RESUMO
Despite considerable advances in recent years in our understanding of the genetic changes occurring in urinary bladder cancer, similar progress in the field of epigenetics has hitherto been lacking. Increasingly, however, focus has shifted in the direction of aberrant DNA methylation as a result of recent studies showing the direct impact of such promoter hypermethylation on the loss of tumor suppressor gene expression and function, therefore potentially affecting tumor genesis and progression. The purpose of this study is the identification and characterization of new DNA methylation markers in urinary bladder cancer, with the expectation that these markers could then be incorporated in a multi-gene panel for clinical use in early cancer detection. In addition, better understanding of the signalling pathways involved will undoubtedly impact the development of new treatment strategies. Potential candidate genes, including the Wnt antagonist SFRP5 among others, will be validated by different epigenetic techniques using invasive and superficial urothelial cell lines as well as tumor and urine samples from bladder cancer patients.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/patologia , Metilação de DNA/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Proteínas Adaptadoras de Transdução de Sinal , Carcinoma de Células de Transição/diagnóstico , Linhagem Celular Tumoral , Deleção Cromossômica , Análise Mutacional de DNA , Diagnóstico Precoce , Epigenômica , Proteínas do Olho/genética , Humanos , Proteínas de Membrana/genética , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Prognóstico , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/diagnósticoRESUMO
We have recently characterized ITIH5 as a new extracellular matrix protein that exhibits clear expression loss in a variety of human tumour entities, including breast cancer. The aim of the present study was to decipher the molecular cause of ITIH5 expression loss in breast cancer and to learn more about the possible role of this molecule in cancer diseases. ITIH5 protein expression was found to be strongly reduced in 42% of invasive breast carcinomas-interestingly, with significant association with poor patient outcome. ITIH5 promoter methylation was frequently detected in breast cell lines and in primary carcinomas (40%), and it was functionally correlated with loss of ITIH5 mRNA expression. Moreover, ITIH5 promoter methylation was also significantly associated with poor clinical patient outcome and also with the occurrence of lymph node and distant metastases. In conclusion, we propose that ITIH5 may represent a novel metastasis repressor in human breast cancer. Both ITIH5 protein expression and ITIH5 promoter methylation may serve as prognostic biomarkers, thereby helping improve clinical patient outcome.
