Hypermethylation of RUNX3 but not WIF1 gene and its association with stage and nodal status of tongue cancers

Institute for Medical Research, Military Medical Academy, Belgrade, Serbia.
Oral Diseases (Impact Factor: 2.43). 07/2011; 17(8):794-800. DOI: 10.1111/j.1601-0825.2011.01838.x
Source: PubMed


Recent studies indicate various molecular abnormalities in oral squamous cell carcinomas (OSCC), including DNA methylation of tumor-associated genes. Although promoter hypermethylation of Wnt pathway antagonists RUNX3 (Runt-related transcription factor 3) and Wnt inhibitory factor 1 (WIF1) has been identified as a common event in a number of carcinomas, methylation status and the role of RUNX3 as a possible tumor suppressor in oral and head and neck cancer are yet controversial. The aim of our study is to determine the occurrence of RUNX3 and WIF1 genes hypermethylation and correlation with tumor and host-related factors and prognosis in tongue carcinomas.
In 76 patients with tongue carcinoma, RUNX3 and WIF1 genes promoter hypermethylation analysis was assessed by nested methylation-specific PCR method.
Hypermethylation of WIF1 and RUNX3 genes promoters was observed in 35% and 25% of carcinomas, respectively. RUNX3 gene promoter hypermethylation was significantly associated with lymph node involvement (P = 0.013) and tumor stage (P = 0.006), but not with the overall survival. Occurrence of RUNX3 and WIF1 genes comethylation was associated with nodal status (P = 0.058) and tumor stage (P = 0.055).
Our findings indicate that RUNX3 and WIF1 are frequently aberrantly methylated and that RUNX3 promoter methylation could be considered as a potential prognostic marker in tongue carcinoma.

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    • "As shown in Table 6, the differentially expressed genes (DEGs) were enriched in 215 pathways, of which 68 were found to be significantly enriched by KEGG pathway enrichment analysis. These included ECM-receptor pathway interaction and focal adhesion pathways, which have both been previously reported in OSCC [29] [30] [31] . "
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    ABSTRACT: Differentially expressed genes are thought to regulate the development and progression of oral squamous cell carcinomas (OSCC). The purpose of this study was to screen differentially expressed mRNAs in OSCC and matched paraneoplastic normal tissues, and to explore the intrinsic mechanism of OSCC development and progression. We obtained the differentially expressed mRNA expression profiles in 10 pairs of fresh-frozen OSCC tissue specimens and matched paraneoplastic normal tissue specimens by high-throughput RNA sequencing. By using Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, the functional significance of the differentially expressed genes were analyzed. We identified 1,120 significantly up-regulated mRNAs and 178 significantly down-regulated mRNAs in OSCC, compared to normal tissue. The differentially expressed mRNAs were involved in 20 biological processes and 68 signal pathways. Compared to adjacent normal tissue, the expression of MAGEA11 was up-regulated; TCHH was down-regulated. These findings were verified by real-time PCR. These differentially expressed mRNAs may function as oncogenes or tumor suppressors in the development and progression of OSCC. This study provides novel insights into OSCC. However, further work is needed to determine if these differentially expressed mRNAs have potential roles as diagnostic biomarkers and candidate therapeutic targets for OSCC. © 2015 the Journal of Biomedical Research. All rights reserved.
    01/2015; 29(5). DOI:10.7555/JBR.29.20140088
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    ABSTRACT: Head and neck cancer is the sixth most common cancer worldwide and one of the most aggressive malignancies in human population. The most common histologic type among the head and neck tumors are the squamous cell carcinomas (SCC). Despite the significant efforts committed during the last decades in its early detection, prevention and treatment, head and neck cancer prognosis remains very poor with the rising incidence in developed countries and younger population. Carcinogenesis of Head and Neck Squamous Cell Carcinoma (HNSCC) is a multistep process, which arises through an accumulation of genetic and epigenetic alterations. Although the impact of genetic changes in oral carcinogenesis is wellknown, over the last decade it has been demonstrated that epigenetic changes, especially aberrant DNA methylation, play a significant role in HNSCC.
    Methylation - From DNA, RNA and Histones to Diseases and Treatment, Edited by Anica Dricu, 11/2012: chapter DNA Methylation in the Pathogenesis of Head and Neck Cancer: pages 185-216; InTech., ISBN: 978-953-51-0881-8
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    ABSTRACT: Background Aberrations in the function of the WNT signaling pathway have been recently implicated in the pathogenesis of head and neck cancer, and the hypermethylation of several WNT cascade inhibitors were shown to be useful in disease prognosis. However, the extent of deregulation of WNT pathway by DNA hypermethylation has not been studied in detail in laryngeal cancer so far. The aim of this study was to establish the frequency of methylation of WNT pathway negative regulators in laryngeal squamous cell carcinomas and evaluate its prognostic significance.Methods Twenty-six laryngeal squamous cell carcinoma cell lines and samples obtained from twenty-eight primary laryngeal carcinoma patients were analyzed. The methylation status of DKK1, LKB1, PPP2R2B, RUNX3, SFRP1, SFRP2, and WIF-1 was assessed using the methylation-specific polymerase chain reaction.ResultsFrequent hypermethylation of DKK1, PPP2R2B, SFRP1, SFRP2, and WIF-1 was detected, and a high methylation index was usually observed. Half of the cell lines analyzed and seventy percent of primary laryngeal carcinoma cases were characterized by the methylation of at least four genes. The hypermethylation of PPP2R2B or WIF-1 was associated with longer survival in laryngeal carcinoma cell lines. Moreover, the concurrent methylation of PPP2R2B and SFRP1 differentiated primary from recurrent laryngeal carcinoma cell lines.Conclusions Frequent hypermethylation of WNT pathway negative regulators is observed in laryngeal squamous cell carcinomas. The possible prognostic significance of the methylation of DKK1, PPP2R2B, and SFRP1 needs to be evaluated in further prospective studies.
    Journal of Oral Pathology and Medicine 04/2014; 43(9). DOI:10.1111/jop.12178 · 1.93 Impact Factor
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