RESUMEN
The conduct of a scientifically sound safety assessment of new ingredients and finished products is essential prior to their introduction into the marketplace. Such assessments are based on a risk assessment paradigm established by the National Academy of Science (NAS, 1983) that consists of a four-step process: hazard identification, dose-response assessment, exposure assessment, and risk characterization. This risk assessment paradigm has been (1) used as a framework for estimating an adverse health risk posed by environmental chemicals, and (2) applied to systemic toxicological endpoints. The general principles of risk assessment may be applied to skin safety evaluation of consumer products, considering that dermal toxicity is also a threshold phenomenon. This study describes a risk assessment-based approach for skin safety evaluation of laundry detergent products.
Asunto(s)
Dermatitis por Contacto/prevención & control , Detergentes/efectos adversos , Seguridad de Productos para el Consumidor , Detergentes/química , Evaluación Preclínica de Medicamentos , Exposición a Riesgos Ambientales , Guías como Asunto , Humanos , Factores de RiesgoRESUMEN
The enhancer of zeste homolog 2 (EZH2) gene has been recently linked to human malignancies where it may serve as a new target for cancer therapy. Here, we analyzed EZH2 expression in primary renal cell carcinoma (RCC) specimens and in nontumorous tissue samples from adult kidney. EZH2 transcripts were detectable in all RCC specimens examined. Expression levels were significantly higher in tumor tissue (p < or = 0.0001) than in samples from normal adult kidney. Moreover, inhibition of endogenous EZH2 expression in RCC cell lines by RNA interference (RNAi) led to reduced proliferation and increased apoptosis in RCC cells. These data show that EZH2 is overexpressed in RCC. Furthermore, they indicate that the EZH2 gene plays a role for both the proliferation and the apoptosis resistance of RCC cells. Targeted inhibition of EZH2 could therefore represent a novel strategy to improve the therapeutic response of RCC.
Asunto(s)
Apoptosis/genética , Carcinoma de Células Renales/patología , Proliferación Celular , Proteínas de Unión al ADN/genética , Neoplasias Renales/patología , Factores de Transcripción/genética , Secuencia de Bases , Carcinoma de Células Renales/genética , Cartilla de ADN , Proteína Potenciadora del Homólogo Zeste 2 , Silenciador del Gen , Humanos , Neoplasias Renales/genética , Complejo Represivo Polycomb 2 , Interferencia de ARN , ARN Mensajero/genética , ARN Interferente Pequeño , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales CultivadasRESUMEN
The malignant phenotype of human papillomavirus (HPV)-positive cancer cells is maintained by the activity of the viral E6 and E7 genes. Here, we identified the polycomb group gene enhancer of zeste homologue 2 (EZH2) as a novel downstream target for the viral oncogenes in HPV-transformed cells. EZH2 expression was activated by HPV16 E7 at the transcriptional level via E7-mediated release of E2F from pocket proteins. RNA interference analyses showed that continuous EZH2 expression is required for the proliferation of HPV-positive tumor cells by stimulating cell cycle progression at the G1-S boundary. In addition to its growth-promoting activity, EZH2 also contributed to the apoptotic resistance of cervical cancer cells. Furthermore, we found that HPV-positive dysplastic and tumorigenic cervical lesions were characterized by high levels of EZH2 protein in vivo. We conclude that the E7 target gene EZH2 is a major determinant for the proliferation of HPV-positive cancer cells and contributes to their apoptotic resistance. Moreover, EZH2 may serve as a novel therapeutic target for the treatment of cervical cancer.