ROS as Regulators of Cellular Processes in Melanoma.

In this review, we examine the multiple roles of ROS in the pathogenesis of melanoma, focusing on signal transduction and regulation of gene expression. In recent years, different studies have analyzed the dual role of ROS in regulating the redox system, with both negative and positive consequences on human health, depending on cell concentration of these agents. High ROS levels can result from an altered balance between oxidant generation and intracellular antioxidant activity and can produce harmful effects.

microRNA-10 and -221 modulate differential expression of Hippo signaling pathway in human astroglial tumors.

Gliomas represent over 70% of all brain tumors, they are highly invasive and structurally vascular neoplasms. Despite the latest technological advance in neuro-surgery the survival of patients with high-grade glioma remains poor. The lack of robust treatment options has propelled the search for new markers that may able allow the identification of patients who can benefit from molecularly targeted therapies.

Genistein reduces proliferation of EP3-expressing melanoma cells through inhibition of PGE2-induced IL-8 expression.

Genistein, a natural isoflavone found in soybean products, is considered as a powerful anti-cancer agent, although the involved mechanisms are not fully understood. There is a growing body of evidence that, among the genes inhibited by genistein and responsible for cell cycle progression, invasion, metastasis, and angiogenesis, IL-8 occupies a relevant place. On the other hand, it is equally well documented that IL-8 is upregulated by prostaglandin E2 (PGE) in different pathological conditions, particularly in neoplastic disease.

miRNA expression profiling regulates necroptotic cell death in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most aggressive types of cancer and is among the leading causes of cancer-related mortality worldwide. Although the dysregulation of microRNAs (miRNAs or miRs) has often been reported in HCC, the precise molecular mechanisms by which miRNAs modulate the process of tumorigenesis and the behavior of cancer cells are not yet clearly understood. In this study, we identified a novel three‑miRNA signature, including miR‑371-5p, miR‑373 and miR‑543, that appears to orchestrate programmed cell necrosis in HCC by directly targeting the caspase‑8 gene (Casp‑8).

DSS1 promoter hypomethylation and overexpression predict poor prognosis in melanoma and squamous cell carcinoma patients.

Previous studies have found a link between high expression levels of the Deleted in Split hand/Split foot 1 (DSS1) gene and cancer progression. The aim of this study was to examine whether overexpression of DSS1 is a feature of melanoma and squamous cell carcinoma (SCC) and if any epigenetic modifications are involved. Evaluation of DSS1 expression profile indicated that the gene is overexpressed in 112 of 130 cutaneous melanomas (86.

miR-92a-3p and MYCBP2 are involved in MS-275-induced and c-myc-mediated TRAIL-sensitivity in melanoma cells.

Increasing evidence has demonstrated that in several tumors c-myc acts either as an oncogène or as a proapoptotic agent, depending on binding partner interactions. Recently, we showed that up-regulation of this gene by the histone deacetylase inhibitor MS-275 was responsible for sensitization to TRAIL-induced apoptosis through c-FLIP repression in melanoma. The present study aimed at investigating whether, in addition to inducing H3 hyperacetylation at the c-myc promoter, MS-275 could enhance cell death through the regulation of miRNAs involved in apoptosis, such as the miR-17-92 cluster.

Epidrugs in the Immunotherapy of Cutaneous and Uveal Melanoma.

Epigenetic modifications can affect numerous mechanisms used by neoplastic cells to evade immune control. In melanoma epigenetic defects, caused by dysregulations in the expression of genome writers, erasers, or readers, play a significant role in the reduced expression of molecules required for efficient immune recognition as well as antigen presentation and processing. Alterations in gene expression were identified in tumor-associated antigens (TAAs), human leukocyte antigen (HLA) complex, co-stimulatory/accessory molecules, antigen processing machinery (APM), and NKG2D ligands that have shown to be silenced or down-regulated in melanoma.

DNA methylation-induced E-cadherin silencing is correlated with the clinicopathological features of melanoma.

E-cadherin, a calcium-dependent cell-cell adhesion molecule, has an important role in epithelial cell function, maintenance of tissue architecture and cancer suppression. Loss of E-cadherin promotes tumor metastatic dissemination and predicts poor prognosis. The present study investigated the clinicopathological significance of E-cadherin expression in cutaneous, mucosal and uveal melanoma related to epigenetic mechanisms that may contribute to E-cadherin silencing.

