Melanoma Development Research Articles

Prevention of cancer-Melanoma development and its diagnosis among Silesian Voivodeship residents: Preliminary results.

Melanoma is a malignant tumor with the highest growth rate in the incidence and is the leading cause of death due to skin cancers. In Poland, approximately 1500 cases of melanoma are detected annually in advanced or metastatic stages. Intensive preventive measures can contribute to its early-stage diagnosis, consequently reducing the number of fatalities. The aim of the study was to assess the occurrence of melanoma risk factors among the residents of Silesia region and their knowledge about the diagnosis and prevention of this cancer. An original questionnaire was used in the study, and its completion was anonymous. The study was conducted among the residents of the Silesian Voivodeship. A total of 400 (100%) individuals were examined. Among them were 243 women and 157 men. The participants' ages ranged from 16 to 84 years (mean age = 34.38 ± 18.39). The participants were burdened with melanoma development risk factors such as fair skin complexion (235; 58.75%), having more than 50 pigmented lesions (158; 39.50%) and sunburns (105; 26.25%). Over 40% (166; 41.50%) of the participants had never examined their pigmented lesions. A staggering 78% (311; 77.75%) of the respondents had never undergone dermatoscopic examination, and over 50% (215; 53.75%) did not know what this examination entailed. Just under 16% (63; 15.75%) of the participants stated that their family doctor had examined their pigmented lesions, and almost % (154; 97.47%) of those with numerous pigmented lesions had never been referred to a dermatologist for dermatoscopy. The surveyed residents of the Silesian Voivodeship were burdened with numerous risk factors for melanoma development, with the most common being fair skin complexion, having more than 50 pigmented lesions, and sunburns. The knowledge of the participants regarding the diagnosis and prevention of melanoma development was insufficient, thus highlighting the necessity for conducting systematic educational initiatives in the mentioned field. These initiatives should ultimately lead to the preservation of health and life, as well as the maintenance of its high quality.

The risk of ultraviolet exposure for melanoma in Fitzpatrick skin types I-IV: A 20-year systematic review with meta-analysis for sunburns.

Within the last two decades, no studies have comprehensively reviewed the risk of varying types of ultraviolet (UV) exposure on melanoma in fairer skinned individuals. Our research objective was to determine whether or not there was a change in the risk of UV exposure with development of melanoma in Fitzpatrick skin types I-IV based on more recent data over the past 20 years. We performed a systematic review from January 2002 to December 2021 analysing UV exposure and melanoma risk in Fitzpatrick type I-IV individuals. Out of 19,852 studies, 26 met inclusion criteria. Data spanned subjects from national and multinational cohorts (USA, Europe, Australia, Asia and South America). Twenty studies (77%, 20/26) identified a significant association between UV exposure and melanoma incidence. Sunburn was the most commonly assessed risk factor. Sunburn studies encompassed 3417 melanoma and found positive significant odds ratios (OR [95% CI]) in 11 out of 13 studies, ranging from 1.23 [1.01-1.49] to 8.48 [4.35-16.54]. Pooled analysis of the risk of melanoma with sunburn history found an unadjusted odds ratio of 1.66 [1.40-1.97] and adjusted odds ratio of 1.23 [1.04-1.46]. Cumulative sun exposure, measured as number of hours of sun exposure or calculated UV flux, was the second most common risk factor, encompassing 913 melanomas with positive significant ORs ranging from 1.1 [1.0-1.2] to 5.2 [2.1-12.5]. For other forms of UV exposure, a majority of studies showed an association with UV index (6/9), outdoor leisure activity (3/3) and left-sided laterality (1/1). Overall, UV exposure should continue to be considered a modifiable risk factor for melanoma in individuals of fairer skin.

