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.MethodsCD147 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.ResultsCD147 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%).ConclusionsPrognostic 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.

Characterization of the breast cancer resistance protein (BCRP/ABCG2) in clear cell renal cell carcinoma

“…4 Percentages do not sum up to 100% due to missing values. Lower mRNA levels were significantly associated with M (metastasis; p = 3.61e À02 ) and G (tumor grade; p = 2.31e À03 ) ( 18 To account for tumor heterogeneity two tumor cores per patient were evaluated. Abbreviations: T, primary tumor; N, regional lymph node; M, distant metastasis present at diagnosis; G, grading variable (Fig.…”

“…15,18 IHC staining was performed using a 1:50 dilution of a validated BCRP/ABCG2 antibody (BXP-21; 19 Alexis Biochemicals, San Diego, CA, USA) and a 1:20 dilution of a previously established MDR1/ABCB1 antibody (JSB-1; [20][21][22] GeneTex, Inc., Irvine, CA, USA). 15,18 IHC staining was performed using a 1:50 dilution of a validated BCRP/ABCG2 antibody (BXP-21; 19 Alexis Biochemicals, San Diego, CA, USA) and a 1:20 dilution of a previously established MDR1/ABCB1 antibody (JSB-1; [20][21][22] GeneTex, Inc., Irvine, CA, USA).…”

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

“…MCT4 expression has been shown to be regulated by DNA methylation in clear cell renal cell carcinoma, whereby a single CpG site within the SLC16A3 promoter was identified to be a prognostic marker for patient survival 29. Of note, promoter DNA methylation of the ancillary protein CD147 did not have an influence on protein expression 84. Furthermore, in patients with temporal lobe epilepsy, cortical MCT4 expression levels were significantly lower at least partially due to SLC16A3 promoter methylation 64…”

DNA Methylation of ADME Genes

“…Independent from unspecific MCT4 inhibitors (e.g., statins), specific MCT4 inhibitors as promising cancer agents are currently under investigation. Interestingly, DNA methylation at a specific CpG site in the 5′ regulatory region of the SLC16A3 promoter has been shown to correlate with expression of this lactate transporter and is strongly associated with survival of patients with clear cell renal cell carcinoma …”