IL-10Rα expression is post-transcriptionally regulated by miR-15a, miR-185, and miR-211 in melanoma.

Background: IL-10 is an immunoregulatory cytokine that increases during malignant diseases. The purpose of this study was to: i) determine the mRNA amounts of IL-10, IL-10Rα, and IL-10Rβ in cutaneous and uveal melanoma cells and specimens; ii) evaluate their post-transcriptional regulation by miRNAs; iii) ascertain whether miRNA dysregulation may affect IL-10-induced proliferation.

Methods: Genome-wide miRNA expression profiling was performed using a human microarray platform.

Role of Genetics and Epigenetics in Mucosal, Uveal, and Cutaneous Melanomagenesis.

Melanoma prevalently occurs on parts of the body that have been overexposed to the sun. However, it can also originate in the nervous system, eye and mucous membranes. Melanoma has been thought for a long time to arise through a series of genetic mechanisms involving numerous irreversible changes within the human genome.

The overriding of TRAIL resistance by the histone deacetylase inhibitor MS-275 involves c-myc up-regulation in cutaneous, uveal, and mucosal melanoma.

Malignant melanoma is a highly aggressive tumor which may occur in the skin, eye, and mucous membranes. The prognosis of melanoma remains poor in spite of therapeutic advances, emphasizing the importance of innovative treatment modalities. Currently, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is showing promising clinical responses, however its use is hampered by intrinsic or acquired melanoma resistance to apoptosis.

Cellular Mechanisms of Oxidative Stress and Action in Melanoma.

Most melanomas occur on the skin, but a small percentage of these life-threatening cancers affect other parts of the body, such as the eye and mucous membranes, including the mouth. Given that most melanomas are caused by ultraviolet radiation (UV) exposure, close attention has been paid to the impact of oxidative stress on these tumors. The possibility that key epigenetic enzymes cannot act on a DNA altered by oxidative stress has opened new perspectives.

Involvement of epimutations in meningioma.

Epimutations are heritable and reversible cell markers, which can influence cell function going beyond the effects of DNA mutations. They result from multiple and coordinated mechanisms able to modulate gene expression. Regarding the significance of epigenetics in meningioma, few and somehow contradictory results are available, although promising information has been obtained.

Heavy metals and epigenetic alterations in brain tumors.

Heavy metals and their derivatives can cause various diseases. Numerous studies have evaluated the possible link between exposure to heavy metals and various cancers. Recent data show a correlation between heavy metals and aberration of genetic and epigenetic patterns.

Epigenetic effects of cadmium in cancer: focus on melanoma.

Cadmium is a highly toxic heavy metal, which has a destroying impact on organs. Exposure to cadmium causes severe health problems to human beings due to its ubiquitous environmental presence and features of the pathologies associated with pro-longed exposure. Cadmium is a well-established carcinogen, although the underlying mechanisms have not been fully under-stood yet.

Epigenetic regulation of p14ARF and p16INK4A expression in cutaneous and uveal melanoma.

Inactivation of p14ARF and p16INK4A by epigenetic changes in cutaneous and uveal melanoma has been here investigated. Compared with melanocytes, p14ARF mRNA reduction and p16INK4A inactivation were frequently noticed. No association between p14ARF promoter methylation and mRNA levels was found, whereas aberrant p16INK4A methylation was associated with gene silencing (p<0.

Epigenetic marks responsible for cadmium-induced melanoma cell overgrowth.

Cadmium (Cd) is a human carcinogen that likely acts via epigenetic mechanisms. However, the precise role of Cd in melanoma remains to be defined. The goals of this study are to: (i) examine the effect of Cd on the proliferation rate of cutaneous and uveal melanoma cells; (ii) identify the genes affected by Cd exposure; (iii) understand whether epigenetic changes are involved in the response to Cd.

Class I-specific histone deacetylase inhibitor MS-275 overrides TRAIL-resistance in melanoma cells by downregulating c-FLIP.

Tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL) has selective killing effect toward malignant cells; however some human melanomas are intrinsically resistant. In this study, we have shown that class I-specific histone deacetylase inhibitor (HDACi) MS-275 can synergize with TRAIL to induce apoptosis in TRAIL-resistant cell lines and to enhance susceptibility of sensitive cells. Conversely, class II-selective HDACi MC1575 has shown no effect on the resistance of melanoma cells and was able exclusively to increase TRAIL-induced cell death in responsive cells.

Identification of microRNA expression patterns in cutaneous and uveal melanoma cell lines.