CDK4 gene copy number increase and concurrent genetic changes in acral melanoma of a Chinese cohort

Acral melanoma (AM) is the most common subtype of melanoma in Asian population. Abnormalities in the p16-cyclin D1-CDK4 signalling pathway play a crucial role in the development and progression of AM. However, the alterations of CDK4 gene copy number in AM are underreported. In this study, we investigated CDK4 gene copy number and concurrent molecular changes in a Chinese cohort with AM, in aim of exploring CDK4 gene alterations and its significance in AM. We examined copy number alterations of CDK4 with fluorescence in situ hybridisation (FISH) in 31 patients with AM. Six patients with CDK4 high-level copy number increase were examined by next-generation sequencing to detect concurrent molecular changes. Using FISH, 12 (12/31, 38.7%) cases showed CDK4 copy number increase, with 6 (6/31, 19.4%) low-level copy number increase and 6 (6/31, 19.4%) high-level copy number increase. Five of six CDK4 low-level copy number increase cases were accompanied by polysomy of chromosome 12, while one case was not. Two of six CDK4 high-level copy number increase cases were accompanied by polysomy of chromosome 12, while four cases were not. CDK4 copy number increase was significantly correlated with younger patient age. In six CDK4 high-level copy number increase cases, one case was found to be accompanied by NRAS mutation, one case was accompanied by HER2 mutation, one case was accompanied by BCL2L11 mutation ​and one case was accompanied by BRAF, HER2 and BCL2L11 mutations. Our study confirmed the presence of CDK4 copy number increase in AM cases. Detecting CDK4 copy number increase by FISH can be reliable in the diagnosis of AM. Some CDK4 copy number increases are the results of polysomy of chromosome 12. CDK4 high-level copy number increase coexists with other pathogenic mutations in AM. CDK4 appears to be a promising target for AM treatment and is expected to be combined with other targeted therapies.

Oxidative State in Cutaneous Melanoma Progression: A Question of Balance.

Reactive oxygen species (ROS) are highly bioactive molecules involved not only in tissue physiology but also in the development of different human conditions, including premature aging, cardiovascular pathologies, neurological and neurodegenerative disorders, inflammatory diseases, and cancer. Among the different human tumors, cutaneous melanoma, the most aggressive and lethal form of skin cancer, is undoubtedly one of the most well-known "ROS-driven tumor", of which one of the main causes is represented by ultraviolet (UV) rays' exposure. Although the role of excessive ROS production in melanoma development in pro-tumorigenic cell fate is now well established, little is known about its contribution to the progression of the melanoma metastatic process. Increasing evidence suggests a dual role of ROS in melanoma progression: excessive ROS production may enhance cellular growth and promote therapeutic resistance, but at the same time, it can also have cytotoxic effects on cancer cells, inducing their apoptosis. In this context, the aim of the present work was to focus on the relationship between cell redox state and the signaling pathways directly involved in the metastatic processes. In addition, oxidative or antioxidant therapeutic strategies for metastatic melanoma were also reviewed and discussed.

No evidence that retinol is protective for skin cancer.

With over 1.5 million new cases annually, skin cancers are the most commonly diagnosed group of cancers worldwide. Among these, melanoma and keratinocyte cancers (KC), comprising squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), are predominant. Retinol, a vitamin A derivative, is essential in the regulation of growth and differentiation of epidermal cells. Moreover, retinol exhibits antioxidant properties, protecting the skin against ultra-violet (UV) radiation induced oxidative damage. Existing research on the impact of retinol on melanoma, SCC and BCC development shows mixed results. Several dietary intake studies have suggested that higher retinol levels reduce skin cancer risk, however, others have failed to find this association. We used two-sample Mendelian randomization (MR) to explore if there is a causal relationship between retinol and the risk of developing melanoma, SCC or BCC. Genetically predicted circulating retinol levels were obtained from a genome wide association study (GWAS) meta-analysis of the INTERVAL (N=11,132) and METSIM (N=6,136) cohorts. Melanoma (30,134 cases and 375,188 controls), SCC (10,557 cases and 537,850 controls) and BCC (36,479 cases and 540,185 controls) risks were derived from published GWAS meta-analyses. We conducted two MR approaches. In the first MR we used a single SNP (rs10882283) that is associated with the levels of Retinol Binding Protein 4 (RBP4) as an instrument variable (IV) for circulating retinol levels. In the second MR we used all independent genetic variants that were strongly associated (P < 5 × 10-8) with retinol levels as IVs. Odds ratios (OR) for skin cancer were calculated for a one standard deviation (SD) increase in genetically predicted retinol levels. The single IV approach revealed that retinol levels were not significantly associated with risk of melanoma (OR = 1.04 [95% confidence interval 0.83, 1.31], P = 0.72), SCC (OR = 1.15 [0.87, 1.51], P = 0.32) or BCC (OR = 1.06 [0.90, 1.23], P = 0.50). Similar null results were observed with the multiple IV approach for melanoma (OR = 1.03 [0.95, 1.11], P = 0.54), SCC (OR = 1.01 [0.91, 1.13], P = 0.83), and BCC (OR = 1.04 [0.96, 1.12], P = 0.38). In conclusion, we found no evidence that circulating retinol levels were causally associated with the development of melanoma, SCC and BCC.

