RESUMO
The ubiquitously expressed actin-binding protein, gelsolin, is known to play a role in the modulation of the actin network and in the regulation of cell growth and cell motility. In the present study, we analysed the expression of gelsolin in 241 matched cDNA pairs from human normal and tumour tissues using a Cancer Profiling Array. We found a decreased expression of gelsolin in cancer tissue from female reproductive organs, including the ovary. On a protein level, we examined the expression of gelsolin in human ovarian cancer cell lines and in a set of 110 cases of human benign and malignant ovarian tumours. Low levels of gelsolin protein were observed in four of six ovarian carcinoma cell lines, in contrast to its expression in normal ovarian surface epithelial cells. In addition, we found a reduced expression of gelsolin in borderline tumours and ovarian carcinomas compared with the epithelium of normal ovaries and benign adenomas. Decreased gelsolin expression was associated with poorly differentiated carcinomas (p=0.014). No significant association between gelsolin expression and other clinicopathological markers or patient survival could be established. In addition, we investigated the growth regulatory function of gelsolin in human ovarian cancer cell lines using cDNA transfections. Re-expression of gelsolin in OAW42 and ES-2 cells resulted in a suppression of tumour cell survival in vitro. To explore the mechanism responsible for the downregulation of gelsolin expression in ovarian carcinoma cells, we treated cells with inhibitors of DNA methylation and histone deacetylation. We observed an upregulation of gelsolin in ovarian cancer cells after treatment with both types of inhibitor. Our results suggest that gelsolin might be involved in the growth regulation of human ovarian cancer.
Assuntos
Gelsolina/metabolismo , Neoplasias Ovarianas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Western Blotting , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Análise de SobrevidaAssuntos
DNA Complementar/genética , Perfilação da Expressão Gênica/métodos , Expressão Gênica/genética , Biblioteca Gênica , Técnica de Subtração , Biotinilação , Encéfalo/metabolismo , Mama/metabolismo , Clonagem Molecular/métodos , Primers do DNA , Sondas de DNA , Feminino , Humanos , Leucócitos/metabolismo , Fígado/metabolismo , Masculino , Músculo Esquelético/metabolismo , Próstata/metabolismo , Recombinases Rec A/genéticaAssuntos
Regulação Neoplásica da Expressão Gênica , Genes ras , Northern Blotting , Linhagem Celular Transformada , DNA Complementar/metabolismo , Regulação para Baixo , Feminino , Humanos , Microscopia de Contraste de Fase , Mutação , Hibridização de Ácido Nucleico , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias Ovarianas/metabolismo , RNA/metabolismo , Transdução de Sinais , Transcrição Gênica , Transfecção , Células Tumorais Cultivadas , Regulação para CimaRESUMO
H-rev107-1 is a growth inhibitory RAS target gene capable of suppressing anchorage independent growth in vitro and in vivo. Using a tumour tissue array with 241 matched tumour and normal tissue cDNA pools, we found down-regulation of H-REV107-1 in 7 out of 14 ovary-derived cDNAs. RT-PCR analysis and immunohistochemical investigation confirmed expression of H-REV107-1 in normal ovarian epithelial cells but down-regulation in high grade ovarian carcinomas. H-REV107-1 is also strongly expressed in immortalized rat and human ovarian epithelial cells in vitro, but suppressed in transformed cells by two different mechanisms. KRAS-transformed rat ovarian cells and PA1 teratocarcinoma cells, reversibly repress H-REV107-1 via MAP/ERK signaling. In contrast, treatment of A27/80 and OVCAR-3 epithelial ovarian cancer cells with IFNgamma stimulated H-REV107-1 expression. In NIH3T3 cells harbouring an estrogen-inducible IRF-1, H-rev107-1 is directly induced after activation of IRF-1, indicating that H-rev107-1 is a target of IRF-1. Stimulation of H-REV107-1 expression was also observed in ovarian epithelial cells suggesting that IRF-1 is involved in H-REV107-1 regulation in human ovarian epithelium. In the IFNgamma-sensitive cell line A27/80, H-REV107-1 suppresses colony formation. A27/80 and OVCAR-3 cells overexpressing H-REV107-1 protein underwent apoptosis. These results demonstrate down-regulation of the class II tumour suppressor H-REV107-1 in human ovarian carcinomas and suggest an involvement of H-REV107-1 in interferon-dependent cell death.