Aims And Background: microRNA (miRNA)-mediated epigenetic regulation of tumor suppressor genes and oncogenes has been shown to play a central role in melanomagenesis. Here, we focused on the identification of miRNA signatures in the cutaneous melanoma cell line G361 and the uveal melanoma cell line OCM-1.

Methods And Study Design: We carried out genome-wide miRNA expression profiling using a human miRNA microarray platform (Agilent Sanger miRBase, release 10.

Impact of DNA methyltransferases on the epigenetic regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor expression in malignant melanoma.

Aberrant promoter methylation and resultant silencing of TRAIL decoy receptors were reported in a variety of cancers, but to date little is known about the relevance of this epigenetic modification in melanoma. In this study, we examined the methylation and the expression status of TRAIL receptor genes in cutaneous and uveal melanoma cell lines and specimens and their interaction with DNA methyltransferases (DNMTs) DNMT1, DNMT3a, and DNMT3b. DR4 and DR5 methylation was not frequent in cutaneous melanoma but on the contrary it was very frequent in uveal melanoma.

NOD2 triggers PGE2 synthesis leading to IL-8 activation in Staphylococcus aureus-infected human conjunctival epithelial cells.

We previously showed that Staphylococcus aureus and Pseudomonas aeruginosa stimulate IL-8 expression in human conjunctival epithelial cells through different signal transduction pathways. As in some cell types both the bacteria may induce the release of prostaglandin E2 (PGE2) and PGE2 may affect the expression of IL-8, we aimed at investigating whether in human conjunctival cells infected with S. aureus or P.

Contact lens wearing and chronic cigarette smoking positively correlate with TGF-β1 and VEGF tear levels and impaired corneal wound healing after photorefractive keratectomy.

Purpose: To study the correlation of gender, contact lens (CL) wearing, chronic drinking and chronic smoking with wound healing cytokine levels and corneal recovery after photorefractive keratectomy (PRK).

Materials And Methods: One hundred and twenty-eight age-matched patients (180 eyes) undergoing PRK were enrolled. PDGF, EGF, VEGF, HGF and TGF-β(1) protein levels were measured in tears by enzyme-linked immunosorbent assay either preoperatively or 2, 7 and 15 days after PRK.

PGE2 induces interleukin-8 derepression in human astrocytoma through coordinated DNA demethylation and histone hyperacetylation.

We have recently reported that in astrocytoma cells the expression of interleukin-8 (IL-8) is upregulated by prostaglandin E2 (PGE2). Unfortunately, the exact mechanism by which this happens has not been clarified yet. Here, we have investigated whether IL-8 activation by PGE2 involves changes in DNA methylation and/or histone modifications in 46 astrocytoma specimens, two astrocytoma cell lines and normal astrocytic cells.

Combined effects of cigarette smoking and alcohol consumption on antioxidant/oxidant balance in age-related macular degeneration.

Background And Aims: To investigate the single and joint effects of chronic cigarette smoking and alcohol consumption on oxidative stress in age-related macular degeneration (ARMD).

Methods: Superoxide dismutase (SOD), glutathione peroxidase (GSHPx), and catalase (CAT) activities; malondialdehyde (MDA) levels; and DNA damage were measured in patients with early ARMD (n=211) and late ARMD (n=205), and control persons (n=262).

Results: When compared with healthy controls, early- and late-ARMD patients showed significant decreases in the activities of SOD and GSHPx, but not CAT, along with marked enhancements of MDA levels and tail parameters (p<0.

Association between oxidative stress and macromolecular damage in elderly patients with age-related macular degeneration.

Background And Aims: The aim of the present study was to determine whether age and gender affect the imbalance between oxidant production and antioxidant levels in age-related macular degeneration (ARMD) patients.

Methods: Total superoxide dismutase (T-SOD), total glutathione peroxidase (T-GSHPx), and catalase (CAT) activities, as well as malondialdehyde (MDA), protein carbonyl (PC), 8-Hydroxy-29-deoxyguanosine (8-OHdG) and total oxidation status (TOS) levels, were measured in the following groups subdivided by age and gender: 156 early-ARMD patients; 80 wet-late ARMD patients; 72 dry-late ARMD patients; and 207 healthy controls.

Results: Among all study participants, women aged 50-54 had higher T-SOD and T-GSHPx activities and lower MDA, PC, TOS and 8-OHdG levels than age-matched men (p<0.