Chemotherapy-induced senescence may promote drug resistance and treatment failure. Precise detection and elimination of senescent cancer cells is considered as a novel promising anticancer strategy. However, data on senescence-associated skin cancer cell surface markers as potential therapeutic targets are limited. In the present study, we have established two models of drug-induced senescence in vitro using DNA damaging chemotherapeutics, namely etoposide (0.75-5 µM) and cisplatin (1.25-5 µM), and ten skin cancer cell lines, both melanoma (n = 8, A375, G-361, MM370, SH-4, SK-MEL-1, MeWo, MM127, RPMI-7951) and non-melanoma (n = 2, A431, MCC13), to investigate the levels of 97 cell surface markers. Initial gene expression analysis revealed the increasing tendency in the levels of seven transcripts (ITGA1, ITGA3, VAMP3, STX4, ARMCX3, ULBP2, and PLAUR) and five transcripts (ITGA1, ITGA3, STX4, ARMCX3, and PLAUR) in five etoposide and cisplatin-induced senescent melanoma cell lines, respectively, compared to corresponding proliferating cells. Elevated pools of integrin α1 (ITGA1) were confirmed at mRNA and protein levels in eight drug-induced senescent melanoma cell lines. Similar pattern of changes in integrin α1 levels was not observed in drug-induced senescent non-melanoma skin cancer cells. Analysis using clinical melanoma samples also showed that the levels of ITGA1 and ITGA3 were correlated with the presence of melanoma cells in a section. We document that integrin α1 can be considered as a novel marker of drug-induced senescent melanoma cells. Thus, we postulate that new integrin α1-based targeted therapies can be designed and tested against drug-induced senescent melanoma cells.

Melanoma, one of the most lethal cancers, demands urgent and effective treatment strategies. However, a successful therapeutic approach requires a precise understanding of the mechanisms underlying melanoma initiation and progression. This review provides an overview of melanoma pathogenesis, identifies current pathogenic factors contributing to mortality, and explores targeted therapy and checkpoint inhibitor therapy. Furthermore, we examine melanoma classification and corresponding therapies, along with advancements in various cell death mechanisms for melanoma treatment. We also discuss the current treatment status along with some drawbacks encountered during research stages such as resistance and metastasis.

The use of cancer vaccines represents a promising avenue in cancer immunotherapy. Advances in next-generation sequencing (NGS) technology, coupled with the development of sophisticated analysis tools, have enabled the identification of somatic mutations by comparing genetic sequences between normal and tumor samples. Tumor neoantigens, derived from these mutations, have emerged as potential candidates for therapeutic cancer vaccines. In this study, raw NGS data from two melanoma patients (NCI_3903 and NCI_3998) were analyzed using publicly available SRA datasets from NCBI to identify patient-specific neoantigens. A comprehensive pipeline was employed to select candidate peptides based on their antigenicity, immunogenicity, physicochemical properties, and toxicity profiles. These validated epitopes were utilized to design multi-epitope chimeric vaccines tailored to each patient. Peptide linkers were employed to connect the epitopes, ensuring optimal vaccine structure and function. The two-dimensional (2D) and three-dimensional (3D) structures of the chimeric vaccines were predicted and refined to ensure structural stability and immunogenicity. Furthermore, molecular docking simulations were conducted to evaluate the binding interactions between the vaccine chimeras and the HLA class I receptors, confirming their potential to elicit a robust immune response. This work highlights a personalized approach to cancer vaccine development, demonstrating the feasibility of utilizing neoantigen-based immunoinformatics pipelines to design patient-specific therapeutic vaccines for melanoma.

