Transformation Of Melanocytes Research Articles

Current Insights into the Role of UV Radiation-Induced Oxidative Stress in Melanoma Pathogenesis.

Cutaneous melanoma accounts for the majority of skin cancer-related deaths, and its incidence increases each year. The growing number of melanoma cases, especially in advanced stages, poses a significant socio-medical challenge throughout the world. Extensive research on melanoma pathogenesis identifies UV radiation as the most important factor in melanocytic transformation. Oxidative effects of UV irradiation exert their influence on melanoma pathogenesis primarily through modification of nucleic acids, proteins, and lipids, further disrupting cellular signaling and cell cycle regulation. Its effects extend beyond melanocytes, leading to immunosuppression in the exposed skin tissue, which consequently creates conditions for immune surveillance evasion and further progression. In this review, we focus on the specific molecular changes observed in the UV-dependent oxidative stress environment and their biological consequences in the course of the disease, which have not been considered in previous reviews on melanoma. Nonetheless, data show that the exact role of oxidative stress in melanoma initiation and progression remains unclear, as it affects cancerous cells differently depending on the specific context. A better understanding of the pathophysiological basis of melanoma development holds promise for identifying potential targets, which could lead to effective melanoma prevention strategies.

Uveal melanoma: molecular-genetic mechanisms of arising and the therapeutic approaches

Uveal melanoma (UM) is a tumor of neuroectodermal origin, which results from malignant transformation of melanocytes of the eye vasculature: iris, ciliary body and chorioidea. UM represents up to 5% of all melanoma cases, but it is extremely aggressive, since half of patients with UM develop metastases within the first 1‒2 years after the tumor appearance. Molecular mechanisms of uveal melanoma carcinogenesis are poorly understood, and have already been shown to be different from those of skin melanoma. Activating mutations in the GNAQ and GNA11 genes, encoding the large G protein subunits Gq and G11, respectively, are found in 90% of UM patients. The main signaling cascade leading to the transformation of melanocytes of the uveal tract is the signaling pathway Gaq/PKC/MAPK, and the major regulators of this cascade are targets for the development of drugs. The development of the metastatic form of UM is most often associated with mutations in the genes BAP1, EIF1AX, GNA11, GNAQ, and SF3B1. A combination of a commercial expression test panel of 15 genes and a mutation panel of 7 genes, supplemented with data on the size of the primary tumor, has been shown to be highly effective prognostic signature in prediction the risk of metastases. The risk of metastases determines the choice of therapy and patient follow-up regimen. At the same time, no systemic therapy for the treatment of metastatic UM has been developed to date; new drugs undergoing clinical trials mostly refer to either targeted therapy aimed at inhibiting the protein products of mutant genes, or immunotherapy designed to stimulate an immune response against specific antigens. In addition to these approaches, the review also considers potential therapeutic targets of epigenetic regulation of UM development.

Bmal1 upregulates ATG5 expression to promote autophagy in skin cutaneous melanoma

BackgroundSkin cutaneous melanoma (SKCM) is a highly aggressive and malignant tumor that arises from the malignant transformation of melanocytes. In light of the limitations of existing treatment modalities, there is a pressing need to identify new drug targets for SKCM. Aryl-hydrocarbon receptor nuclear translocator-like (ARNTL), also known as Bmal1, is a gene that has been linked to the onset and progression of cancer. However, its role in SKCM remains understudied. MethodsThe expression of Bmal1 mRNA and protein was detected using TCGA, GTEx, CCLE, and ULCAN databases. Moreover, survival analysis was performed to investigate the association between Bmal1 and immune invasion and gene expression in immune infiltrating cells via CIBERSORT, R programming, TIMER, Sangerbox, Kaplan-Meier. The study also explored the role of proteins associated with Bmal1 by using R programming and databases (STRING and GSEA). Both in vitro and in vivo studies were conducted to examine the potential role of Bmal1 in SKCM. ResultsCompared to normal tissues, the expression level of Bmal1 was significantly reduced in SKCM. Which has been associated with its poor prognosis. Similarly, its expression in SKCM was substantially correlated with immune infiltration, while biogenic analysis indicated that it could potentially influence the tumor immune microenvironment (TME) by influencing tumor-associated neutrophils (TANs). Moreover, Bmal1 overexpression suppressed the proliferation and invasion of melanoma cells and enhanced apoptosis, migration, and cell colony formation. ConclusionThis study concluded that Bmal1 is a novel biomarker that functions as both a diagnostic and prognostic indicator for the progression of SKCM.

