title: MCT4 surpasses the prognostic relevance of the ancillary protein CD147 in clear cell renal cell carcinoma.
abstract: Cluster of differentiation 147 (CD147/BSG) is a transmembrane glycoprotein mediating oncogenic processes partly through its role as binding partner for monocarboxylate transporter MCT4/SLC16A3. As demonstrated for MCT4, CD147 is proposed to be associated with progression in clear cell renal cell carcinoma (ccRCC). In this study, we evaluated the prognostic relevance of CD147 in comparison to MCT4/SLC16A3 expression and DNA methylation.
  
  
  METHODS
  CD147 protein expression was assessed in two independent ccRCC-cohorts (n = 186, n = 59) by immunohistochemical staining of tissue microarrays and subsequent manual as well as automated software-supported scoring (Tissue Studio, Definien sAG). Epigenetic regulation of CD147 was investigated using RNAseq and DNA methylation data of The Cancer Genome Atlas. These results were validated in our cohort. Relevance of prognostic models for cancer-specific survival, comprising CD147 and MCT4 expression or SLC16A3 DNA methylation, was compared using chi-square statistics.
  
  
  RESULTS
  CD147 protein expression generated with Tissue Studio correlated significantly with those from manual scoring (P < 0.0001, rS = 0.85), indicating feasibility of software-based evaluation exemplarily for the membrane protein CD147 in ccRCC. Association of CD147 expression with patient outcome differed between cohorts. DNA methylation in the CD147/BSG promoter was not associated with expression. Comparison of prognostic relevance of CD147/BSG and MCT4/SLC16A3, showed higher significance for MCT4 expression and superior prognostic power for DNA methylation at specific CpG-sites in the SLC16A3 promoter (e.g. CD147 protein: P = 0.7780,Harrell's c-index = 53.7% vs. DNA methylation: P = 0.0076, Harrell's c-index = 80.0%).
  
  
  CONCLUSIONS
  Prognostic significance of CD147 protein expression could not surpass that of MCT4, especially of SLC16A3 DNA methylation, corroborating the role of MCT4 as prognostic biomarker for ccRCC.
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.|University of Tuebingen, Tuebingen, Germany.
authors.forename: Pascale
authors.initials: P
authors.lastname: Fisel
authors.affiliation: Department of Urology, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Viktoria
authors.initials: V
authors.lastname: Stühler
authors.affiliation: Department of Urology, University Hospital Tuebingen, Tuebingen, Germany.|German Cancer Consortium (DKTK) and German Cancer Reseach Center (DKFZ), Heidelberg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Bedke
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.|University of Tuebingen, Tuebingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Winter
authors.affiliation: Department of Urology, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Rausch
authors.affiliation: Department of Urology, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Hennenlotter
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.|University of Tuebingen, Tuebingen, Germany.
authors.forename: Anne T
authors.initials: AT
authors.lastname: Nies
authors.affiliation: Department of Urology, University Hospital Tuebingen, Tuebingen, Germany.|German Cancer Consortium (DKTK) and German Cancer Reseach Center (DKFZ), Heidelberg, Germany.
authors.forename: Arnulf
authors.initials: A
authors.lastname: Stenzl
authors.affiliation: Institute of Pathology and Neuropathology, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Scharpf
authors.affiliation: Institute of Pathology and Neuropathology, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Falko
authors.initials: F
authors.lastname: Fend
authors.affiliation: Department of Urology, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Kruck
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.|University of Tuebingen, Tuebingen, Germany.|German Cancer Consortium (DKTK) and German Cancer Reseach Center (DKFZ), Heidelberg, Germany.|Department of Clinical Pharmacology, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.|University of Tuebingen, Tuebingen, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Schaeffeler
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051926:Basigin / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D055815:Young Adult
chemical_list: C497886:BSG protein, human; D014408:Biomarkers, Tumor; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D012333:RNA, Messenger; C406962:SLC16A4 protein, human; D051926:Basigin
keywords: CD147; DNA methylation; MCT4; Pathology Section; ccRCC; prognosis