WNT5a expression is associated with a MAPK inhibitor resistant phenotype in melanoma driving cell polarity and invasion. No small molecules specifically targeting WNT5a are available. Promising results of targeting non-canonical WNT5a-dependent WNT signalling with a pan-PKC inhibitor in uveal melanoma prompted us to investigate the relevance of PKC inhibition in cutaneous melanoma. We revealed PKC signalling and WNT5a expression to be associated in a positive feedback loop, suggesting pan-PKC inhibitor as a potent inhibitor of WNT5a in cutaneous melanoma. Combinatorial PKC and MAPK pathway inhibition significantly reduced proliferation and invasion by induction of apoptosis in targeted therapy-resistant melanoma in vitro. In in vivo xenograft studies, we found less proliferation and apoptosis induction in the PKC inhibitor single and combination treatment group with MAPK pathway inhibitors than in the standard of care treatment group. Thus, targeting the non-canonical WNT signalling pathway via combinatorial PKC and MAPK pathway inhibition is beneficial for therapy-resistant cutaneous melanoma combating tumour heterogeneity in vivo. With our study, we are providing an alternate treatment strategy we think is worth investigating as future clinical interventions in cutaneous melanoma.

Melanoma, a highly aggressive malignancy characterized by rapid metastasis and elevated mortality rates, predominantly originates in cutaneous tissues. While surgical interventions, immunotherapy, and targeted therapies have advanced, the prognosis for advanced-stage melanoma remains dismal. Globally, melanoma incidence continues to rise, with the United States alone reporting over 100,000 new cases and 7,000 deaths annually. Despite the exponential growth of tumor data facilitated by next-generation sequencing (NGS), current analytical approaches predominantly emphasize single-gene analyses, neglecting critical insights into complex gene interaction networks. This study aims to address this gap by systematically exploring immune gene regulatory dynamics in melanoma progression.

We developed a bidirectional, weighted, signed, and directed topological immune gene regulatory network to compare transcriptional landscapes between benign melanocytic nevi and cutaneous melanoma. Advanced network analysis tools were employed to identify structural disparities and functional module shifts. Key driver genes were validated through topological centrality metrics. Additionally, deep learning models were implemented to predict drug-target interactions, leveraging molecular features derived from network analyses.

Significant topological divergences emerged between nevi and melanoma networks, with dominant functional modules transitioning from cell cycle regulation in benign lesions to DNA repair and cell migration pathways in malignant tumors. A group of genes, including AURKA, CCNE1, APEX2, and EXOC8, were identified as potential orchestrators of immune microenvironment remodeling during malignant transformation. The deep learning framework successfully predicted 23 clinically actionable drug candidates targeting these molecular drivers.

The observed module shift from cell cycle to invasion-related pathways provides mechanistic insights into melanoma progression, suggesting early therapeutic targeting of DNA repair machinery might mitigate metastatic potential. The identified hub genes, particularly AURKA and DDX19B, represent novel candidates for immunomodulatory interventions. Our computational drug prediction strategy bridges molecular network analysis with clinical translation, offering a paradigm for precision oncology in melanoma. Future studies should validate these targets in preclinical models and explore network-based biomarkers for early detection.

Melanoma is a highly heterogeneous disease, and a deeper molecular classification is essential for improving patient stratification and treatment approaches. Here, we describe the histopathology-driven proteogenomic landscape of 142 treatment-naïve metastatic melanoma samples to uncover molecular subtypes and clinically relevant biomarkers.

We performed an integrative proteogenomic analysis to identify proteomic subtypes, assess the impact of BRAF V600 mutations, and study the molecular profiles and cellular composition of the tumor microenvironment. Clinical and histopathological data were used to support findings related to tissue morphology, disease progression, and patient outcomes.

Our analysis revealed five distinct proteomic subtypes that integrate immune and stromal microenvironment components and correlate with clinical and histopathological parameters. We demonstrated that BRAF V600-mutated melanomas exhibit biological heterogeneity, where an oncogene-induced senescence-like phenotype is associated with improved survival. This led to a proposed mortality risk-based stratification that may contribute to more personalized treatment strategies. Furthermore, tumor microenvironment composition strongly correlated with disease progression and patient outcomes, highlighting a histopathological connective tissue-to-tumor ratio assessment as a potential decision-making tool. We identified a melanoma-associated SAAV signature linked to extracellular matrix remodeling and SAAV-derived neoantigens as potential targets for anti-tumor immune responses.

This study provides a comprehensive stratification of metastatic melanoma, integrating proteogenomic insights with histopathological features. The findings may aid in the development of tailored diagnostic and therapeutic strategies, improving patient management and outcomes.

