RESUMEN
Pathological staging and histological grading systems are useful, but imperfect, predictors of recurrence in head and neck squamous cell carcinoma (HNSCC). Aberrant promoter methylation is the main type of epigenetic modification that plays a role in the inactivation of tumor suppressor genes. To identify new potential prognostic markers, we investigated the promoter methylation status of five neuropeptide receptor genes. The methylation status of the target genes was compared with clinical characteristics in 278 cases; 72 hypopharyngeal cancers, 54 laryngeal cancers, 75 oropharyngeal cancers, and 77 oral cavity cancers were studied. We found that the NTSR1, NTSR2, GHSR, MLNR, and NMUR1 promoters were methylated in 47.8%, 46.8%, 54.3%, 39.2%, and 43.5% of the samples, respectively. GHSR and NMUR1 promoter methylation independently predicted recurrence in HNSCC. In patients with oropharyngeal cancer (n = 75), GHSR and NMUR1 promoter methylation significantly correlates with survival in surgically treated patients. We classified our patients as having a low, intermediate, or high-risk of death based on three factors: HPV status, and GHSR and NMUR1 promoter methylation. The disease-free survival (DFS) rates were 87.1%, 42.7%, and 17.0%, respectively. Combined data analysis of the methylation status of ten-eleven translocation (TET) family genes indicated a trend toward greater methylation indices as the number of TET methylation events increased. In the current study, we presented the relationship between the methylation status of the GHSR and NMUR1 genes and recurrence in HNSCC, specifically in risk classification of oropharyngeal carcinomas cases with HPV status.
Asunto(s)
Metilación de ADN/genética , Neoplasias Orofaríngeas/genética , Receptores de Ghrelina/genética , Receptores de Neurotransmisores/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Proteínas de Unión al ADN/genética , Dioxigenasas/genética , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oxigenasas de Función Mixta/genética , Recurrencia Local de Neoplasia/genética , Estadificación de Neoplasias , Neoplasias Orofaríngeas/patología , Neoplasias Orofaríngeas/cirugía , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/cirugíaRESUMEN
The constitutive expression of CYP2D9 is sexually dimorphic, namely, strong in males, but diminutive in females. Repetition of mimic growth hormone (GH) secretion pattern impressively returned the mRNA expression level to that in intact mice: the GH secretion pattern's regulation of CYP2D9 mRNA expression has been predominantly disrupted by exogenous GH-administration. The extensive decline of CYP2D9 mRNA expression becoming a sexually non-specific P450 in 9-week-old male mice exposed as neonates to monosodium L-glutamate (MSG) suggested that the male GH secretion pattern is a key to the regulation of male-specific CYP2D9 mRNA expression in adult mice. Dexamethasone (Dex) showed possibility to induce CYP2D9 mRNA expression in adult MSG-neonatally treated mice of either sex. However, the antagonism was observed by co-administration of Dex and GH in the males. Dex-administration in adrenalectomized mice significantly elevated CYP2D9 mRNA expression levels. These findings suggest that an adrenal hormone participates in the regulatory mechanism of CYP2D9 mRNA expression in association with GH.
Asunto(s)
Corticoesteroides/farmacología , Sistema Enzimático del Citocromo P-450/biosíntesis , Hormona del Crecimiento/farmacología , ARN Mensajero/biosíntesis , Adrenalectomía , Animales , Animales Recién Nacidos , Sistema Enzimático del Citocromo P-450/genética , Familia 2 del Citocromo P450 , Dexametasona/farmacología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Caracteres Sexuales , Glutamato de Sodio/farmacologíaRESUMEN
The expression of eight mouse hepatic cytochrome P450s (P450s) genes was investigated at the mRNA level in relation with the pattern of growth hormone (GH) administration. The constitutive expression of five sex-dependent P450s was sexually dimorphic, namely female>male for CYP2A4, CYP2B9, CYP2B10, and CYP3A41, and male>female for CYP2D9. In mice neonatally treated with monosodium L-glutamate to produce GH-deficiency, GH was found to be an essential factor with GH archetype as a determinant in the regulatory mechanism of hepatic CYP2D9 and CYP3A41 expression, and GH was shown to be a repressive factor for the constitutive expression in females. Implantation with micro-osmotic pump containing GH (to yield a constant release of GH to mimic the plasma GH profile in females) to male mice increased CYP2A4, CYP2B9, CYP2B10, and CYP3A41, but decreased CYP2D9, expression to female levels, while conversely, twice-daily administration of GH (to produce the so-called male pattern of plasma GH levels) to female mice resulted in the repression of female-specific, CYP2B9 and CYP3A41, as well as female-predominant, CYP2A4 and CYP2B10, expression, and induction of male-specific CYP2D9 expression. Thus, the sex-dependent plasma GH profile (referred to hereafter as the GH archetype) was a decisive factor for the expression of sex-specific P450 genes in adult mouse liver. On the other hand, the regulation of CYP1A2, CYP2C29, and CYP3A11 expression was either sex-independent or GH archetype-independent, considering the comparable levels between sexes of the constitutive expression and GH-inducible expression of these isoforms. Moreover, the observations suggested for the first time that the expression of CYP2B9 and CYP2A4 was not entirely GH-independent, but rather involved an imprinting GH-related factor that participated in the regulatory mechanism of P450 expression in females.