carcinoma.
abstract: OBJECTIVE
  The SLC8A1 gene, which encodes the Na(+)/Ca(2+) exchanger, has a key role in calcium homeostasis. Our previous gene expression oligoarray data revealed SLC8A1 under expression in penile carcinoma. We investigated whether dysregulation of SLC8A1 expression is associated with apoptosis and cell proliferation in penile carcinoma via modulation of the calcium concentration. The underlying mechanisms of SLC8A1 under expression were also explored, focusing on copy number alteration and miRNA.
  
  
  METHODS
  Transcript levels of the SLC8A1 gene and miR-223 were evaluated by quantitative polymerase chain reaction to compare penile carcinoma samples with normal glans tissue. SLC8A1 copy number was evaluated by microarray based comparative genomic hybridization. In normal and tumor samples we investigated caspase-3 and Ki-67 immunostaining as well as calcium distribution by laser ablation imaging inductively coupled plasma mass spectrometry.
  
  
  RESULTS
  SLC8A1 under expression was detected in penile carcinoma samples (p = 0.001), confirming our previous data. It was not associated with gene copy number loss. In contrast, miR-223 over expression (p = 0.002) inversely correlated with its putative repressor SLC8A1 (r = -0.426, p = 0.015). SLC8A1 under expression was associated with decreased calcium distribution, high Ki-67 and low caspase-3 immunoexpression in penile carcinoma compared to normal tissue.
  
  
  CONCLUSIONS
  Down-regulation of the SLC8A1 gene, most likely mediated by its regulator miR-223, can lead to decreased calcium in penile carcinoma and consequently to suppressed apoptosis and increased tumor cell proliferation. These data suggest that the miR-223-NCX1-calcium signaling axis may represent a potential therapeutic approach to penile carcinoma.
authors.affiliation: International Research Center (JJM, MCB-F, FAM, SRR), A.C. Camargo Cancer Center, São Paulo, Brazil; Department of Pelvic Surgery (AL), A.C. Camargo Cancer Center, São Paulo, Brazil; Department of Pathology, Barretos Cancer Hospital (CS-N), São Paulo, Brazil; Department of Genetics, Institute of Biosciences (JJM), São Paulo State University-Universidade Estadual Paulista, Botucatu, Brazil; Department of Urology, Faculty of Medicine (SAD, JCSTF, SRR), São Paulo State University-Universidade Estadual Paulista, Botucatu, Brazil; Group of Spectrometry, Sample Preparation and Mechanization (GSP, MAZA), Institute of Chemistry, State University of Campinas, Campinas, Brazil; National Institute of Science and Technology for Bioanalytics, Institute of Chemistry, State University of Campinas, Campinas, Brazil.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Muñoz
authors.affiliation: International Research Center (JJM, MCB-F, FAM, SRR), A.C. Camargo Cancer Center, São Paulo, Brazil; Department of Pelvic Surgery (AL), A.C. Camargo Cancer Center, São Paulo, Brazil; Department of Pathology, Barretos Cancer Hospital (CS-N), São Paulo, Brazil; Department of Genetics, Institute of Biosciences (JJM), São Paulo State University-Universidade Estadual Paulista, Botucatu, Brazil; Department of Urology, Faculty of Medicine (SAD, JCSTF, SRR), São Paulo State University-Universidade Estadual Paulista, Botucatu, Brazil; Group of Spectrometry, Sample Preparation and Mechanization (GSP, MAZA), Institute of Chemistry, State University of Campinas, Campinas, Brazil; National Institute of Science and Technology for Bioanalytics, Institute of Chemistry, State University of Campinas, Campinas, Brazil.
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Drigo
authors.affiliation: International Research Center (JJM, MCB-F, FAM, SRR), A.C. Camargo Cancer Center, São Paulo, Brazil; Department of Pelvic Surgery (AL), A.C. Camargo Cancer Center, São Paulo, Brazil; Department of Pathology, Barretos Cancer Hospital (CS-N), São Paulo, Brazil; Department of Genetics, Institute of Biosciences (JJM), São Paulo State University-Universidade Estadual Paulista, Botucatu, Brazil; Department of Urology, Faculty of Medicine (SAD, JCSTF, SRR), São Paulo State University-Universidade Estadual Paulista, Botucatu, Brazil; Group of Spectrometry, Sample Preparation and Mechanization (GSP, MAZA), Institute of Chemistry, State University of Campinas, Campinas, Brazil; National Institute of Science and Technology for Bioanalytics, Institute of Chemistry, State University of Campinas, Campinas, Brazil.
