Identification of a methylation hotspot in the death receptor Fas/CD95 in bladder cancer
| العنوان: | Identification of a methylation hotspot in the death receptor Fas/CD95 in bladder cancer |
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| المؤلفون: | Perry Maxwell, D. O'Rouke, Kate E. Williamson, Paul Canning, John J. Mcknight, P. L. Hyland, Hugh O'Kane, Chris J Watson, O. Sharaf, István Peták |
| المصدر: | International Journal of Oncology. |
| بيانات النشر: | Spandidos Publications, 2011. |
| سنة النشر: | 2011 |
| مصطلحات موضوعية: | Male, Cancer Research, Fas Ligand Protein, Mitomycin, Apoptosis, Biology, Transfection, Fas ligand, Cell Line, Tumor, Humans, Gene Silencing, fas Receptor, Promoter Regions, Genetic, Aged, Carcinoma, Transitional Cell, Exons, Receptors, Death Domain, Methylation, DNA Methylation, Cell cycle, Genes, p53, Fas receptor, Molecular biology, Introns, Up-Regulation, Urinary Bladder Neoplasms, Oncology, CpG site, Drug Resistance, Neoplasm, Mutation, DNA methylation, Cancer research, CpG Islands, Female, Caco-2 Cells, Follow-Up Studies |
| الوصف: | We characterized Fas immunoreactivity, functionality and its role in the response to mitomycin-C (MMC) chemotherapy in vitro in cell lines and in vivo in bladder washings from 23 transitional cell carcinoma of the bladder (TCCB) patients, harvested prior to and during MMC intravesical treatment. Having established the importance of functional Fas, we investigated the methylation and exon 9 mutation as mechanisms of Fas silencing in TCCB. For the first time, we report p53 up-regulation in 9/14 and Fas up-regulation in 7/9 TCCB patients during intravesical MMC treatment. Fas immunoreactivity was strong in the TCCB cell line T24 and in 17/20 (85%) tumor samples from patients with advanced TCCB. T24 and HT1376 cells were resistant to MMC and recombinant Fas ligand, whilst RT4 cells were responsive to Fas ligand and MMC. Using RT4 cells as a model, siRNA targeting p53 significantly reduced MMC-induced p53 and Fas up-regulation and stable DN-FADD transfection decreased MMC-induced apoptosis, suggesting that functional Fas enhances chemotherapy responses in a p53-dependent manner. In HT1376 cells, 5-aza-2-deoxycytidine (12 µM) induced Fas immunoreactivity and reversed methylation at CpG site -548 within the Fas promoter. This site was methylated in 13/24 (54%) TCCB patient samples assessed using Methylation-Specific Polymerase Chain Reaction. There was no methylation at either the p53 enhancer region within the first intron or at the SP-1 binding region in the promoter and no mutation within exon 9 in tumor DNA extracted from 38 patients. Methylation at CpG site -548 is a potential target for demethylating drugs. |
| تدمد: | 1791-2423 1019-6439 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bc869cc690b8bbabeb28f0bf0cb396abTest https://doi.org/10.3892/ijo.2011.1250Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....bc869cc690b8bbabeb28f0bf0cb396ab |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17912423 10196439 |
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