Giant congenital melanocytic nevus in an 8-year-old female: a case report

Giant congenital melanocytic nevus are melanocytic lesions secondary to abnormal melanoblast migration during the embryogenesis. The incidence reported is in 1 case for every 20 000 newborns and it is present since birth. The importance of its detection relies on the associated complications, such as melanoma development or neurocutaneous melanosis, as well as the psychological and social impact they generate; patients will require a long-term multidisciplinary attention. There is no elective treatment, management is still controversial, it must be individualized according to the characteristics of the nevus and the age of the patient. We present the case of an 8-year-old patient where the diagnosis of giant congenital melanocytic nevus is determined for the first time.

Non-coding RNAs in BRAF-mutant melanoma: targets, indicators, and therapeutic potential.

Melanoma, a highly aggressive skin cancer, is often driven by BRAF mutations, such as the V600E mutation, which promotes cancer growth through the MAPK pathway and contributes to treatment resistance. Understanding the role of non-coding RNAs (ncRNAs) in these processes is crucial for developing new therapeutic strategies. This review aims to elucidate the relationship between ncRNAs and BRAF mutations in melanoma, focusing on their regulatory roles and impact on treatment resistance. We comprehensively reviewed current literature to synthesize evidence on ncRNA-mediated regulation of BRAF-mutant melanoma and their influence on therapeutic responses. Key ncRNAs, including microRNAs and long ncRNAs, were identified as significant regulators of melanoma development and therapy resistance. MicroRNAs such as miR-15/16 and miR-200 families modulate critical pathways like Wnt signaling and melanogenesis. Long ncRNAs like ANRIL and SAMMSON play roles in cell growth, invasion, and drug susceptibility. Specific ncRNAs, such as BANCR and RMEL3, intersect with the MAPK pathway, highlighting their potential as therapeutic targets or biomarkers in BRAF-mutant melanoma. Additionally, ncRNAs involved in drug resistance, such as miR-579-3p and miR-1246, target processes like autophagy and immune checkpoint regulation. This review highlights the pivotal roles of ncRNAs in regulating BRAF-mutant melanoma and their contribution to drug resistance. These findings underscore the potential of ncRNAs as biomarkers and therapeutic targets, paving the way for innovative treatments to improve outcomes for melanoma patients.

Molecular Susceptibility and Treatment Challenges in Melanoma.

Melanoma is the most aggressive subtype of cancer, with a higher propensity to spread compared to most solid tumors. The application of OMICS approaches has revolutionized the field of melanoma research by providing comprehensive insights into the molecular alterations and biological processes underlying melanoma development and progression. This review aims to offer an overview of melanoma biology, covering its transition from primary to malignant melanoma, as well as the key genes and pathways involved in the initiation and progression of this disease. Utilizing online databases, we extensively explored the general expression profile of genes, identified the most frequently altered genes and gene mutations, and examined genetic alterations responsible for drug resistance. Additionally, we studied the mechanisms responsible for immune checkpoint inhibitor resistance in melanoma.