authors.forename: Mateus C
authors.initials: MC
authors.lastname: Barros-Filho
authors.affiliation: International Research Center (JJM, MCB-F, FAM, SRR), A.C. Camargo Cancer Center, São Paulo, Brazil; Department of Pelvic Surgery (AL), A.C. Camargo Cancer Center, São Paulo, Brazil; Department of Pathology, Barretos Cancer Hospital (CS-N), São Paulo, Brazil; Department of Genetics, Institute of Biosciences (JJM), São Paulo State University-Universidade Estadual Paulista, Botucatu, Brazil; Department of Urology, Faculty of Medicine (SAD, JCSTF, SRR), São Paulo State University-Universidade Estadual Paulista, Botucatu, Brazil; Group of Spectrometry, Sample Preparation and Mechanization (GSP, MAZA), Institute of Chemistry, State University of Campinas, Campinas, Brazil; National Institute of Science and Technology for Bioanalytics, Institute of Chemistry, State University of Campinas, Campinas, Brazil.
authors.forename: Fábio A
authors.initials: FA
authors.lastname: Marchi
authors.affiliation: International Research Center (JJM, MCB-F, FAM, SRR), A.C. Camargo Cancer Center, São Paulo, Brazil; Department of Pelvic Surgery (AL), A.C. Camargo Cancer Center, São Paulo, Brazil; Department of Pathology, Barretos Cancer Hospital (CS-N), São Paulo, Brazil; Department of Genetics, Institute of Biosciences (JJM), São Paulo State University-Universidade Estadual Paulista, Botucatu, Brazil; Department of Urology, Faculty of Medicine (SAD, JCSTF, SRR), São Paulo State University-Universidade Estadual Paulista, Botucatu, Brazil; Group of Spectrometry, Sample Preparation and Mechanization (GSP, MAZA), Institute of Chemistry, State University of Campinas, Campinas, Brazil; National Institute of Science and Technology for Bioanalytics, Institute of Chemistry, State University of Campinas, Campinas, Brazil.
authors.forename: Cristovam
authors.initials: C
authors.lastname: Scapulatempo-Neto
authors.affiliation: International Research Center (JJM, MCB-F, FAM, SRR), A.C. Camargo Cancer Center, São Paulo, Brazil; Department of Pelvic Surgery (AL), A.C. Camargo Cancer Center, São Paulo, Brazil; Department of Pathology, Barretos Cancer Hospital (CS-N), São Paulo, Brazil; Department of Genetics, Institute of Biosciences (JJM), São Paulo State University-Universidade Estadual Paulista, Botucatu, Brazil; Department of Urology, Faculty of Medicine (SAD, JCSTF, SRR), São Paulo State University-Universidade Estadual Paulista, Botucatu, Brazil; Group of Spectrometry, Sample Preparation and Mechanization (GSP, MAZA), Institute of Chemistry, State University of Campinas, Campinas, Brazil; National Institute of Science and Technology for Bioanalytics, Institute of Chemistry, State University of Campinas, Campinas, Brazil.
authors.forename: Gustavo S
authors.initials: GS
authors.lastname: Pessoa
authors.affiliation: International Research Center (JJM, MCB-F, FAM, SRR), A.C. Camargo Cancer Center, São Paulo, Brazil; Department of Pelvic Surgery (AL), A.C. Camargo Cancer Center, São Paulo, Brazil; Department of Pathology, Barretos Cancer Hospital (CS-N), São Paulo, Brazil; Department of Genetics, Institute of Biosciences (JJM), São Paulo State University-Universidade Estadual Paulista, Botucatu, Brazil; Department of Urology, Faculty of Medicine (SAD, JCSTF, SRR), São Paulo State University-Universidade Estadual Paulista, Botucatu, Brazil; Group of Spectrometry, Sample Preparation and Mechanization (GSP, MAZA), Institute of Chemistry, State University of Campinas, Campinas, Brazil; National Institute of Science and Technology for Bioanalytics, Institute of Chemistry, State University of Campinas, Campinas, Brazil.