An InVivo Study of LNS8801, a GPER Agonist, in a Spontaneous Melanoma-Prone Mouse Model, TGS.

Melanoma is the most aggressive and deadly form of skin cancer that arises from the transformation of melanocytes, the pigment producing cells of the skin. In the year 2024 there will be approximately 10,000 new cases of melanoma diagnosed and approximately 8,000 deaths attributed to melanoma in the United States. In this study we treated a group of male and female transgenic mice that spontaneously develop metastatic melanoma, TGS, with a G-protein-coupled estrogen receptor agonist LNS8801 to assess the efficacy on disease progression. A second group of male and female TGS mice was also exposed to UVB irradiation to mimic exposure to sunlight. Over the course of the 32-week experiment, visible images were taken by the small animal imaging IVIS system to track tumor progression, and blood and tissue samples were collected for molecular analyses. Results showed that sex-biased effects were observed in the efficacy of LNS8801 and that LNS8801 shows a UV-protective influence in both male and female TGS mice.

ZnO nanoparticles induce melanoma-like lesions via recruiting dermal dendritic cells in barrier-damaged skin in mice

ZnO nanoparticles (NPs) are used in skin treatments and cosmetics, the toxicity of long-term and continuous exposure to ZnO NPs is unknown. Mice with epidermal barrier dysfunction revealed melanoma-like lesions after continuous exposure to ZnO NPs. However, the effects of metallic NPs on the skin microenvironment and immune system remain poorly understood. Mice with epidermal barrier failure were given continuous exposure to ZnO NPs for 7 weeks. The malignant transformation of melanocytes was induced with ZnO NPs 2.5 μg/ml for 72 h exposure. The supernatant of the culture medium from dendritic cells after being exposed to 10 μg/ml ZnO NPs for 24 h was applied to melanocytes to explore the effect of recruitment of DCs. The expressure of ZnO NPs resulted in a tendency of malignant transformation of melanocytes, the recruitment of DCs induces this process by produce inflammatory factors such as TNF-α. These DC-produced inflammatory factors, which were induced by ZnO NP exposure, increased the production of matrix metalloproteinases in melanocytes and expedited the malignant transformation process. Our findings revealed that the disrupted cutaneous microenvironment by ZnO NPs penetrated directly promoted the malignant transformation of melanocytes, which process also indirectly enhanced by the TNF-αsecreted from the recruited DCs.

Malignant Melanoma: An Overview, New Perspectives, and Vitamin D Signaling.

Melanoma, originating through malignant transformation of melanin-producing melanocytes, is a formidable malignancy, characterized by local invasiveness, recurrence, early metastasis, resistance to therapy, and a high mortality rate. This review discusses etiologic and risk factors for melanoma, diagnostic and prognostic tools, including recent advances in molecular biology, omics, and bioinformatics, and provides an overview of its therapy. Since the incidence of melanoma is rising and mortality remains unacceptably high, we discuss its inherent properties, including melanogenesis, that make this disease resilient to treatment and propose to use AI to solve the above complex and multidimensional problems. We provide an overview on vitamin D and its anticancerogenic properties, and report recent advances in this field that can provide solutions for the prevention and/or therapy of melanoma. Experimental papers and clinicopathological studies on the role of vitamin D status and signaling pathways initiated by its active metabolites in melanoma prognosis and therapy are reviewed. We conclude that vitamin D signaling, defined by specific nuclear receptors and selective activation by specific vitamin D hydroxyderivatives, can provide a benefit for new or existing therapeutic approaches. We propose to target vitamin D signaling with the use of computational biology and AI tools to provide a solution to the melanoma problem.

The role of macrophage migration inhibitory factor family and CD74 in the pathogenesis of melanoma.

