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.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is a heterogenous and complex disease with high incidence and mortality rate worldwide
In order to determine the level of WW-domain-containing oxidoreductase (WWOX) expression in HNSCC tumors, we performed quantitative analysis using real-time Real Time PCR (RT-PCR), in a cohort of 80 tumor samples and compared these with the expression levels in the adjacent non-cancerous tissue samples from the same patient
The WWOX gene is located at a common fragile region (FRA16D) and behaves as a tumor suppressor gene [5,6]
Summary
Head and neck squamous cell carcinoma (HNSCC) is a heterogenous and complex disease with high incidence and mortality rate worldwide. Most of the tumors arise in the oral cavity, oropharynx, hypopharynx and larynx [1]. Despite aggressive multidiciplinary treatment approaches such as surgery, radiation and chemotherapy for patients with advanced disease the 5 year survival rate is lower than 50% and the overall 5 year survival rate is only 50–60% [2,3]. The most important risk factors for the development of HNSCC remain tobacco use and alcohol consumption [4]. Little information is available on the molecular mechanisms that underlie HNSCC progression. To improve the outcome of the disease, PLOS ONE | DOI:10.1371/journal.pone.0115353. To improve the outcome of the disease, PLOS ONE | DOI:10.1371/journal.pone.0115353 January 22, 2015
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