Oncotarget

Research Papers: Pathology:

MCT4 surpasses the prognostic relevance of the ancillary protein CD147 in clear cell renal cell carcinoma

Pascale Fisel, Viktoria Stühler, Jens Bedke, Stefan Winter, Steffen Rausch, Jörg Hennenlotter, Anne T. Nies, Arnulf Stenzl, Marcus Scharpf, Falko Fend, Stephan Kruck, Matthias Schwab and Elke Schaeffeler _

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Oncotarget. 2015; 6:30615-30627. https://doi.org/10.18632/oncotarget.5593

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Abstract

Pascale Fisel1,2,*, Viktoria Stühler3,*, Jens Bedke3,4,*, Stefan Winter1,2, Steffen Rausch3, Jörg Hennenlotter3, Anne T. Nies1,2, Arnulf Stenzl3,4, Marcus Scharpf5, Falko Fend5, Stephan Kruck3, Matthias Schwab1,2,4,6 and Elke Schaeffeler1,2

1 Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany

2 University of Tuebingen, Tuebingen, Germany

3 Department of Urology, University Hospital Tuebingen, Tuebingen, Germany

4 German Cancer Consortium (DKTK) and German Cancer Reseach Center (DKFZ), Heidelberg, Germany

5 Institute of Pathology and Neuropathology, University Hospital Tuebingen, Tuebingen, Germany

6 Department of Clinical Pharmacology, University Hospital Tuebingen, Tuebingen, Germany

* These authors have contributed equally to this article

Correspondence to:

Elke Schaeffeler, email:

Matthias Schwab, email:

Keywords: CD147, MCT4, DNA methylation, ccRCC, prognosis, Pathology Section

Received: July 15, 2015 Accepted: August 22, 2015 Published: September 10, 2015

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.


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