Melanoma is an aggressive tumour with poor prognosis that arises from the malignant transformation of melanocytes. Over the past few decades, intense research into the pathogenesis of melanoma has led to the development of BRAF and immune checkpoint inhibitors, including antibodies against programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), which have shown clinically significant efficacy. However, some tumours do not respond to these therapies initially or become treatment resistant. Most melanoma tissues appear to possess biological characteristics that allow them to evade these treatments, and identifying these characteristics is one of the major challenges facing cancer researchers. One such characteristic that has recently gained attention is the role of macrophage migration inhibitory factor (MIF) and its receptor CD74. This review outlines the cellular and molecular functions of CD74, MIF and their family of proteins. We then review their roles in tumours based on previous reports, highlight their pathological significance in melanoma and discuss their potential as therapeutic targets.

SIRT7 promotes mitochondrial biogenesis to render the adaptive resistance to MAPK inhibition in melanoma

Melanoma, arising from the malignant transformation of melanocytes, stands as the most lethal type of skin cancer. While significant strides have been made in targeted therapy and immunotherapy, substantially enhancing therapeutic efficacy, the prognosis for melanoma patients remains unoptimistic. SIRT7, a nuclear-localized deacetylase, plays a pivotal role in maintaining cellular homeostasis and adapting to external stressors in melanoma, with its activity closely tied to intracellular nicotinamide adenine dinucleotide (NAD+). However, its involvement in adaptive resistance to targeted therapy remains unclear. Herein, we unveil that up-regulated SIRT7 promotes mitochondrial biogenesis to render the adaptive resistance to MAPK inhibition in melanoma. Initially, we observed a significant increase of SIRT7 expression in publicly available datasets following targeted therapy within a short duration. In consistent, we found elevated SIRT7 expression in melanoma cells subjected to BRAF or MEK inhibitors in vitro. The up-regulation of SIRT7 expression was also confirmed in xenograft tumors in mice after targeted therapy in vivo. Furthermore, we proved that SIRT7 deficiency led to decreased cell viability upon prolonged exposure to BRAF or MEK inhibitors, accompanied by an increase in cell apoptosis. Mechanistically, SIRT7 deficiency restrained the upregulation of genes associated with mitochondrial biogenesis and intracellular ATP levels in response to targeted therapy treatment in melanoma cells. Ultimately, we proved that SIRT7 deficieny could sensitize BRAF-mutant melanoma cells to MAPK inhibition targeted therapy in vivo. In conclusion, our findings underscore the role of SIRT7 in fostering adaptive resistance to targeted therapy through the facilitation of mitochondrial biogenesis. Targeting SIRT7 emerges as a promising strategy to overcome MAPK inhibitor adaptive resistance in melanoma.

Revisiting the Role of B-RAF Kinase as a Therapeutic Target in Melanoma.

Malignant melanoma is the rarest but most aggressive and deadly skin cancer. Melanoma is the result of a malignant transformation of melanocytes, which leads to their uncontrolled proliferation. Mutations in the mitogen-activated protein kinase (MAPK) pathway, which are crucial for the control of cellular processes, such as apoptosis, division, growth, differentiation, and migration, are one of its most common causes. BRAF kinase, as one of the known targets of this pathway, has been known for many years as a prominent molecular target in melanoma therapy, and the following mini-review outlines the state-of-the-art knowledge regarding its structure, mutations and mechanisms.

Melanoma-associated melanocortin 1 receptor variants confer redox signaling-dependent protection against oxidative DNA damage

Cutaneous melanoma, a lethal skin cancer, arises from malignant transformation of melanocytes. Solar ultraviolet radiation (UVR) is a major environmental risk factor for melanoma since its interaction with the skin generates DNA damage, either directly or indirectly via oxidative stress. Pheomelanin pigments exacerbate oxidative stress in melanocytes by UVR-dependent and independent mechanisms. Thus, oxidative stress is considered to contribute to melanomagenesis, particularly in people with pheomelanic pigmentation. The melanocortin 1 receptor gene (MC1R) is a major melanoma susceptibility gene. Frequent MC1R variants (varMC1R) associated with fair skin and red or yellow hair color display hypomorphic signaling to the cAMP pathway and are associated with higher melanoma risk. This association is thought to be due to production of photosensitizing pheomelanins as well as deficient induction of DNA damage repair downstream of varMC1R. However, the data on modulation of oxidative DNA damage repair by MC1R remain scarce. We recently demonstrated that varMC1R accelerates clearance of reactive oxygen species (ROS)-induced DNA strand breaks in an AKT-dependent manner. Here we show that varMC1R also protects against ROS-dependent formation of 8-oxodG, the most frequent oxidative DNA lesion. Since the base excision repair (BER) pathway mediates clearance of these DNA lesions, we analyzed induction of BER enzymes in human melanoma cells of varMC1R genotype. Agonist-mediated activation of both wildtype (wtMC1R) and varMC1R significantly induced OGG and APE-1/Ref1, the rate-limiting BER enzymes responsible for repair of 8-oxodG. Moreover, we found that NADPH oxidase (NOX)-dependent generation of ROS was responsible for AKT activation and oxidative DNA damage repair downstream of varMC1R. These observations provide a better understanding of the functional properties of melanoma-associated MC1R alleles and may be useful for the rational development of strategies to correct defective varMC1R responses for efficient photoprotection and melanoma prevention in fair-skinned individuals.

