Current knowledge on the active form of Vitamin D synthesized in the skin and its effects on malignant melanoma.

The link between sunlight and skin cancer is a frequently discussed topic. However, ultraviolet radiation also induces the production of Vitamin D in the body. Keratinocytes and their ability to synthesize the active form of Vitamin D, which is consumed at the place of its origin in the skin, have a unique place in this discussion. We observe a remarkable sunshine-related paradox when we monitor the relationship between the dose of solar radiation and one type of skin cancer - malignant melanoma. Recent knowledge of the non-calcemic effects of Vitamin D, which include growth regulation, DNA repair, differentiation, apoptosis, membrane transport, metabolism, cell adhesion and oxidative stress, could help to further clarify this relationship. In this context, adjuvant Vitamin D therapy is currently being considered in patients with malignant melanoma, and this is expected to reduce tumor invasiveness and micrometastases and thus improve patient prognosis and reduce the risk of relapse.

[The Importance of MITF Signaling Pathway in the Regulation of Proliferation and Invasiveness of Malignant Melanoma]. / Význam signálnej dráhy MITF pri regulácii proliferácie a invazivity malígneho melanómu.

BACKGROUND: Malignant melanoma is one of the most aggressive types of cancers. Melanoma is derived from pigment-producing cells, melanocytes, which are characterized by a specific survival mechanism. Microphthalmia-associated transcription factor (MITF-M) plays a role in the metabolism of melanoma and is involved in the regulation of the expression of multiple genes mediating processes such as melanogenesis, proliferation, differentiation, and melanocyte survival. The expression of this transcription factor in melanocytes is activated by several signaling pathways, and reduced expression or function of MITF-M can cause the dysregulation of anti-apoptotic mechanisms. MITF-M is also involved in matrix metalloproteinase 14 (MMP14) activity, which is responsible for shape changes in melanocytes and increases in their motility and invasiveness. Very low levels of expression of MITF-M are found in human melanocytes with an invasive phenotype, indicating that this transcription factor acts as a suppressor of the metastatic process. Cancer cells with low expression of cytosolic/nuclear ß-catenin have a small amount of MITF-M 14 that is insufficient to inhibit MMP transcription. The enzyme catalyzes the degradation of laminin and fibronectin, thereby changing the shape of melanocytes, which leads to their increased mobility and invasiveness. AIMS: This review describes the regulatory pathway of MITF-M activation, its involvement in the proliferation of transformed melanocytes, and its role in increasing the invasiveness of malignant melanoma. A detailed understanding of the MITF-M signaling pathway is highly topical and could help to develop new diagnostic and therapeutic applications for patients with malignant melanoma.Key words: neoplastic cell transformation - melanoma - MITF transcription factorThis work was supported by grant projects VEGA 1/0115/14 and VEGA 1/0873/16.The authors declare they have no potential confl icts of interest concerning drugs, products, or services used in the study.The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 4. 12. 2015Accepted: 14. 6. 2016.

[Effect of vitamin d receptor polymorphisms on the development and progression of malignant melanoma]. / Prehlad vplyvu polymorfizmov receptora vitamínu D na vznik a progresiu malígneho melanómu.

BACKGROUND: Malignant melanoma is one of the most aggressive cutaneous tumors in men and women. The risk of developing a malignant melanoma depends on several external factors along with deregulation of mutual interaction of genotype and phenotype. Nowadays, growing attention is focused on the study of the interactions of the active form of vitamin D3 with its receptor and inhibitory effect of vitamin D3 receptor polymorphisms on multiple signaling pathways involved in proliferative and metastatic processes. OBJECTIVES: This review article addresses the relationship between factors involved in the development of malignant melanoma through Hedgehog signaling pathway (HH). It summarizes current knowledge of malignant melanoma in regard to the role of the active form of vitamin D3 binding to vitamin D3 receptor (VDR), as well as it describes the influence of polymorphisms of VDR on the inhibition of HH. Understanding of these mechanisms and critical assessment of available data is beneficial to both primary and secondary prevention of malignant melanoma particularly by means of chemo -preventive substances.

Expression of selected inflammatory proteins and metalloproteinases in periodontitis.

OBJECTIVE: Periodontitis is a chronic inflammatory disease caused by microbial dental plaque which leads to the destruction and loss of supporting tissues of the tooth. Microbial plaque alone, however, is not enough to cause the disease. The body's response plays an important role, in which an imbalance between the pro-inflammatory and anti-inflammatory effects of cytokines leads to an inflammatory reaction. PATIENTS AND METHODS: We detected changes in mRNA expression and protein levels of MIP-1α, and metalloproteinases (MMP-2, MMP-9) contributing to cascades in the initiation and progression of inflammatory bone resorption and destruction of periodontal soft tissues in patients with aggressive (AP) or chronic (CP) forms of periodontitis in comparison with healthy individuals (control). RESULTS: MIP-1α mRNA levels were highest in AP (280 ± 23% higher than the control) also in comparison with CP. The difference in protein level was less pronounced. MMP-2 mRNA expression values were similar (300 ± 12% higher in comparison with control), but protein levels were lower, also when compared to CP. Only in CP MMP-9 mRNA levels were significantly higher than the control (30 ± 8%), while protein levels were again higher in AP. Both AP and CP showed a positive correlation between the level of MIP-1a and MMP-2 (0.879, and 0.954 respectively). However, a strong positive correlation was only found between the levels of MMP-2 and MMP-9 in CP (0.812). CONCLUSIONS: MIP-1α, MMP-2 and MMP-9 mRNA expression, along with the concentration of proteins in saliva in patients with periodontal disease, is higher than in healthy individuals and correlates with the severity of the disease.