Intradermal vaccination with a phytoglycogen nanoparticle and STING agonist induces cytotoxic T lymphocyte-mediated antitumor immunity

A critical aspect of cancer vaccine development is the formulation with effective adjuvants. This study evaluated whether combining a cationic plant-derived nanoparticle adjuvant (Nano-11) with the clinically tested STING agonist ADU-S100 (MIW815) could stimulate anticancer immunity by intradermal vaccination. Nano-11 combined with ADU-S100 (NanoST) synergistically activated antigen-presenting cells, facilitating protein antigen cross-presentation in vitro and in vivo. Intradermal vaccination using ovalbumin (OVA) as a tumor antigen and combined with Nano-11 or NanoST prevented the development of murine B16-OVA melanoma and E.G7-OVA lymphoma tumors. The antitumor immunity was abolished by CD8+ T cell depletion but not by CD4+ T cell depletion. Therapeutic vaccination with NanoST increased mouse survival by inhibiting B16-OVA tumor growth, and this effect was further enhanced by PD-1 checkpoint blockade. Our study provides a strong rationale for developing NanoST as an adjuvant for intradermal vaccination and next-generation preventative and therapeutic cancer vaccines by STING-targeted activation.

Frequency of BRAF Mutations in Dysplastic Nevi, Lentigo Maligna, and Melanoma In Situ.

Background: In melanomas, mutations in the BRAF gene are common and their occurrence represents an early oncogenic event. Our goal was to determine and compare the frequency of BRAF gene mutations in dysplastic nevi (ND) and melanomas in situ (MIS), as well as whether there is a correlation between the presence of BRAF gene mutations and various anamnestic, clinical, and histopathologic variables. Methods: A total of 175 patients-106 with ND, 41 with MIS, and 28 with lentigo maligna (LM) were included in the study. DNA was extracted from tissue samples and analyzed using the competitive allele-specific TaqMan chain reaction by polymerase in real time to detect the presence of BRAF V600E and V600K mutations. The data were compared with anamnestic, clinical, and histopathological data. Results: There is a statistically significant correlation between the presence of BRAF mutation and the diagnosis of melanoma in situ (χ2 test, χ2 = 29.17, p < 0.0001). Patients with LM had a significantly lower incidence of BRAF mutations compared to patients with ND and MIS. There was a significant correlation between the presence of a BRAF mutation and tumor localization, as well as the age of the patient, but no statistically significant correlation between the presence of a BRAF mutation and sex, tumor size, or previous melanoma diagnosis. Conclusions: BRAF mutations in ND are essentially required; however, they are an insufficient oncogenic trigger for the development of melanoma. This research contributes to a better understanding of the etiopathogenesis of melanoma and the role of ND as possible precursor lesions.

Peptide Degrader-Based Targeting of METTL3/14 Improves Immunotherapy Response in Cutaneous Melanoma.

METTL3 has emerged as a promising therapeutic target in cancer treatment, although its oncogenic functions in melanoma development and potential for therapeutic targeting drug have not been fully explored. In this study, we define the oncogenic role of METTL3 in melanoma development and progression. Building on this insight, we examine our recently designed peptide inhibitor RM3, which targets the binding interface of METTL3/14 complex for disruption and subsequent ubiquitin-mediated proteasomal degradation via the E3 ligase STUB1. RM3 treatment reduces proliferation, migration, and invasion, and induces apoptosis in melanoma cells in vitro and in vivo. Subsequent transcriptomic analysis identified changes in immuno-related genes following RM3-mediated suppression of METTL3/14 N6-methyladenosine (m6A) methyltransferase activity, suggesting a potential for interaction with immunotherapy. A combination treatment of RM3 with anti-PD-1 antibody results in significantly higher beneficial tumor response in vivo, with a good safety profile. Collectively, these findings not only delineate the oncogenic role of METTL3 in melanoma but also showcase RM3, acting as a peptide degrader, as a novel and promising strategy for melanoma treatment.

Loss of Lkb1 cooperates with BrafV600E and ultraviolet radiation, increasing melanoma multiplicity and neural-like dedifferentiation.

