title: Genetic alterations of WWOX in Wilms' tumor are involved in its carcinogenesis.
abstract: Loss of heterozygosity (LOH) in 16q appears in ~20-30% cases of Wilms' tumor. Within this region, known as common fragile site FRA16D, the WWOX tumor suppressor gene is located. Abnormalities of WWOX gene expression levels were observed in many tumor types and were associated with worse prognosis. The purpose of this study was to investigate the role of the WWOX tumor suppressor gene in Wilms' tumor samples. We evaluated the correlation between expression of WWOX and genes involved in proliferation (Ki67), apoptosis (BCL2, BAX), signal transduction (ERBB4, ERBB2, EGFR), cell cycle (CCNE1, CCND1), cell adhesion (CDH1) and transcription (TP73) using real-time RT-PCR in 23 tumor samples. We also analyzed the potential causes of WWOX gene expression reduction i.e., promoter methylation status (MethylScreen method) and loss of heterozygosity (LOH) status. We revealed a positive correlation between WWOX expression and BCL2, BCL2/BAX ratio, EGFR, ERBB4 isoform JM-a, TP73 and negative correlation with both cyclins. Loss of heterozygosity of the WWOX gene was observed only at intron 8, however, it had no influence on the reduction of its expression levels. Contrary to LOH, methylation of the region covering the 3' end of the promoter and part of exon 1 was associated with statistically significant reduction of WWOX gene expression levels. In the present study we reveal that in Wilms' tumors the WWOX expression levels are positively associated with the process of apoptosis, signal transduction through the ErbB4 pathway and EGFR and negatively with the regulation of the cell cycle (by cyclin E1 and D1). Moreover, our analysis indicates that in this type of tumor the expression of the WWOX gene can be regulated by an epigenetic mechanism--its promoter methylation.
authors: Department of Molecular Cancerogenesis, Medical University of Lodz, 90-752 Lodz, Poland. elzbieta.pluciennik@umed.lodz.pl
authors: Elżbieta
authors: E
authors: Płuciennik
authors: Magdalena
authors: M
authors: Nowakowska
authors: Wioletta I
authors: WI
authors: Wujcicka
authors: Anna
authors: A
authors: Sitkiewicz
authors: Bernarda
authors: B
authors: Kazanowska
authors: Elżbieta
authors: E
authors: Zielińska
authors: Andrzej K
authors: AK
authors: Bednarek
mesh_terms: D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005091:Exons; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007223:Infant; D019394:Ki-67 Antigen / Q000235:genetics; D007680:Kidney Neoplasms / Q000235:genetics*; D019656:Loss of Heterozygosity; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D010088:Oxidoreductases / Q000235:genetics*; D011401:Promoter Regions, Genetic; D066247:Receptor, ErbB-4; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D000074584:WW Domain-Containing Oxidoreductase; D009396:Wilms Tumor / Q000235:genetics*; D051028:bcl-2-Associated X Protein / Q000235:genetics
chemical_list: C494826:BAX protein, human; C530104:CCND1 protein, human; C475820:CCNE1 protein, human; D019927:Cyclin E; D019394:Ki-67 Antigen; D015513:Oncogene Proteins; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D019938:Cyclin D1; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4