BackgroundMetformin is a biguanide, belonging to the oral hypoglycemic agents and is a widely used in the treatment of type 2 diabetes. Evidence indicate that Metformin inhibits cell proliferation in several human cancers and inhibits the Warburg phenomenon in tumor cells.ResultsLow PDH levels were observed in OSCC, and Metformin promotes an increase in PDH levels in hypoxic conditions. Metformin also reduced HIF-1α mRNA and protein levels. Metformin demonstrated antiproliferative effects, inhibited migration, increased the number of apoptotic cells and increased the transcription of caspase 3.ObjectiveThe present study aims to explore the effects of Metformin in hypoxic conditions. Specifically, we focused on pyruvate dehydrogenase (PDH), (hypoxia-inducible factor 1α) HIF-1α levels and the oral squamous cell carcinoma (OSCC) cell phenotype. Additionally, we also investigated a theoretical consequence of Metformin treatment.MethodsPDH levels in patients with OSCC and oral dysplasia were evaluated. Metformin was administered in vitro to test the effect of Metformin under hypoxic conditions. The results were complemented by Bioinformatics analyses.ConclusionsIn conclusion, our current findings show that Metformin reduces HIF-1α gene expression and increases PDH expression. Metformin inhibits cell proliferation and migration in the OSCC cell line model. Additionally, Metformin enhances the number of apoptotic cells and caspase 3 levels. Interestingly enough, Metformin did not increase the mutant p53 levels under hypoxic conditions.

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The aim of the present study was to evaluate the role of HIF-1α genetic polymorphisms and protein expression in the development of metastasis in upper aerodigestive tract cancer (UADTC) patients. The expression of pro-angiogenic markers was also evaluated. Protein expression was analysed using immunohistochemistry, and RFLP analysis was used to investigate HIF-1α C1779T and G1790A polymorphisms in 52 patients with UADTC. Primary lesions were divided into 2 groups according to the absence or presence of metastasis. Lymph node samples were divided into 3 groups: metastatic lymph nodes, non-metastatic lymph nodes (both derived from patients with metastatic disease), and control lymph nodes, which were obtained from patients without any metastasis. The allele T was more frequently found in patients with metastatic disease. HIF-1α protein expression in the lymph nodes was increased in the presence of the T allele. Metastatic lymph nodes showed lower levels of HIF-1α, VEGFR1, and MMP-9 proteins compared to lymph nodes without metastasis, while VEGFR2 protein levels were increased. In agreement, HIF-1α expression was correlated with MMP-9. Cox regression analysis demonstrated that higher HIF-1α and MMP-9 protein expression levels and GA and GG genotypes were associated with poor survival. Our findings show that the C1772T and G1790A polymorphisms of the HIF-1α gene are associated with increased expression of the HIF-1α protein in UADTC. The present data indicate that non-metastatic tissues express higher levels of HIF-1α, VEGFR1, and MMP-9, while in metastatic lymph nodes, VEGFR2 protein expression is elevated. The present study also shows that the HIF-1α G1790A polymorphism and its protein expression have an impact on the prognosis of UADTC patients.

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Genetic polymorphisms in the promoter region of the tumour necrosis factor-α (TNF-α) gene are involved in the regulation of the expression levels of its cytokine. Besides, these polymorphisms have been associated with the clinical behaviour of cancer. We investigated the -308 promoter region polymorphisms of the TNF-α gene and its association with the clinicopathological factors of a head and neck squamous cell carcinoma (HNSCC) sample. Furthermore, we analysed the impact of all the variables on the overall survival of patients. A sample of HNSCC (n=89) was evaluated. Clinicopathological factors and overall survival data were gathered. The TNF-α gene was analysed by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Data analyses were performed by using bivariate and multivariate statistical tests. Significance was set at p<0.05. HNSCC subjects carrying the A allele (GA/AA) exhibited associations with poor performance status (OR=2.82, p=0.039), lesions located on posterior areas (OR=4.02, p=0.002), and large-size tumours (OR=2.91, p=0.015). Subjects carrying only AA genotype exhibited association with poor performance status (OR=6.667, p=0.007). A worse overall survival was noted in subjects with large tumours (OR=4.87, p=0.005) and locoregional metastatic disease (OR=2.50, p=0.018). Our data suggests that the presence of the A allele/AA haplotype in HNSCC individuals might contribute to the higher clinical aggressiveness of malignant disease.

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This study investigated the immunodetection of CD57+ inflammatory cells in patients with head and neck squamous cell carcinoma (HNSCC) and its association with clinicopathological parameters and overall survival. Data collected from the morphological analysis and immunohistochemical reaction testing of archived HNSCC specimens (n=70) were statistically analyzed by bivariate and multivariate statistical testing at a significance level of P<0.05. The results indicate that CD57+ inflammatory cells predominate within the peritumoral stroma of HNSCC lesions and the existence of two significant relationships: between high CD57+ cell density and the development of a tumor of a large size [odds ratio (OR)=5.610, 95% confidence interval (CI)=1.516-20.763) and between high CD57+ cell density and the development of locoregional metastatic disease (OR=3.401, 95% CI=1.162-9.951). A significant difference in the rate of survival was detected only in HNSCC patients that presented large size tumors (OR=4.747, 95% CI=1.281-17.594). Together, these results suggest that although high CD57+ inflammatory cell density is associated with HNSCC lesions of greater clinical severity, the variable of cell density is not an independent predictor of HNSCC patient survival. Our findings also suggest that the relatively aggressive infiltration of CD57+ inflammatory cells in the peritumoral stroma of head and neck carcinomas may contribute to an ineffective locoregional antitumoral response.