The mechanisms that work alongside BRAFV600E oncogene in melanoma development, in addition to ultraviolet (UV) radiation (UVR), are of great interest. Analysis of human melanoma tumors [data from The Cancer Genome Atlas (TCGA)] revealed that 50% or more of the samples expressed no or low amounts of serine/threonine protein kinase STK11 (also known as LKB1) protein. Here, we report that, in a mouse model, concomitant neonatal BrafV600E activation and Lkb1 tumor suppressor ablation in melanocytes led to full melanoma development. A single postnatal dose of UVB radiation had no effect on melanoma onset in Lkb1-depleted mice compared with BrafV600E-irradiated mice, but increased tumor multiplicity. In concordance with these findings and previous reports, Lkb1-null irradiated mice exhibited deficient DNA damage repair (DDR). Histologically, tumors lacking Lkb1 were enriched in neural-like tumor morphology. Genetic profiling and gene set enrichment analyses of tumor sample mutated genes indicated that loss of Lkb1 promoted the selection of altered genes associated with neural differentiation processes. Thus, these results suggest that the loss of Lkb1 cooperates with BrafV600E and UVR, impairing the DDR and increasing melanoma multiplicity and neural-like dedifferentiation.

New Aspects Regarding the Fluorescence Spectra of Melanin and Neuromelanin in Pigmented Human Tissue Concerning Hypoxia.

Melanin is a crucial pigment in melanomagenesis. Its fluorescence in human tissue is exceedingly weak but can be detected through advanced laser spectroscopy techniques. The spectral profile of melanin fluorescence distinctively varies among melanocytes, nevomelanocytes, and melanoma cells, with melanoma cells exhibiting a notably "red" fluorescence spectrum. This characteristic enables the diagnosis of melanoma both in vivo and in histological samples. Neuromelanin, a brain pigment akin to melanin, shares similar fluorescence properties. Its fluorescence can also be quantified with high spectral resolution using the same laser spectroscopic methods. Documented fluorescence spectra of neuromelanin in histological samples from the substantia nigra substantiate these findings. Our research reveals that the spectral behavior of neuromelanin fluorescence mirrors that of melanin in melanomas. This indicates that the typical red fluorescence is likely influenced by the microenvironment around (neuro)melanin, rather than by direct pigment interactions. Our ongoing studies aim to further explore this distinctive "red" fluorescence. We have observed this red fluorescence spectrum in post-mortem measurements of melanin in benign nevus. The characteristic red spectrum is also evident here (unlike the benign nevus in vivo), suggesting that hypoxia may contribute to this phenomenon. Given the central role of hypoxia in both melanoma development and treatment, as well as in fundamental Parkinson's disease mechanisms, this study discusses strategies aimed at reinforcing the hypothesis that red fluorescence from (neuro)melanin serves as an indicator of hypoxia.

Melanoma as Subsequent Primary Malignancy in Hematologic Cancer Survivors-A Literature Review.

The occurrence of second primary malignancies is becoming increasingly important among cancer survivors. Melanoma, an aggressive neoplasm originating from the melanocytes, is responsible for most skin cancer-related deaths. This review aims to explore the risk of melanoma occurrence as a second primary cancer after the most common subtypes of hematologic neoplasia, a malignant disease originating from myeloid or lymphocytic cell lineages. Chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) are among the most associated subtypes with melanoma development. We also discuss the underlying hypotheses that may explain the associations between these malignancies and the impact of melanoma on survival. The review emphasizes the importance of increasing awareness of melanoma risk in hematologic cancer survivors, as it can lead to prompt recognition, improved skin surveillance, and better survival outcomes.

Sphingolipid metabolism and regulated cell death in malignant melanoma.

Malignant melanoma (MM) is a highly invasive and therapeutically resistant skin malignancy, posing a significant clinical challenge in its treatment. Programmed cell death plays a crucial role in the occurrence and progression of MM. Sphingolipids (SP), as a class of bioactive lipids, may be associated with many kinds of diseases. SPs regulate various forms of programmed cell death in tumors, including apoptosis, necroptosis, ferroptosis, and more. This review will delve into the mechanisms by which different types of SPs modulate various forms of programmed cell death in MM, such as their regulation of cell membrane permeability and signaling pathways, and how they influence the survival and death fate of MM cells. An in-depth exploration of the role of SPs in programmed cell death in MM aids in unraveling the molecular mechanisms of melanoma development and holds significant importance in developing novel therapeutic strategies.