Abstract 867: Molecular and functional characterization of melanocyte subpopulations in human epidermis based on single-cell RNA sequencing

Abstract The biological and molecular mechanisms that underpin the malignant transformation of normal melanocytes to melanomas are largely unknown. In part, this is due to the limited understanding of normal human melanocyte homeostasis and how melanocytes respond to oncogenic insults such as ultraviolet radiation (UVR). This is particularly true for interfollicular epidermal melanocytes, which have the highest levels of UVR exposure and from whence most melanomas are thought to arise. These knowledge gaps impede the development of strategies for active, targeted prevention of melanoma formation. We thus evaluated epidermal melanocytes transcriptionally, phenotypically and functionally after isolating them from human skin. Using single-cell RNA sequencing (scRNA-seq), we identified multiple transcriptionally distinct subpopulations within human epidermal melanocytes. RNA velocity analysis revealed subpopulations in different states of melanocytic differentiation, and immunohistochemistry staining demonstrated their distinct anatomical distribution throughout follicular and interfollicular epidermal compartments. Notably, one melanocyte subgroup, marked by increased expression of neurotrophic receptor tyrosine kinase 2 (NTRK2) and genes associated with ribosome biogenesis, exhibited molecular characteristics of progenitor cells. This subpopulation displayed human embryonic stem cell (hESC)-derived melanoblast markers, and their anatomical localization corresponded to that of intermediate melanocyte progenitors. NTRK2+ melanocytes demonstrated enhanced clonogenicity after UVR exposure in primary cell cultures and in ex vivo whole skin explants. In contrast, NTRK2- melanocytes were suppressed by UVR. Furthermore, scRNA-seq data of ex vivo melanocytes after UVR exposure revealed the upregulation of genes associated with cell proliferation within NTRK2-expressing melanocytes. In mouse back skin, the ratio of Ntrk2+ melanocytes increased within 24 hours of UVB irradiation, suggesting a proliferative response in these cells in vivo following UVR. We thus report the discovery in human epidermis of a putative melanocytic cell hierarchy, and of a candidate melanocyte progenitor subpopulation that responds proliferatively to UVR and is thus a candidate cell of origin of melanoma. Citation Format: Peinan Zhao, Fumihito Noguchi, Christopher Chew, Gamze Kuser Abali, Pacman Szeto, Youfang Zhang, Malaka Ameratunga, Isobel Leece, Jen G. Cheung, Miles Andrews, Nicholas C. Wong, Anthony T. Papenfuss, Mark Shackleton. Molecular and functional characterization of melanocyte subpopulations in human epidermis based on single-cell RNA sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 867.

Comparative Evaluation of Anticancer Activity of Natural Methoxylated Flavones Xanthomicrol and Eupatilin in A375 Skin Melanoma Cells.