Is there a role for the IGF system and epidermal growth factor (EGF) in the pathogenesis of adrenocortical adenomas? A preliminary case-control study.

Adrenal incidentalomas (AI) are very common and mostly they are non-functioning adenomas (NFA). NFAs are often associated with insulin resistance and metabolic syndrome. Several biomarkers, including certain growth factors, may participatein the pathogenesis ofmetabolic changes in patients with adrenal adenomas.Patients with NFA and age-matched control subjects were enrolled in the study. Data on age, gender, presence of metabolic syndrome or its components were obtained for each subject. Blood samples were obtained and glycemia, insulinemia, lipid profile, and selected growth factor levels were measured. Forty-three patients with NFA and 40 controls were included in the study. Differences were not found in the metabolic syndrome and its components prevalence or in the biochemical profile between patients and the control group. Significant differences were noticed in the levels of IGF1, IGF2, and IGFBP3 (p=0.016, p=0.005, p=0.004, respectively), but there were no differences in VEGF or EGF concentrations. In NFA patients, an association between glycemia and EGF levels was present (p=0.026). No significant correlations between tumor size and insulin or growth factor concentrations were present in AI patients. Significantly higher serum IGF1, IGF2, and IGFBP3 concentrations in NFA patients may support the role of the IGF axis in the pathogenesis of adrenocortical lesions.No correlation between IGFs or IGFBP3 and parameters of glucose or lipid metabolism was found. Present results may support the role of the growth hormone axis rather than hyperinsulinemia and insulin resistance in the pathogenesis of adrenocortical adenomas.

Hypoxia factors suppression effect on the energy metabolism of a malignant melanoma cell SK-MEL-30.

OBJECTIVE: Malignant melanoma (MM), as well as other cancers, is a disorder in the cell life cycle at many levels. In terms of energy, the sync of cytosolic and mitochondrial metabolism is required for each cell. Mismatches also caused by hypoxic factors accumulate defects leading to the formation, development and invasiveness of malignant melanoma. Our aim was to compare the effect of HIF-1α and miR-210 on the metabolism of malignant melanoma cells in normoxia and pseudohypoxia. Further, we also investigated how gene silencing affects the viability in order to evaluate the potential of gene therapy in the treatment of MM. MATERIALS AND METHODS: We targeted oxidative phosphorylation by genetically suppressing HIF-1α and miR-210. We have examined mitochondrial activity, cytosolic glycolysis and cell viability. RESULTS: The ratio of NADH/NAD+ in the cytoplasm under normal conditions is stable and can thus serve as a specific cellular metabolic marker. Therefore, the study was aimed at finding the cause of the reduction in NADH levels in increasing hypoxia under ideal in vitro conditions on the SK-MEL-30 malignant melanoma cells. The relationship between HIF-1α and miR-210, their effect on transcriptional level, and the subsequent effect on metabolic process attenuation in cells was investigated. Obtained results indicate that the NADH which is accumulated by cells in hypoxia was significantly decreased upon gene silencing. CONCLUSIONS: Our studies have shown that small regulatory molecules with organelle-specific effect (such as miRs) need to be targeted, and that the resultant effect is comparable to silencing of "general" hypoxic transcription factors.

Molecular recognition of aortic valve stenosis and regurgitation.

OBJECTIVE: Aortic valve stenosis (AS) presents a disease during which there are changes of the aortic valve structure that modify the blood structure of patients. The aim of this study was to improve the effectiveness of differential diagnostics of aortic stenosis and aortic regurgitation using molecular techniques on both mRNA (RT-PCR) and protein (biochip protein). PATIENTS AND METHODS: An experimental group (n = 58) consisting of patients with aortic valve stenosis (n = 26) and aortic regurgitation (AR, n = 32) was compared with a control group (n = 35). Both blood serum and valve tissue samples were used for the determination of gene expression specific genes related to inflammatory response (CRP, IL6, IL2R, IL6R, TNFR1, and 2) as well as genes and proteins involved in remodeling of the extracellular matrix (MMP9, TIMP, Emilin-1). RESULTS: We found that hsCRP and IL6 plasma levels of patients with AS were higher than both controls and patients with AR (mean 5.6 ng/ml). The differences between AS and AR were detected only in mRNA levels of MMP9 and TIMP where increased levels characteristic for AS were found (about 74%, p < 0.01 and 87%, p < 0.001 higher than AR). CONCLUSIONS: The achieved results could contribute to the improvement of early diagnosis of selected cardiovascular disease in the future and improve the quality of patient's life.