RESUMO
BACKGROUND: Several cancer-related genes are silenced by promoter hypermethylation in skin cancers. However, to date the somatic epigenetic events that occur in cutaneous squamous cell carcinoma (SCC) tumorigenesis have not been well defined. OBJECTIVES: To examine epigenetic abnormalities of FOXE1, a gene located on chromosome 9q22, a region frequently lost in SCC. METHODS: We investigated the methylation status of FOXE1 in 60 cases of cutaneous SCC by methylation-specific polymerase chain reaction, and comparatively examined mRNA and protein expression by real-time polymerase chain reaction and Western blot, respectively. RESULTS: We found a higher frequency of FOXE1 promoter hypermethylation in SCCs (55%), as compared with the adjacent uninvolved skin (12%) and blood control samples (9.5%). FOXE1 methylation was frequently seen in association with a complete absence of or downregulated gene expression. Treatment with the demethylating agent 5-Aza-2'-deoxycytidine resulted in profound reactivation of FOXE1 expression. CONCLUSIONS: These results indicate that FOXE1 is a crucial player in development of cutaneous SCC.
Assuntos
Carcinoma de Células Escamosas/genética , Metilação de DNA , Fatores de Transcrição Forkhead/genética , Neoplasias Cutâneas/genética , Idoso , Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/análogos & derivados , Azacitidina/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , DNA de Neoplasias/genética , Decitabina , Feminino , Fatores de Transcrição Forkhead/biossíntese , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , RNA Neoplásico/genética , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/metabolismoRESUMO
Plasminogen activator inhibitor type-1 (PAI-1), the most important physiological fibrinolysis inhibitor, is considered an independent factor of cardiovascular risk in Type 2 diabetes mellitus (T2DM). In previous papers we demonstrated that a T2DM population without complications presents: 1) PAI-1 not increased with respect to a control group; and 2) a negative correlation between PAI-1 and lipoprotein(a) [Lp(a)], suggesting that in these subjects PAI-1 levels could be modulated by the "endothelial stress" induced by Lp(a) and diabetes. This work has been performed in order to better verify this intriguing hypothesis, and the endothelial stress has been evaluated through a marker of endothelial damage, fibronectin (FNC). For this purpose we chose a T2DM population without complications (n=73) and a control group (n=46). Plasma concentrations of FNC, Lp(a), PAI-1 antigen and activity, and the main parameters of lipo- and glycometabolic balance were determined. Fibronectin was significantly higher in diabetics with respect to controls (p<0.01). As expected, significant correlation between PAI-1 antigen, PAI-1 activity and Lp(a) (r=-0.54,p<0.01 and r=-0.39,p<0.01, respectively) was found only in diabetic patients. In the same group FNC showed a significant correlation with PAI-1 antigen and activity (r=-0.49,p<0.01 and r=-0.47; p<0.01, respectively), while no relationship was found between Lp(a) and FNC. Multiple regression analysis showed statistically significant correlation between PAI-1 antigen and PAI-1 activity with FNC and Lp(a) in diabetic patients without complications (p<0.05). These data suggest that in absence of complications, the endothelium is able to modulate PAI-1 levels, favouring in that way the fibrinolytic pathway and, subsequently, the recovery of the endothelial integrity. This modulation seems to be related to parameters such as Lp(a) and FNC, although the mechanisms of the endothelial stress of these two molecules seem to be different.
