ABSTRACT
The HIF-1 transcriptional complex is responsible for controlling transcription of over 100 genes involved in cell hypoxia response. HIF-1alpha subunit is stabilized in hypoxia conditions, creating the HIF-1 nuclear transcription factor. In inflammatory cells, high HIF-1alpha expression induces lymphocytic immunosuppression, decreasing tumoral antigen recognition, which promotes tumor growth. The present work investigated the relationship between HIF-1alpha expression in lymphocytes populating the intratumoral and peritumoral region of 56 patients with oral cancer. Our data indicates a prognostic value for this expression. High HIF-1alpha expression in peritumoral inflammatory cells is significantly related to worse patient outcome, whereas high expression in the intratumoral lymphoid cells correlates with a better prognosis. A risk profile indicating the chance of disease relapse and death was designed based on HIF-1alpha expression in tumoral inflammatory cells, defining low, intermediate and high risks. This risk profile was able to determine that high HIF-1alpha expression in peritumoral cells correlates with worse prognosis, independently of intratumoral expression. Low HIF-1alpha in tumor margins and high expression in the tumor was considered a low risk profile, showing no cases of disease relapse and disease related death. Intermediate risk was associated with low expression in tumor and tumor margins. Our results suggest that HIF-1alpha expression in tumor and peritumoral inflammatory cells may play an important role as prognostic tumor marker.
Subject(s)
Biomarkers, Tumor/metabolism , Carcinoma, Squamous Cell/diagnosis , Carcinoma, Squamous Cell/pathology , Gene Expression Regulation, Neoplastic , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Mouth Neoplasms/diagnosis , Mouth Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Carcinoma, Squamous Cell/metabolism , Female , Humans , Inflammation/pathology , Lymphocytes/metabolism , Male , Middle Aged , Mouth Neoplasms/metabolism , Prognosis , Tumor MicroenvironmentABSTRACT
Inflammatory gene variants have been associated with several diseases, including cancer, diabetes, vascular diseases, neurodegenerative diseases, arthritis, and others. Therefore, determining the population genetic composition of inflammation-related genes can be useful for the determination of general risk, prognostic and therapeutic strategies to prevent or cure specific diseases. We have aimed to identify polymorphism genotype frequencies in genes related to the inflammatory response in the Brazilian population, namely, IκBL -62AT, IκBL -262CT, tumor necrosis factors alpha (TNFa) -238GA, TNFa -308GA, lymphotoxin-alpha (LTa) +80AC, LTa +252AG, FAS -670AG, and FASL -844TC, considering the white, black, and Pardo ethnicities of the São Paulo State. Our results suggest that the Brazilian population is under a miscegenation process at the current time, since some genotypes are not in the Hardy-Weinberg equilibrium. In addition, we conclude that the Pardo ethnicity is derived from a complex mixture of ethnicities, including the native Indian population.
Subject(s)
Genetic Variation , Inflammation/genetics , Adaptor Proteins, Signal Transducing , Adult , Aged , Aged, 80 and over , Brazil/epidemiology , Fas Ligand Protein/genetics , Female , Genetics, Population , Genotype , Histocompatibility Antigens Class II/genetics , Humans , Lymphotoxin-alpha/genetics , Male , Middle Aged , Tumor Necrosis Factor-alpha/geneticsABSTRACT
FAS/FASL altered expression may cause tumor protecting immunomodulation, with a direct impact on patient prognosis. FAS expression was studied in 60 squamous cell carcinomas of the oral cavity. FAS expression did not show a significant association with tumor histopathological characteristics, but was significantly associated with lymph node positivity. FAS expression was significantly associated with disease specific death and negative FAS expression was an independent risk factor, increasing risk 4 times when compared to positive expression. When FAS and FASL expression results were combined, we were able to define high, intermediate and low risk profiles. Disease-free and disease-specific survival were significantly correlated with FAS/FASL expression profiles. The high risk category was an independent marker for earlier disease relapse and disease-specific death, with approximately 4- and 6-fold increased risk, respectively, when compared to the low risk profile. Risk profiles based on FAS/FASL expression showed that high risk was significantly associated with increased disease relapse and death, as well as shorter disease-free or disease-specific survival. This categorization, added to patient clinical data, may facilitate the choice of therapy, minimizing treatment failure and increasing disease control.
