Abstract
The aim of the present study was to determine the roles of the WWOX tumor suppressor and cancer-related genes in bladder tumor carcinogenesis. Reverse transcription-quantitative polymerase chain reaction was used to analyze the status of WWOX promoter methylation (using MethylScreen™ technology) and loss of heterozygosity (LOH) in papillary urothelial cancer tissues. The associations between the expression levels of the following tumorigenesis-related genes were also assessed: The WWOX tumor suppressor gene, the MKI67 proliferation gene, the BAX, BCL2 and BIRC5 apoptotic genes, the EGFR signal transduction gene, the VEGF vascular endothelial growth factor gene, and the CCND1 and CCNE1 cell cycle genes. The results reveal a high frequency of LOH in intron 1 in the WWOX gene, as well as an association between reduced WWOX expression levels and increased promoter methylation. In addition, the present study demonstrates that in bladder tumors, apoptosis is inhibited by increased expression levels of the BCL2 gene. A correlation between the proliferation indices of the MKI67 and the BIRC5 genes was also revealed. Furthermore, the expression levels of VEGF were identified to be positively associated with those of the EGFR gene.
Highlights
Bladder cancer is the most common tumor of the urinary system
These mechanisms have been shown to be important in the regulation of the expression of WWOX, a tumor suppressor gene whose expression is frequently altered in a number of tumor types
Further studies have revealed that loss of heterozygosity (LOH) is associated with a reduction in WWOX expression in gastric [29], esophageal [15], pancreatic [14], lung [30] and breast cancer [31], as well as in glioblastoma multiforme [25]
Summary
Bladder cancer is the most common tumor of the urinary system. In 2010, bladder cancer was the third and thirteenthKey words: WWOX tumor suppressor, bladder cancer, reverse transcription‐quantitative polymerase chain reaction, methylation, loss of heterozygosity most commonly diagnosed type of cancer in males and females, respectively, in Poland [1].Various carcinogenesis pathways in bladder cells have been proposed, including one which assumes that a single distinct molecular pathway exists for low-grade non-invasive tumors and another exists for muscle-invasive tumors. Bladder cancer is the most common tumor of the urinary system. In 2010, bladder cancer was the third and thirteenth. Various carcinogenesis pathways in bladder cells have been proposed, including one which assumes that a single distinct molecular pathway exists for low-grade non-invasive tumors and another exists for muscle-invasive tumors. The first type of tumor develops from hyperplasia, and is characterized by molecular alternations in the RAF/MEK/ERK and PIK3CA signal transduction pathways, while the second, the muscle-invasive tumor type, progresses from a dysplastic urothelium that is characterized by disruptions in the RB and p53 signaling pathways [2]. Epigenetic regulation of gene expression is common and predominantly affects genes associated with tumor development and survival, such as RUNX3, RASSF1A, p16, RARβ and CDH1 [2,3,4,5]
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