Abstract
Chondrosarcoma (CS) is a rare cancer, but it is the second most common primary malignant bone tumor and highly resistant to conventional chemotherapy and radiotherapy. Aberrant DNA methylation in the promoter CpG island of Wnt inhibitory factor 1 (WIF1) has been observed in different cancers. However, no studies have shown the relationship between WIF1 methylation and CS. In this study, we found promoter methylated WIF1 in both CS cell lines (CS-1 and SW1353) and tumor tissues. Western blot analysis confirmed loss WIF1 expression and activation of Wnt pathway proteins (Wnt5a/b, LRP6, and Dvl2). We subsequently examined the correlation between levels of WIF1 methylation and overall survival (OS) and progression-free survival (PFS) in CS patient samples with a follow-up spanning 234 months (mean: 57.6 months). Kaplan-Meier survival curves and log-rank tests revealed that high levels of WIF1 methylation were associated with lower OS and PFS rates (p < 0.05). Multivariate Cox hazard analysis suggested that detection of high level methylation of WIF1 could be an independent prognostic factor in OS and PFS. In conclusion, we found that WIF1 is epigenetically silenced via promoter DNA methylation in CS and propose that WIF1 methylation may serve as a potential prognostic marker for patients with CS.
Highlights
Chondrosarcoma (CS) is a heterogeneous subtype of malignant cartilage forming tumor
We examined the methylation levels of Wnt inhibitory factor 1 (WIF1) promoter (Fig. 1A) in CS cell lines CS-1 and SW1353
We found 97.33% of WIF1 promoters were methylated in CS-1 and 96.22% in SW1353, respectively (Fig. 1C)
Summary
Chondrosarcoma (CS) is a heterogeneous subtype of malignant cartilage forming tumor. It is a rare cancer in humans and is diagnosed in approximately 600 patients per year in the United States. Accumulating data has shown that DNA methylation of tumor-related genes may serve as biomarkers to indicate the diagnosis and/or prognosis of human cancers, including CS14. WIF1 is believed to function as a tumor suppressor gene by disrupting Wnt signaling, including the Wnt canonical pathway that regulates gene transcription, and could activate various downstream oncogenes. Wnt antagonists, including WIF1, are able to collapse this pathway by inhibiting the binding of Wnt ligands to receptor complexes, followed by β-catenin phosphorylation and degradation, and blocking the TCF/LEF transcription of a wide range of oncogenes, preventing tumorogenesis[21, 23]. Protein expression levels of WIF1 and members of the Wnt family were measured to assess the potential tumor suppressor role of methylated WIF1 in the Wnt pathway in CS
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