Wnt inhibitory factor 1 (WIF1) methylation and its association with clinical prognosis in patients with chondrosarcoma

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.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. CS is the second most common primary bone cancer after osteosarcoma 1, 2 . CS accounts for more than 20% of all primary bone malignancies and affects people at any age with a predilection for proximal femur and pelvic sites 3-5 . Pathological identification and radiographic imaging remain important diagnostic tools in the clinical management of patients with CS. However, the reliability of diagnosis by the current subjective imaging and histological criteria has been controversial 6 . CS, especially conventional CS, is notoriously resistant to both chemotherapy and radiation treatment 7 . Thus, surgical resection remains the primary treatment for localized lesions and radiotherapy is limited to the definitive treatment of inoperable micro-lesions and in the palliation of local symptoms 6 . The outcome of patients with CS is relatively poor largely due to the potent capacity for local invasion and distant metastasis 8,9 . Five-year survival rates of patients with dedifferentiated CS are less than 20% as a result of early disseminated metastases 6, 10-12 . Therefore, there is an urgent need to develop novel strategies for diagnosis, treatment, and prognosis of CS to improve outcomes for patients.Recently, aberrant DNA methylation and epigenetic changes have been found to play a pivotal role in the pathogenesis of human malignancies. Hypermethylation mostly presents at the promoter CpG island of tumor suppressor genes and inactivates gene expression, while hypomethylation commonly affects repetitive DNA sequences and/or gene regulatory re...

Therapeutic effect of palbociclib in chondrosarcoma: implication of cyclin-dependent kinase 4 as a potential target

“…Human chondrosarcoma cell line CS-1 was established in our laboratory as previously reported [19–21] and human chondrosarcoma cell line SW1353 was obtained from the American Type Culture Collection (Rockville, Maryland, USA). Cells were incubated in standard RPMI 1640 medium added with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin (Hyclone, USA) in a condition of 37 °C, 5% CO 2 .…”

Chondrosarcoma: A Rare Misfortune in Aging Human Cartilage? The Role of Stem and Progenitor Cells in Proliferation, Malignant Degeneration and Therapeutic Resistance

“…Recombinant WNT inhibitory factor 1 (WIF1), which inhibits WNT signaling by binding of several WNT ligands including WNT3A and WNT5A, prevented WNT induced MSPC growth by neutralizing rWNT3A-mediated inhibition of chondrogenesis in micromass cultures of embryonic chick limb bud cells [ 203 ]. WIF1 is epigenetically silenced via promoter methylation in human chondrosarcoma tissues and cell lines, and loss of WIF1 protein expression correlated with lower progression free and overall survival rates [ 204 ]. Interestingly, aging reduced expression of β-catenin in bone marrow derived MSPC, while β-catenin phosphorylation increased, indicating enhanced proteasomal degradation [ 61 ].…”

Mutation profiling in eight cases of vagal paragangliomas

“…For example, the CHST4 gene, which is associated with colon mucinous adenocarcinoma (Mala-Cards database); CLCA4, a tumor suppressor gene encoding for the calcium-activated chloride channel A4 that can inhibit tumor cell proliferation, migration, and invasion [55,56]; ESR1, characterized by mutations responsible for the resistance to endocrine therapy in breast cancer [57]; P2RY1, involved in the regulation of multidrug chemoresistance of bladder cancer cells [58]; and PATZ1, which acts as a tumor suppressor gene in thyroid cancer and is associated with the development of testicular tumors, sarcoma, and lung cancer [59][60][61][62]. Furthermore, we found alterations in the PRKCI gene related to many tumors [63][64][65] and WIF1 hypermethylation, frequently observed in cancer cells [66][67][68][69].…”