Melanoma is a skin cancer caused by the malignant transformation of melanocytes and cutaneous melanoma represents the most aggressive and deadliest type of skin cancer with an increasing incidence worldwide. The main purpose of the present research was to evaluate the anticancer effects of the natural bioactive compounds xanthomicrol (XAN) and eupatilin (EUP) in human A375 malignant skin melanoma cells, a cell line widely used as an in vitro model of cutaneous melanoma. XAN and EUP are lipophilic methoxylated flavones with antioxidant, anti-inflammatory, and antitumor properties. The effects of XAN and EUP on cell viability, morphology, lipid profile, oxidative status, apoptosis, and mitochondrial membrane polarization were determined and compared in A375 cells. At 24 h-incubation (MTT assay), XAN significantly reduced viability at the dose range of 2.5-200 μM, while EUP showed a significant cytotoxicity from 25 μM. Moreover, both methoxylated flavones induced (at 10 and 25 μM, 24 h-incubation) marked cell morphological alterations (presence of rounded and multi-nucleated cells), signs of apoptosis (NucView 488 assay), and a noteworthy mitochondrial membrane depolarization (MitoView 633 assay), coupled to a marked lipid profile modulation, including variations in the ratio of phospholipid/cholesterol and a decrease in the oleic, palmitic, and palmitoleic acid amounts. Moreover, a remarkable time-dependent ROS generation (2',7'-dichlorodihydrofluorescein diacetate assay) was observed during 3 h-incubation of A375 cancer cells in the presence of XAN and EUP (10 and 25 μM). Our results confirm the potential antitumor effect of natural EUP and XAN in cutaneous melanoma by the activation of multiple anticancer mechanisms.

Uveal Melanoma: Molecular and Genetic Mechanisms of Development and Therapeutic Approaches

Uveal melanoma (UM) is a neuroectodermal tumor that results from malignant transformation of melanocytes in the eye uvea, including the iris, the ciliary body, and the choroid. UM accounts for 5% of all melanoma cases and is extremely aggressive with half of the UM patients developing metastases within the first 1-2 years after tumor development. Molecular mechanisms of UM carcinogenesis are poorly understood, but are known to differ from those of skin melanoma. Activating mutations of the GNAQ and GNA11 genes, which code for the large G protein subunits Gq and G11, respectively, are found in 90% of UM patients. The Gaq/PKC/MAPK signaling pathway is a main signaling cascade that leads to the transformation of melanocytes of the uveal tract, and major regulators of the cascade provide targets for the development of drugs. Metastatic UM (MUM) is most often associated with mutations of BAP1, EIF1AX, GNA11, GNAQ, and SF3B1. A combination of a commercial expression test panel of 15 genes and a mutation panel of 7 genes, supplemented with data on the size of the primary tumor, is highly efficient in predicting the risk of metastasis. The risk of metastasis determines the choice of therapy and the patient follow-up regimen. However, no systemic therapy for MUM has been developed to date. New drugs undergoing clinical trials are mostly targeted drugs designed to inhibit the protein products of mutant genes or immunotherapeutic agents designed to stimulate the immune response against specific antigens. In addition to these approaches, potential therapeutic targets of epigenetic regulation of UM development are considered in the review.

Efficacy of immunotherapy in patients with metastatic melanoma

Introduction. Melanoma is an aggressive form of skin cancer caused by the transformation of melanocytes into malignant cells. Currently, immunotherapy is one of the most promising treatment methods, but searching the most optimal treatment regimens is still ongoing.Objective. To evaluate the effectiveness and safety of the use of immune checkpoint inhibitors (ICIs) in patients with metastatic melanoma.Materials and methods. The study included 229 patients (114 men and 115 women) aged 21 to 91 years who received (ICIs) as nivolumab (n = 168; 73,4%) and pembrolizumab (n = 30; 13,1%) monotherapy, and combination of nivolumab and ipilimumab (n = 31; 13,5%). The objective response of the tumor to treatment was recorded in the presence of partial or complete regression of the tumor. The tumor response to treatment was determined in accordance with the iRECIST criteria.Results. Complete regression was observed in 16.7, 15.9 and 8,7% of patients, partial – in 11.1, 11.4 and 17.4%, stabilization was detected in 51.2, 50.0 and 34.8% and progression – in 21.0, 22.7 and 39.1% of patients with first, second and third and more-line setting, respectively. The median response time was 3.14, 5.18 and 3.63 months, the median response duration was 16.21, 8.96 and 30.15 months in first, second and third and more-line setting, respectively. Grade 3–4 immuno-related adverse events (irAEs) were observed in 8 (3.5%) patients.Conclusions. Immunotherapy of metastatic melanoma allows achieving high rates of objective response and disease control (27.5 and 76.9%, respectively). This method of treatment is characterized by an insignificant amount of grade 3–4 irAEs (3.5% according to our data), which indicates an acceptable safety profile.