authors.forename: Gustavo C
authors.initials: GC
authors.lastname: Guimarães
authors.affiliation: International Research Center (JJM, MCB-F, FAM, SRR), A.C. Camargo Cancer Center, São Paulo, Brazil; Department of Pelvic Surgery (AL), A.C. Camargo Cancer Center, São Paulo, Brazil; Department of Pathology, Barretos Cancer Hospital (CS-N), São Paulo, Brazil; Department of Genetics, Institute of Biosciences (JJM), São Paulo State University-Universidade Estadual Paulista, Botucatu, Brazil; Department of Urology, Faculty of Medicine (SAD, JCSTF, SRR), São Paulo State University-Universidade Estadual Paulista, Botucatu, Brazil; Group of Spectrometry, Sample Preparation and Mechanization (GSP, MAZA), Institute of Chemistry, State University of Campinas, Campinas, Brazil; National Institute of Science and Technology for Bioanalytics, Institute of Chemistry, State University of Campinas, Campinas, Brazil.
authors.forename: José Carlos S
authors.initials: JC
authors.lastname: Trindade Filho
authors.affiliation: International Research Center (JJM, MCB-F, FAM, SRR), A.C. Camargo Cancer Center, São Paulo, Brazil; Department of Pelvic Surgery (AL), A.C. Camargo Cancer Center, São Paulo, Brazil; Department of Pathology, Barretos Cancer Hospital (CS-N), São Paulo, Brazil; Department of Genetics, Institute of Biosciences (JJM), São Paulo State University-Universidade Estadual Paulista, Botucatu, Brazil; Department of Urology, Faculty of Medicine (SAD, JCSTF, SRR), São Paulo State University-Universidade Estadual Paulista, Botucatu, Brazil; Group of Spectrometry, Sample Preparation and Mechanization (GSP, MAZA), Institute of Chemistry, State University of Campinas, Campinas, Brazil; National Institute of Science and Technology for Bioanalytics, Institute of Chemistry, State University of Campinas, Campinas, Brazil.
authors.forename: Ademar
authors.initials: A
authors.lastname: Lopes
authors.affiliation: International Research Center (JJM, MCB-F, FAM, SRR), A.C. Camargo Cancer Center, São Paulo, Brazil; Department of Pelvic Surgery (AL), A.C. Camargo Cancer Center, São Paulo, Brazil; Department of Pathology, Barretos Cancer Hospital (CS-N), São Paulo, Brazil; Department of Genetics, Institute of Biosciences (JJM), São Paulo State University-Universidade Estadual Paulista, Botucatu, Brazil; Department of Urology, Faculty of Medicine (SAD, JCSTF, SRR), São Paulo State University-Universidade Estadual Paulista, Botucatu, Brazil; Group of Spectrometry, Sample Preparation and Mechanization (GSP, MAZA), Institute of Chemistry, State University of Campinas, Campinas, Brazil; National Institute of Science and Technology for Bioanalytics, Institute of Chemistry, State University of Campinas, Campinas, Brazil.
authors.forename: Marco A Z
authors.initials: MA
authors.lastname: Arruda
authors.affiliation: International Research Center (JJM, MCB-F, FAM, SRR), A.C. Camargo Cancer Center, São Paulo, Brazil; Department of Pelvic Surgery (AL), A.C. Camargo Cancer Center, São Paulo, Brazil; Department of Pathology, Barretos Cancer Hospital (CS-N), São Paulo, Brazil; Department of Genetics, Institute of Biosciences (JJM), São Paulo State University-Universidade Estadual Paulista, Botucatu, Brazil; Department of Urology, Faculty of Medicine (SAD, JCSTF, SRR), São Paulo State University-Universidade Estadual Paulista, Botucatu, Brazil; Group of Spectrometry, Sample Preparation and Mechanization (GSP, MAZA), Institute of Chemistry, State University of Campinas, Campinas, Brazil; National Institute of Science and Technology for Bioanalytics, Institute of Chemistry, State University of Campinas, Campinas, Brazil. Electronic address: silvia.rogatto@cipe.accamargo.org.br.
authors.forename: Silvia R
authors.initials: SR
authors.lastname: Rogatto
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D010412:Penile Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D019831:Sodium-Calcium Exchanger / Q000235:genetics*; D055815:Young Adult
chemical_list: D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1; D002118:Calcium
keywords: MIRN223 microRNA; calcium; carcinoma; human; penis; sodium-calcium exchanger 1