Melanoma is a rare but highly malignant form of skin cancer. Although recent targeted and immune-based therapies have improved survival rates by 10-15%, effective melanoma treatment remains challenging. Therefore, novel, combinatorial therapy options such as non-thermal atmospheric pressure plasma (NTP) are being investigated to inhibit and prevent chemoresistance. Although several studies have reported the apoptotic and inhibitory effects of reactive oxygen species produced by NTP in the context of melanoma, the intricate molecular network that determines the role of microRNAs (miRNAs) in regulating NTP-mediated cell death remains unexplored.

This study aimed to explore the molecular mechanisms and miRNA networks regulated by NTP-induced oxidative stress in melanoma cells.

Melanoma cells were exposed to NTP and then subjected to high-throughput miRNA sequencing to identify NTP-regulated miRNAs. Various biological processes and underlying molecular mechanisms were assessed using Alamar Blue, propidium iodide (PI) uptake, cell migration, and clonogenic assays followed by qRT-PCR and flow cytometry.

NTP exposure for 3 min was sufficient to modulate the expression of several miRNAs, inhibiting cell growth. Persistent NTP exposure for 5 min increased differential miRNA regulation, PI uptake, and the expression of genes involved in cell cycle arrest and death. qPCR confirmed that miR-200b-3p and miR-215-5p upregulation contributed to decreased cell viability and migration. Mechanistically, inhibiting miR-200b-3p and miR-215-5p in SK-2 cells enhancedZEB1, PI3K, and AKT expression, increasing cell proliferation and viability.

This study demonstrated that NTP exposure for 5 min results in the differential regulation of miRNAs related to the PI3K-AKT-ZEB1 axis and cell cycle dysregulation to facilitate melanoma suppression.

Besides the important pathogenic mechanisms of melanoma, including BRAF-driven and immunosuppressive microenvironment, genomic instability and abnormal DNA double-strand breaks (DSB) repair are significant driving forces for its occurrence and development. This suggests investigating novel therapeutic strategies from the synthetic lethality perspective. Poly (ADP-ribose) polymerase 4 (PARP4) is known to be a member of the PARP protein family. The low expression of PARP4 is significantly associated with defective DSB repair markers and poor prognosis in melanoma. Further research revealed that PARP4 plays a role in DSB repair by regulating the non-homologous end joining (NHEJ) pathway through its involvement in Ku80 mono-ADP-ribosylation. Moreover, from a synthetic lethality perspective, PARP4 expression is associated with ATM inhibitor sensitivity. Overall, our study provides new and valuable insights into the function of PARP4 and melanoma pathogenesis and suggests that ATM inhibitor may be a promising therapeutic approach for treating melanoma with low PARP4 expression.

Hyperglycemia-induced effects on cellular metabolic properties and reactive oxygen species (ROS) generation play pivotal roles in the pathogenesis of malignant melanoma (MM). This study assessed how metabolic states, ROS production, and related gene expression are modulated by antidiabetic agents. The anti-diabetic agents metformin (Met) and imeglimin (Ime), inhibitors of fatty acid-binding proteins 5/7 (MF6) and microphthalmia-associated transcription factor (MITF) (ML329), and siRNA-mediated knockdown of angiopoietin-like protein 4 (ANGPTL4), which affect mitochondrial respiration, ROS production, and related gene expression, were tested in A375 (MM cell line) cells cultured in low (5.5 mM) and high glucose (50 mM) conditions. Cellular metabolic functions were significantly and differently modulated by Met, Ime, MF6, or ML329 and knockdown of ANGPTL4. High glucose significantly enhanced ROS production, which was alleviated by Ime but not by Met. Both MF6 and ML329 reduced ROS levels under both low and high glucose conditions. Knockdown of ANGPTL4 enhanced the change in glucose-dependent ROS production. Gene expression related to mitochondrial respiration and the pathogenesis of MM was significantly modulated by different glucose conditions, antidiabetic agents, MF6, and ML329. These findings suggest that glucose-dependent changes in cellular metabolism and redox status are differently modulated by antidiabetic agents, inhibition of fatty acid-binding proteins or MITF, and ANGPTL4 knockdown in A375 cells.

