RESUMO
A relationship between inactivation of mitotic checkpoint genes and sensitivity of cancer cells to anticancer agents has been reported. We investigated the effect of epigenetic inactivation by aberrant hypermethylation of the mitotic checkpoint gene CHFR (checkpoint with forkhead and ring finger) on the sensitivity of cervical cancer cells to taxanes. Methylation-specific PCR (MSP) of cervical smears showed aberrant methylation of CHFR in 12.3% (2/14) of adenocarcinoma specimens. In contrast, aberrant DNA methylation was not detected in normal cervical cells or squamous cell carcinoma cells. Aberrant methylation of CHFR was also analyzed in 6 human cervical carcinoma-derived cell lines and was observed in SKG-IIIb and HeLa cells. These cell lines showed high sensitivity to taxanes, but became taxane-resistant upon treatment with 5-azacytidine. Furthermore, suppression of CHFR expression in siRNA-transfected SKG-IIIa cells caused increased sensitivity to taxanes. In conclusion, aberrant methylation of the CHFR gene may be useful as a molecular marker for selection of therapy for patients with cervical adenocarcinoma with a poor prognosis, and may also suggest a new therapeutic strategy of targeting CHFR in cervical cancer. To our knowledge, this study is the first to examine epigenetic inactivation by aberrant hypermethylation of CHFR in cervical cancer.
Assuntos
Antineoplásicos/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Proteínas de Ciclo Celular/genética , Epigênese Genética , Inativação Gênica/efeitos dos fármacos , Proteínas de Neoplasias/genética , Taxoides/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma Mucinoso/tratamento farmacológico , Adenocarcinoma Mucinoso/genética , Antimetabólitos Antineoplásicos/farmacologia , Azacitidina/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Metilação de DNA , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Tolerância a Medicamentos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose , Regiões Promotoras Genéticas/genética , RNA Interferente Pequeno/farmacologia , Células Tumorais Cultivadas , Ubiquitina-Proteína LigasesRESUMO
BACKGROUND: p16 has been reported to disappear by hypermethylation in various cancers. However, the relationship between the frequency of hypermethylation of p16 and the mechanism of its inactivation has not been completely elucidated in endometrial cancer. MATERIALS AND METHODS: Hypermethylation in the promoter region of the p16 gene and the expression of the p16 protein in 51 specimens, including 8 endometrial cancer cell lines, 7 normal endometrial tissues, 12 atypical endometrial hyperplasia tissues and 32 endometrial cancer tissues were analyzed. RESULTS: Five out of 8 endometrial cancer cell lines showed hypermethylation with high frequency, although only 1 showed loss of gene expression. However, no endometrial cancer tissue of the 32 specimens showed hypermethylation. Furthermore, loss of expression was immunohistochemically observed in 3 out of the 20 specimens. CONCLUSION: These results suggest that hypermethylation of p16 rarely occurs and, thus, has no significant effect on the carcinogenesis of endometrial cancer in Japanese patients.