Comprehensive analysis of aberrantly methylated differentially expressed genes and validation of CDC6 in melanoma

BackgroundSkin Cutaneous Melanoma (SKCM) is a highly aggressive malignant tumor with a significant increase in mortality upon metastasis. The molecular mechanisms driving melanoma progression remain largely unclear. Recent studies have highlighted the importance of epigenetic alterations, especially DNA methylation, in melanoma development. This study aims to identify and analyze methylation-regulated differentially expressed genes (MeDEGs) in genome-wide profiles between primary and metastatic melanoma.MethodsGene expression profiling datasets GSE8401 and gene methylation profiling datasets GSE86355 were collected from the GEO database. Differentially expressed genes (DEGs) and differentially methylated genes (DMGs) were systematically identified. Integration of DEGs and DMGs yielded a set of MeDEGs, which subsequently underwent functional enrichment analysis. The protein-protein interaction (PPI) network was constructed using STRING and visualized using Cytoscape software. Survival analysis was used to select prognostic hub genes. In addition, 37 SKCM and 37 normal skin tissues from the First Affiliated Hospital of Soochow University (FAHSU) were collected for immunohistochemical (IHC) staining and evaluation. Furthermore, DNA methylation patterns of CDC6 were analyzed. To validate these findings, SKCM cell cultures were utilized to elucidate the expression and behavioral characteristics of CDC6. Additionally, gene set enrichment analysis (GSEA) and immune infiltration analysis were conducted for CDC6.ResultsIn our study, we discovered 120 hypomethylated-upregulated genes and 212 hypermethylated-downregulated genes. The hypomethylated-upregulated genes were notably associated with biological processes such as spindle assembly checkpoint signaling, mitotic spindle assembly, and negative regulation of mitotic metaphase/anaphase transition. Our pathway analysis revealed significant enrichment in pathways related to dilated cardiomyopathy, amino sugar metabolism, progesterone-mediated oocyte maturation, and chemical carcinogenesis. Conversely, hypermethylated-downregulated genes were found to be enriched in processes like epidermis development, keratinocyte differentiation, and skin development. Additionally, pathway analysis highlighted associations with estrogen signaling, Staphylococcus aureus infection, axon guidance, and arachidonic acid metabolism. Following the establishment of PPI networks and survival analysis, we identified 11 prognostic hub genes: CCNA2, CDC6, CDCA3, CKS2, DTL, HJURP, KRT5, KRT14, KRT15, KRT16, and NEK2. Notably, among the 11 hub genes, our findings indicate that CDC6 plays a pivotal role in enhancing the proliferation, migration, and invasion capabilities of melanoma cells in vitro.ConclusionsOur comprehensive genomic analyses reveal that genes with aberrant methylation exhibit differential expression during the transition from primary to metastatic melanoma. The identified genes, especially CDC6, which plays a crucial role in enhancing melanoma cell proliferation, migration, and invasion, provide valuable insights into potential methylation-based biomarkers. These findings could contribute significantly to advancing precision medicine in SKCM.

Iris melanoma in an Australian cohort.

To report the clinicopathological features and epidemiology of iris melanoma in Queensland, Australia. This was a retrospective study of 86 patients with iris melanoma treated between 2001 and 2022 at the Queensland Ocular Oncology Service, Brisbane, Australia. Main outcome measures included demographics, clinical and phenotypic features, age-adjusted incidence and relative survival. Eighty-six patients (63% female) were included. Mean age was 54 years (range 17-82 years). The majority of patients (97%) were Caucasian, with blue eyes, fair skin and Fitzpatrick Skin Type I or II. Demographic features and clinical history showed a tendency for high ultraviolet radiation (UVR) exposure in the cohort. Histopathology was available in 69 cases (82%), and of these, 77% tumours were of spindle cell origin, with low-risk genetic profiles. Patients were followed for a mean of 8 years (median 7, range 1-21 years) after diagnosis, and only one case of metastasis was documented. The association of iris freckles, history of UVR exposure and dermatologic findings supports the role of UVR in iris melanoma. Occupation and avocation history, as well as evaluation of iris freckles may offer an easily accessible way of stratifying the risk of an individual for development of UVR-related uveal melanoma.

