Reduced promoter methylation and increased expression of CSPG4 negatively influences survival of HNSCC patients

• Published in: International journal of cancer 2014-12, Vol.135 (11), p.2727-2734
• Main Authors: Warta, Rolf, Herold‐Mende, Christel, Chaisaingmongkol, Jittiporn, Popanda, Odilia, Mock, Andreas, Mogler, Carolin, Osswald, Florian, Herpel, Esther, Küstner, Sabine, Eckstein, Volker, Plass, Christoph, Plinkert, Peter, Schmezer, Peter, Dyckhoff, Gerhard
• Format: Article
• Language: English
• Subjects: Cancer; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - mortality; Carcinoma, Squamous Cell - pathology; Case-Control Studies; Chondroitin Sulfate Proteoglycans - genetics; Chondroitin Sulfate Proteoglycans - metabolism; CpG Islands; CSPG4 methylation and expression; DNA Methylation; DNA microarrays; Follow-Up Studies; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Head & neck cancer; Head and neck; Head and neck carcinoma; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - mortality; Head and Neck Neoplasms - pathology; HNSCC; Humans; Immunoenzyme Techniques; Medical research; Membrane Proteins - genetics; Membrane Proteins - metabolism; Neoplasm Staging; Patients; Prognosis; Promoter Regions, Genetic - genetics; Proteins; Proteoglycans; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Squamous cell carcinoma; Stem cells; survival; Survival Rate; Tumor Cells, Cultured; Tumors; Young Adult
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.28906

Proteoglycans are often overexpressed in tumors and can be found on several normal and neoplastic stem cells. In this study, we analyzed in‐depth the role of CSPG4 in head and neck squamous cell carcinomas (HNSCC). Analysis of CSPG4 in a homogeneous study sample of HPV‐negative stage IVa HNSCCs revealed overexpression of protein and mRNA levels in a subgroup of HNSCC tumors and a significant association of high CSPG4 protein levels with poor survival. This could be validated in three publicly available microarray datasets. As a potential cause for upregulated CSPG4 expression, we identified DNA hypomethylation in a CpG‐island of the promoter region. Accordingly, we found an inverse correlation of methylation and patient outcome. Finally, CSPG4 re‐expression was achieved by demethylating treatment of highly methylated HNSCC cell lines establishing a direct link between methylation and CSPG4 expression. In conclusion, we identified CSPG4 as a novel biomarker in HNSCC on several biological levels and established a causative link between DNA methylation and CSPG4 protein and mRNA expression. What's New? Head and neck squamous cell carcinoma (HNSCC) is a frequent cancer characterized by clinical and biological heterogeneity and poor disease outcome. Here, the authors examined the expression level of the stem cell‐associated proteoglycan CSPG4 as a potential novel biomarker in HNSCC. Studies were restricted to stage IVa tumors negative for human papilloma virus infection and showed increased expression of CSPG4 mRNA and protein expression accompanied by decreased promoter methylation. Promoter methylation was inversely correlated with disease outcome and could be reversed with demethylating agents, underscoring the therapeutic potential of CSPG4 targeting in the treatment of HNSCC patients.