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. 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. 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%). 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.
Highlights
Cluster of differentiation 147 (CD147), known as extracellular matrix metalloproteinase inducer (EMMPRIN) or basigin, encoded by the BSG gene, is a transmembrane glycoprotein, which is involved in various physiological as well as pathophysiological processes
CD147 represents the obligatory binding partner for several proteins involved in carcinogenesis, e.g., the monocarboxylate transporters (MCT) 1 and MCT4 [6], which mediate the export of lactate from highly glycolytic tumor cells
We could show that MCT4 expression is regulated by DNA methylation in the SLC16A3 promoter and that DNA methylation status at single cytosine phosphate guanine (CpG) sites is predictive for patient survival [8]
Summary
Cluster of differentiation 147 (CD147), known as extracellular matrix metalloproteinase inducer (EMMPRIN) or basigin, encoded by the BSG gene, is a transmembrane glycoprotein, which is involved in various physiological as well as pathophysiological processes. In clear cell renal cell carcinoma (ccRCC), which is characterized by a glycolytic Warburg phenotype, MCT4 has been shown to be a metabolic target to reverse the Warburg effect [7], as shown by Gerlinger et al in a genome-wide siRNA screening study in RCC cell lines, but is proposed to be a prognostic marker for patient outcome. Due to its tumorigenic properties, CD147 represents a promising target for therapeutic intervention [9, 10] and it is suggested that CD147 expression alone or together with other factors such as VEGF expression, could serve as a marker for prognosis and outcome in ccRCC [11,12,13]
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