DHPS-Mediated Hypusination Regulates METTL3 Self-m6A-Methylation Modification to Promote Melanoma Proliferation and the Development of Novel Inhibitors.

Discovering new treatments for melanoma will benefit human health. The mechanism by which deoxyhypusine synthase (DHPS) promotes melanoma development remains elucidated. Multi-omics studies have revealed that DHPS regulates m6A modification and maintains mRNA stability in melanoma cells. Mechanistically, DHPS activates the hypusination of eukaryotic translation initiation factor 5A (eIF5A) to assist METTL3 localizing on its mRNA for m6A modification, then promoting METTL3 expression. Structure-based design, synthesis, and activity screening yielded the hit compound GL-1 as a DHPS inhibitor. Notably, GL-1 directly inhibits DHPS binding to eIF5A, whereas GC-7 cannot. Based on the clarification of the mode of action of GL-1 on DHPS, it is found that GL-1 can promote the accumulation of intracellular Cu2+ to induce apoptosis, and antibody microarray analysis shows that GL-1 inhibits the expression of several cytokines. GL-1 shows promising antitumor activity with good bioavailability in a xenograft tumor model. These findings clarify the molecular mechanisms by which DHPS regulates melanoma proliferation and demonstrate the potential of GL-1 for clinical melanoma therapy.

Functional Test of a Naturally Occurred Tumor Modifier Gene Provides Insights to Melanoma Development.

Occurrence of degenerative interactions is thought to serve as a mechanism underlying hybrid unfitness. However, the molecular mechanisms underpinning the genetic interaction and how they contribute to overall hybrid incompatibilities are limited to only a handful of examples. A vertebrate model organism, Xiphophorus , is used to study hybrid dysfunction and it has been shown from this model that diseases, such as melanoma, can occur in certain interspecies hybrids. Melanoma development is due to hybrid inheritance of an oncogene, xmrk , and loss of a co-evolved tumor modifier. It was recently found that adgre5 , a G protein-coupled receptor involved in cell adhesion, is a tumor regulator gene in naturally hybridizing Xiphophorus species X. birchmanni and X. malinche . We hypothesized that one of the two parental alleles of adgre5 is involved in regulation of cell proliferation, migration and melanomagenesis. Accordingly, we assessed the function of adgre5 alleles from each parental species of the melanoma-bearing hybrids using in vitro cell proliferation and migration assays. In addition, we expressed each adgre5 allele with the xmrk oncogene in transgenic medaka. We found that cells transfected with the X. birchmanni adgre5 exhibited decreased proliferation and migration compared to those with the X. malinche allele. Moreover, X. birchmanni allele of adgre5 completely inhibited melanoma development in xmrk transgenic medaka, while X. malinche adgre5 expression did not exhibit melanoma suppressive activity in medaka. These findings showed that adgre5 is a natural melanoma suppressor and provide new insight in melanoma etiology.

Lipid traits and lipid-lowering drug target genes and risk of melanoma: a mendelian randomization study.

Our study aimed to investigate the role of lipids in melanoma risk and the effect of lipid-lowering drug targets on melanoma. Using Mendelian Randomization analysis, we examined the genetic agents of nine lipid-lowering drugs and their association with melanoma risk. We found that genetically proxied inhibition of HMGCR, ABCG5/ABCG8, and ANGPTL3 was associated with a reduced risk of melanoma. On the other hand, inhibition of LPL and Apo-B100 was significantly associated with an increased risk of melanoma. Sensitivity analyses did not reveal any statistical evidence of bias from pleiotropy or genetic confounding. We did not find a robust association between lipid traits NPC1L1, PCSK9, APOC3 inhibition, and melanoma risk. These findings were validated using two independent lipid datasets. Our analysis also revealed that HMGCR, ANGPTL3, and ABCG5/ABCG8 inhibitors reduced melanoma risk independent of their effects on lipids. This suggests that these targets may have potential for melanoma prevention or treatment. In conclusion, our study provides evidence for a causal role of lipids in melanoma risk and highlights specific lipid-lowering drug targets that may be effective in reducing the risk of melanoma. These findings contribute to the understanding of the underlying mechanisms of melanoma development and provide potential avenues for further research and therapeutic interventions.