DNA Hypomethylation-Mediated Overexpression of Carbonic Anhydrase 9 Induces an Aggressive Phenotype in Ovarian Cancer Cells
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Purpose: Both genetic and epigenetic alterations can lead to abnormal expressionof metastasis-regulating genes in tumor cells. Recent studies suggest that aberrantepigenetic alterations, followed by differential gene expression, leads to an aggressive cancer cell phenotype. We examined epigenetically regulated genes that are involved in ovarian cancer metastasis. Materials and Methods: We developedSK-OV-3 human ovarian carcinoma cell xenografts in mice. We comparedthe mRNA expression and DNA methylation profiles of metastatic tissues to those of the original SK-OV-3 cell line. Results: Metastatic implants showed increased mRNA expression of the carbonic anhydrase 9 (CA9) gene and hypomethylationat CpG sites in the CA9 promoter. Treatment of wild-type SK-OV-3 cells with the DNA methyltransferase inhibitor 5-aza-2’-deoxycytidine reduced methylation of the CA9 promoter and increased CA9 mRNA expression. Eight CpGs, which were located at positions -197, -74, -19, -6, +4, +13, +40, and +86, relative to the transcription start site, were hypomethylated in metastatic tumor implants, compared to that of wild-type SK-OV-3. Overexpression of CA9 inducedan aggressive phenotype, including increased invasiveness and migration, in SK-OV-3 cells. Conclusion: Alterations in the DNA methylation profile of the CA9 promoter were correlated with a more aggressive phenotype in ovarian cancercells.
Abstract
Purpose: Both genetic and epigenetic alterations can lead to abnormal expressionof metastasis-regulating genes in tumor cells. Recent studies suggest that aberrantepigenetic alterations, followed by differential gene expression, leads to an aggressive cancer cell phenotype. We examined epigenetically regulated genes that are involved in ovarian cancer metastasis. Materials and Methods: We developedSK-OV-3 human ovarian carcinoma cell xenografts in mice. We comparedthe mRNA expression and DNA methylation profiles of metastatic tissues to those of the original SK-OV-3 cell line. Results: Metastatic implants showed increased mRNA expression of the carbonic anhydrase 9 (CA9) gene and hypomethylationat CpG sites in the CA9 promoter. Treatment of wild-type SK-OV-3 cells with the DNA methyltransferase inhibitor 5-aza-2’-deoxycytidine reduced methylation of the CA9 promoter and increased CA9 mRNA expression. Eight CpGs, which were located at positions -197, -74, -19, -6, +4, +13, +40, and +86, relative to the transcription start site, were hypomethylated in metastatic tumor implants, compared to that of wild-type SK-OV-3. Overexpression of CA9 inducedan aggressive phenotype, including increased invasiveness and migration, in SK-OV-3 cells. Conclusion: Alterations in the DNA methylation profile of the CA9 promoter were correlated with a more aggressive phenotype in ovarian cancercells.
참고문헌 (17)
- Szabó L, "A detailed semiologic analysis of childhood psychogenic nonepileptic seizures", Epilepsia, 53, pp.565~570 (2012)
- Szaflarski JP, "Four-year incidence of psychogenic nonepileptic seizures in adults in hamilton county, OH", Neurology, 55, pp.1561~1563 (2000)
- Benbadis SR, "An estimate of the prevalence of psychogenic non-epileptic seizures", Seizure, 9, pp.280~281 (2000)
- Shen W, "Presenting the diagnosis of pseudoseizure", Neurology, 40, pp.756~759 (1990)
- Lancman ME, "Psychogenic seizures in children: long-term analysis of 43 cases", J Child Neurol, 9, pp.404~407 (1994)
- Finlayson RE, "Pseudoepileptic seizures in children and adolescents", Mayo Clin Proc, 54, pp.83~87 (1979)
- Silva W, "Clinical features and prognosis of nonepileptic seizures in a developing country", Epilepsia, 42, pp.398~401 (2001)
- Bodde NM, "Psychogenic non-epileptic seizures--diagnostic issues:a critical review", Clin Neurol Neurosurg, 111, pp.1~9 (2009)
- Lempert T, "Natural history and outcome of psychogenic seizures: a clinical study in 50 patients", J Neurol, 237, pp.35~38 (1990)
- Reuber M, "Non-epileptic seizures and other functional neurological symptoms: predisposing, precipitating, and perpetuating factors", Psychosomatics, 48, pp.230~238 (2007)
- Kanner AM, "Psychiatric and neurologic predictors of psychogenic pseudoseizure outcome", Neurology, 53, pp.933~938 (1999)
- Ettinger AB, "A comprehensive profile of clinical, psychiatric, and psychosocial characteristics of patients with psychogenic nonepileptic seizures", Epilepsia, 40, pp.1292~1298 (1999)
- Wyllie E, "Psychogenic seizures in children and adolescents:outcome after diagnosis by ictal video and electroencephalographic recording", Pediatrics, 85, pp.480~484 (1990)
- LaFrance WC Jr, "Pilot pharmacologic randomized controlled trial for psychogenic nonepileptic seizures", Neurology, 75, pp.1166~1173 (2010)
- Vincentiis S, "Risk factors for psychogenic nonepileptic seizures in children and adolescents with epilepsy", Epilepsy Behav, 8, pp.294~298 (2006)
- Wyllie E, "Psychiatric features of children and adolescents with pseudoseizures", Arch Pediatr Adolesc Med, 153, pp.244~248 (1999)
- Baslet G, "Psychogenic nonepileptic seizures: a treatment review. What have we learned since the beginning of the millennium?", Neuropsychiatr Dis Treat, 8, pp.585~598 (2012)