Integrative analysis of autophagy-related genes reveals that CAPNS1 is a novel prognostic biomarker and promotes the malignancy of melanoma via Notch signaling pathway.

Skin cutaneous melanoma (SKCM) is a highly fatal form of skin cancer that develops from the malignant transformation of epidermal melanocytes. There is substantial evidence linking autophagy to cancer etiology and immunotherapy efficacy. This study aimed to conduct a comprehensive analysis of autophagy-related genes (ARGs) using TCGA datasets and further explore the potential function of critical ARGs in SKCM progression. We performed comprehensive bioinformatics analysis uses the TCGA dataset. RT-PCR was applied to examine the expression of CAPNS1 in SKCM cells. Lost-of-function experiments were performed to detect the expression of the related proteins. In this search, we screed 70 differentially expressed autophagy-related genes (DE-ARGs), including 33 up-DE-ARGs and 37 down-DE-ARGs. Enrichment assays revealed that these 70 DE-ARGs may exert influence on critical cellular processes such as autophagy, protein kinase activity, and signaling pathways, impacting cell growth, differentiation, survival, and tumor development. Then, we further explore the prognostic value of 70 DE-ARGs and confirmed 18 survival-related DE-ARGs in SKCM patients. Nearly all the 18 DE-ARGs' methylation was negatively correlated with their corresponding expression in SKCM. The 12 survival-related DE-ARGs were used to develop a unique predictive model that effectively classified SKCM patients into high- and low-risk groups with regard to overall survival. Furthermore, tumor environment analysis indicated that the risk score was associated with several immune cells. Among the 12 survival-related DE-ARGs, our attention focused on CAPNS1 which was highly expressed in SKCM patients and predicted a poor prognosis. In addition, we confirmed that knockdown of CAPNS1 distinctly suppressed the proliferation, metastasis and EMT of SKCM cells, and promoted autophagy via regulating Notch signaling pathway. Overall, this study enhances our understanding of the intricate molecular landscape of SKCM progression and presents promising avenues for future research and clinical applications.

The possible and intriguing relationship between bullous pemphigoid and melanoma: speculations on significance and clinical relevance.

Bullous pemphigoid (BP) is the most common autoimmune bullous disease: it most commonly affects individuals over 70 years old and impacts severely on their quality of life. BP represents a paradigm for an organ-specific autoimmune disease and is characterized by circulating IgG autoantibodies to hemidesmosomal components: BP180 and BP230. While the crucial role of these autoantibodies in triggering BP inflammatory cascade is fully acknowledged, many ancillary etiological mechanisms need to be elucidated yet. Cutaneous melanoma is due to a malignant transformation of skin melanocytes, that produce and distribute pigments to surrounding keratinocytes. Melanoma is the most fatal skin cancer because of its increasing incidence and its propensity to metastasize. Several data such as: i) reported cases of concomitant melanoma and BP; ii) results from association studies; iii) BP onset following immune check-point inhibitors therapy; iv) expression of BP antigens in transformed melanocytes; and vi) circulating autoantibodies to BP antigens in melanoma patients suggest an intriguing, although unproven, possible association between melanoma and BP. However, a possible causative link is still debated and the putative pathogenetic mechanism underlying this association is unclear. This review aims to describe and discuss the possible relationship between BP and melanoma and give an overview of the speculations for or against this association. Of note, if demonstrated, this association could unwrap considerations of clinical relevance that represent new research frontiers.

Impact of Physical Exercise on Melanoma Hallmarks: Current Status of Preclinical and Clinical Research.

In recent years, accumulating evidence from preclinical and clinical studies consistently indicated that physical activity/exercise plays a crucial role in reducing the incidence and recurrence of various malignancies, by exerting a beneficial modulation of cancer hallmarks. Moreover, physical activity is suggested to attenuate certain adverse effects of anticancer therapy, including the reduction of cardiovascular toxicity and symptoms related to depression and anxiety, among others, while preserving muscular strength. In the case of melanoma, the relationship with physical activity has been critically debated. Historically, several cohort studies and meta-analyses reported a positive association between physical activity/exercise and melanoma risk. This association was primarily attributed to outdoor activities that may expose the skin to UV radiation, a well-known risk factor for melanocyte transformation. However, more recent evidence does not support such association and recognizes physical activity/exercise role in both melanoma prevention and progression. Nevertheless, sun protection is recommended during outdoor training to minimize UV radiation exposure. This narrative review summarizes preclinical and clinical data about physical activity effects on melanoma hallmarks. Specifically, experimental evidence is reported concerning (i) invasion and metastasis, (ii) reprogramming of energy metabolism, (iii) angiogenesis, (iv) resistance to cell death, (v) evasion from immune destruction, and (vi) tumor-promoting inflammation.

