RESUMEN
The present study was the first comprehensive investigation of genetic mutation and expression levels of the p53 signaling genes in cutaneous melanoma through various genetic databases providing large datasets. The mutational landscape of p53 and its signaling genes was higher than expected, with TP53 followed by CDKN2A being the most mutated gene in cutaneous melanoma. Furthermore, the expression analysis showed that TP53, MDM2, CDKN2A, and TP53BP1 were overexpressed, while MDM4 and CDKN2B were under-expressed in cutaneous melanoma. Overall, TCGA data revealed that among all the other p53 signaling proteins, CDKN2A was significantly higher in both sun and non-sun-exposed healthy tissues than in melanoma. Likewise, MDM4 and TP53BP1 expressions were markedly greater in non-sun-exposed healthy tissues compared to other groups. However, CDKN2B expression was higher in the sun-exposed healthy tissues than in other tissues. In addition, various genes were expressed significantly differently among males and females. In addition, CDKN2A was highly expressed in the SK-MEL-30 skin cancer cell line, whereas, Immune cell type expression analysis revealed that the MDM4 was highly expressed in naïve B-cells. Furthermore, all six genes were significantly overexpressed in extraordinarily overweight or obese tumor tissues compared to healthy tissues. MDM2 expression and tumor stage were closely related. There were differences in gene expression across patient age groups and positive nodal status. TP53 showed a positive correlation with B cells, MDM2 with CD8+T cells, macrophages and neutrophils, and MDM4 with neutrophils. CDKN2A/B had a non-significant correlation with all six types of immune cells. However, TP53BP1 was positively correlated with all five types of immune cells except B cells. Only TP53, MDM2, and CDKN2A had a role in cutaneous melanoma-specific tumor immunity. All TP53 and its regulating genes may be predictive for prognosis. The results of the present study need to be validated through future screening, in vivo, and in vitro studies.
RESUMEN
Background: Both hormonal and genetic data reveal that the stress hormone cortisol and its regulating genes may affect the level of testosterone in humans. It is uncertain whether type 2 diabetes mellitus would manifest similarly. Furthermore, a genetic strategy to screen out the stress system genes that may contribute to testosterone decline in humans is less understood. Objectives: In this study, we aimed to elucidate the link between stress and testosterone levels, both hormonally and genetically. Method: This study comprised 37 individuals with type 2 diabetes mellitus and 50 healthy individuals. For the analysis of hormones and the targeted genes, we used the RIA system and bioinformatics expertise. Results: The patients had significantly elevated cortisol and lower testosterone readings, according to data from hormonal analyses. The bioinformatics approach reveals that SHBG was intracellularly suppressed by 2 defined stress system genes: FKB5 and CYP17. TCF4/TCF8, ATRX, and AR in skeletal muscle were inversely related to stress system genes. Furthermore, all testosterone regulated genes were positively linked with SHBG in the current study. A strong relationship between GNAS and PKA with CYP17 and FKBP5 reveals that the Gαs-cAMP/PKA signaling pathway may be one of the regulatory pathways through which the suppression of testosterone system genes happens. In conclusion, this study demonstrated that beyond stress, the key stress system genes might affect cortisol levels, which in turn affect testosterone figures via the Gαs-cAMP/PKA signaling pathway.
