Avaliação de candidatos a marcadores moleculares envolvidos no carcinoma renal de células claras
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Data
2009-02-18
Autores
Valsechi, Marina Curado [UNESP]
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
O tumor renal é a mais letal das doenças urológicas. É uma doença histologicamente heterogênea, sendo o carcinoma renal de células claras o subtipo histológico mais comum. Embora a nefrectomia e imunoterapia sejam tratamentos bem estabelecidos, aproximadamente 30% dos pacientes tratados são acometidos por metástases. Alterações na expressão gênica e na inativação transcricional, devido ao mecanismo de metilação, são evidentes em células cancerosas. A metilação do DNA é um evento epigenético intimamente relacionado com o silenciamento da expressão gênica, e está envolvida em vários processos, dentre eles, a carcinogênese. Dessa forma, este trabalho teve como objetivos investigar se os genes selecionados, GPC3, CRABP2, KTN1 e ADAM23 apresentam expressão alterada nas amostras tumorais, verificar se a expressão gênica está associada com a progressão tumoral, e analisar o padrão de metilação de ilhas CpGs. Os quatro genes selecionados foram validados pela técnica de PCR em Tempo Real. Para validação desses genes foram utilizadas 35 amostras de carcinoma renal de células claras e 35 amostras de córtex renal normal. Os genes GPC3, CRABP2, KTN1 e ADAM23 apresentaram redução de expressão significativa em amostras de carcinoma renal de células claras quando comparadas ao pool de amostras de córtex renal normal. Observou-se que a redução da expressão do gene ADAM23 está diretamente relacionada com o avanço do estadiamento tumoral. Foi observada uma freqüência elevada de hipermetilação do gene ADAM23, entretanto, não houve associação do padrão de metilação com os dados clínicos. A análise da expressão gênica e dos mecanismos responsáveis pela inativação transcricional dos genes CRABP2, KTN1 e ADAM23, estudados pela primeira vez em carcinoma renal, e GPC3, podem fornecer informações relevantes para o conhecimento e desenvolvimento do carcinoma renal de células claras.
The renal tumor, which is the most lethal of urological diseases, is a histologically heterogeneous disease, and the clear cell renal cell carcinoma the most common histological subtype. Although the treatment of nephrectomy and immunotherapy are established, approximately 30% of patients are affected by metastases. Changes in gene expression and transcriptional inactivation, due to the methylation mechanism are evident in cancer cells. The DNA methylation is an epigenetic event closely related to the silencing of gene expression, and is involved in several cases, including the carcinogenesis. The aim of this study was to investigate the gene expression of GPC3, CRABP2, KTN1 and ADAM23, check if gene expression was associated with tumor progression and analyze methylation pattern of CpG island. The four selected genes were validated by the quantitative RT-PCR. Thirty five samples of clear cell renal cell carcinoma and 35 samples of normal renal cortex were used for validation. The genes GPC3, CRABP2, KTN1 and ADAM23 showed significant reduction of expression in samples of clear cell renal cell carcinoma when compared to a pool of samples of normal renal cortex. It was observed that the lower expression of ADAM23 is directly related to the advancement of the tumor staging. Despite the high frequency of hypermethylation of ADAM23, there was no association with the methylation pattern of the clinical data. The analysis of gene expression and the mechanisms responsible for the transcriptional inactivation of genes CRABP2, KTN1 and ADAM23, first studied in clear cell renal cell carcinoma, and GPC3, may provide relevant information for the clear cell renal cell carcinoma understanding and development.
The renal tumor, which is the most lethal of urological diseases, is a histologically heterogeneous disease, and the clear cell renal cell carcinoma the most common histological subtype. Although the treatment of nephrectomy and immunotherapy are established, approximately 30% of patients are affected by metastases. Changes in gene expression and transcriptional inactivation, due to the methylation mechanism are evident in cancer cells. The DNA methylation is an epigenetic event closely related to the silencing of gene expression, and is involved in several cases, including the carcinogenesis. The aim of this study was to investigate the gene expression of GPC3, CRABP2, KTN1 and ADAM23, check if gene expression was associated with tumor progression and analyze methylation pattern of CpG island. The four selected genes were validated by the quantitative RT-PCR. Thirty five samples of clear cell renal cell carcinoma and 35 samples of normal renal cortex were used for validation. The genes GPC3, CRABP2, KTN1 and ADAM23 showed significant reduction of expression in samples of clear cell renal cell carcinoma when compared to a pool of samples of normal renal cortex. It was observed that the lower expression of ADAM23 is directly related to the advancement of the tumor staging. Despite the high frequency of hypermethylation of ADAM23, there was no association with the methylation pattern of the clinical data. The analysis of gene expression and the mechanisms responsible for the transcriptional inactivation of genes CRABP2, KTN1 and ADAM23, first studied in clear cell renal cell carcinoma, and GPC3, may provide relevant information for the clear cell renal cell carcinoma understanding and development.
Descrição
Palavras-chave
Rins - Câncer, Cancer - Aspectos geneticos, Expressão gênica, Carcinoma renal de células claras, Expressão genética, Metilação do DNA, Clear cell renal cell carcinoma, Gene expression, Methylation
Como citar
VALSECHI, Marina Curado. Avaliação de candidatos a marcadores moleculares envolvidos no carcinoma renal de células claras. 2009. 130 f. Dissertação (mestrado) - Universidade Estadual Paulista, Instituto de Biociências, Letras e Ciências Exatas, 2009.