Epigenetic and Genetic Alterations Affect the WWOX Gene in Head and Neck Squamous Cell Carcinoma

Abstract

Different types of genetic and epigenetic changes are associated with HNSCC. The molecular mechanisms of HNSCC carcinogenesis are still undergoing intensive investigation. WWOX gene expression is altered in many cancers and in a recent work reduced WWOX expression has been associated with miR-134 expression in HNSCC. In this study we investigated the WWOX messenger RNA expression levels in association with the promoter methylation of the WWOX gene and miR-134 expression levels in 80 HNSCC tumor and non-cancerous tissue samples. Our results show that WWOX expression is down-regulated especially in advanced-stage tumor samples or in tumors with SCC. This down-regulation was associated with methylation of the WWOX promoter region but not with miR-134 expression. There was an inverse correlation between the expression level and promoter methylation. We also analyzed whole exons and exon/intron boundries of the WWOX gene by direct sequencing. In our study group we observed 10 different alterations in the coding sequences and 18 different alterations in the non-coding sequences of the WWOX gene in HNSCC tumor samples. These results indicate that the WWOX gene can be functionally inactivated by promoter methylation, epigenetically or by mutations affecting the sequences coding for the enzymatic domain of the gene, functionally. We conclude that inactivation of WWOX gene contributes to the progression of HNSCC.

Recurrent alterations of the WW domain containing oxidoreductase gene spanning the common fragile site FRA16D in multiple myeloma and monoclonal gammopathy of undetermined significance

“…This is consistent with findings that WWOX methylation correlates with poor prognosis of patients with ovarian cancer (47), head and neck cancer (58), and chorangiocarcinoma (59).…”

Silencing of Wwox Increases Nuclear Import of Dvl proteins in Head and Neck Cancer

“…In 2009 Bouteille et al (12) reported that the tumor suppressor protein WWOX is a negative regulator of the Wnt/β-catenin pathway and inhibits the transcriptional activity of this pathway by preventing nuclear import of the Dvl proteins. In our previous study we showed that the WWOX gene is inactivated in HNSCC as a result of genetic or epigenetic alterations (16). Here, to investigate the effect of Wwox on the cellular localization of Dvl proteins in HNSCC we silenced the WWOX gene in the HET-1A cell line.…”

“…In addition to the homozygous deletion of the WWOX gene its decreased or aberrant expression has also been reported in multiple human cancers (13)(14)(15)(16). In our previous study we have shown that the WWOX gene is inactivated in HNSCC as a result of genetic and epigenetic alterations (16). In the present study we aimed to investigate the association between Wwox and Dvl proteins in human HNSCC tumors and cell lines.…”

Integrated analysis of the miRNA-mRNA network associated with LMP1 gene in nasopharyngeal carcinoma

“…As many studies showed, miR-134 not only functions as a tumor repressor, but also acts as a cancer promoter. High expression of miR-134 contributes to head and neck carcinogenesis by targeting the WW Domain-Containing Oxidoreductase (WWOX) gene [34]. However, overexpression of miR-134 can inhibit the cell cycle progression of human human ovarian cancer stem cells and decrease the tumorigenicity in nude mice [35].…”