Active natural compounds perturb the melanoma risk-gene network.

Cutaneous melanoma is an aggressive type of skin cancer with a complex genetic landscape caused by the malignant transformation of melanocytes. This study aimed at providing an in silico network model based on the systematic profiling of the melanoma-associated genes considering germline mutations, somatic mutations, and genome-wide association study signals accounting for a total of 232 unique melanoma risk genes. A protein-protein interaction network was constructed using the melanoma risk genes as seeds and evaluated to describe the functional landscape in which the melanoma genes operate within the cellular milieu. Not only were the majority of the melanoma risk genes able to interact with each other at the protein level within the core of the network, but this showed significant enrichment for genes whose expression is altered in human melanoma specimens. Functional annotation showed the melanoma risk network to be significantly associated with processes related to DNA metabolism and telomeres, DNA damage and repair, cellular ageing, and response to radiation. We further explored whether the melanoma risk network could be used as an in silico tool to predict the efficacy of anti-melanoma phytochemicals, that are considered active molecules with potentially less systemic toxicity than classical cytotoxic drugs. A significant portion of the melanoma risk network showed differential expression when SK-MEL-28 human melanoma cells were exposed to the phytochemicals harmine and berberine chloride. This reinforced our hypothesis that the network modeling approach not only provides an alternative way to identify molecular pathways relevant to disease but it may also represent an alternative screening approach to prioritize potentially active compounds.

Effects of Resveratrol on Mouse B16 Melanoma Cell Proliferation through the SHCBP1-ERK1/2 Signaling Pathway.

Melanoma originates from the malignant mutational transformation of melanocytes in the basal layer of the epidermal layer of the skin. It can easily spread and metastasize in the early stage, resulting in a poor prognosis. Therefore, it is particularly important to find effective antitumor adjuvant drugs to inhibit the occurrence and development of melanoma. In this study, we found that resveratrol, a polyphenolic compound from grape plants, can significantly inhibit the proliferation, colony formation and migration of mouse melanoma B16 cells. Notably, resveratrol was also found to inhibit the expression of SHCBP1 in B16 cells. Transcriptional analysis and cellular studies showed that SHCBP1 can activate the MAPK/ERK signaling pathway to regulate cyclin expression and promote the G1/S phase transition of the cell cycle by upregulating ERK1/2 phosphorylation levels. Resveratrol further downregulates the phosphorylation level of ERK1/2 by inhibiting SHCBP1 expression, thus inhibiting tumor cell proliferation. In conclusion, resveratrol inhibits the proliferation of B16 cells by regulating the ERK1/2 signaling pathway through SHCBP1. As an upstream protein of the ERK1/2 signaling pathway, SHCBP1 may be involved in the process of resveratrol-mediated inhibition of tumor cell proliferation.

Piezo1 Activation Prevents Spheroid Formation by Malignant Melanoma SK-MEL-2 Cells.

Melanoma is a highly aggressive type of skin cancer produced through the malignant transformation of melanocytes, and it is usually associated with a poor prognosis. Clinically, melanoma has several stages associated with migration and invasion of the cells through the skin's layers, the rapid spreading of cells and the formation of tumors in multiple organs. The main problem is the emergence of resistance in melanoma to the applied methods of treatment; thus, it is of primary importance to find more crucial signaling pathways that control the progression of this type of cancer and could be targeted to prevent melanoma spreading. Here, we uncover novel aspects of the role of the mechanosensitive ion channel Piezo1 in melanoma tumor formation. Using a combinative approach, we showed the functional expression of mechanosensitive Piezo1 channels in the aggressive human melanoma SK-MEL-2 cell line. We found that chemical activation of Piezo1 by its agonist, Yoda1, prevents melanoma spheroid formation; thus, Piezo1 could be a potential target for selective modulation aimed at the prevention of melanoma development.