Itraconazole, a widely used antifungal medication, has shown potential in inhibiting tumor growth and reducing angiogenesis. However, its role in melanoma tumor growth remains insufficiently explored. This study investigates the inductive effect of itraconazole on autophagy-mediated apoptosis in melanoma cells.

Potential drug targets were identified using the PMF machine learning algorithm. Apoptosis and cell cycle in melanoma cell lines A375 and A2058 were assessed via flow cytometry. Western blot analysis was performed to examine autophagy and associated signaling proteins, while autophagy flux and autophagosome formation were visualized using fluorescence microscopy. A melanoma cell xenograft mouse model was established to evaluate the inhibitory mechanisms of itraconazole on tumor cell proliferation.

Using the PMF machine learning algorithm, SQSTM1 was identified as the primary target of itraconazole. Itraconazole inhibited melanoma cell proliferation by inducing G1 phase arrest and autophagy-mediated apoptosis in A375 and A2058 cells. Furthermore, itraconazole suppressed Hedgehog signaling and counteracted the activation of the Hedgehog agonist recombinant human Sonic Hedgehog (rhShh). In vivo, itraconazole significantly reduced tumor growth in A375 and A2058 xenograft models.

Itraconazole induces autophagy-mediated apoptosis in melanoma cells by inhibiting Hedgehog signaling, underscoring its potential as a therapeutic option for melanoma treatment.

Cutaneous melanoma (CM) is strongly associated with ultraviolet (UV) radiation, which contributes to the transformation of melanocytes into melanoma by inducing specific DNA damage. Here, we investigated the causal relationship between CM and genes related to sun-damaged skin, exploring specific target genes through various bioinformatics analyses.

The Gene Expression Omnibus (GEO) database was used to obtain differential genes for CM and normal skin, and the Genome-Wide Association Studies (GWAS) analysis offered summary-level melanoma data for CM. Mendelian randomization (MR) analyses were used to examine the correlated linkage between CM and sun-exposed skin genes. The MR studies were conducted mainly using Inverse Variance Weighting (IVW), MR-Egger, Weighted Median, simple and weighted patterns to predict the correlation between sun-exposed skin and CM. Finally, the role of target genes in CM was revealed by pan-cancer analysis, expression and immune-infiltration evaluations, immuno-checking targeting analysis, immunotherapy response analysis, survival analysis, and protein-protein interactions (PPI) network and enrichment analyses.

Using matrix data from the GSE15605, GSE46517, and GSE111452 datasets, bioinformatics analysis revealed 232 differentially expressed genes (DEGs) between CM and typical tissues. MR analysis indicated that only CTSS has a deleterious effect linking skin exposure to sunlight and CM. Analysis of CTSS expression in tumors and tissues, along with the construction of a prognostic model, revealed that CTSS expression was higher in both primary CM and metastatic CM compared to normal skin tissue. However, patients with higher CTSS expression had a higher prognosis. In addition, high CTSS expression was significantly and positively correlated with tumor mutation rate, tumor microenvironment, immune cell infiltration, immune checkpoints and immunotherapy efficacy.

Using MR analysis, we found a positive causal relationship between the CTSS gene in sun-exposed skin and CM. Additionally, increased CTSS may provide a basis for biomarker prediction of CM prognosis, immune status and immunotherapy.

This study aims to perform a comprehensive bibliometric analysis of global research on BRAF and MEK inhibitor resistance in melanoma, identifying key research trends, influential contributors, and emerging themes from 2003 to 2024.

A systematic search was conducted in the Web of Science Core Collection (WoSCC) database to retrieve publications related to BRAF and MEK inhibitor resistance from 1 January 2003, to 1 September 2024. Bibliometric analyses, including publication trends, citation networks, and keyword co-occurrence patterns, were performed using VOSviewer and CiteSpace. Collaborative networks, co-cited references, and keyword burst analyses were mapped to uncover shifts in research focus and global cooperation.

A total of 3,503 documents, including 2,781 research articles and 722 review papers, were analyzed, highlighting significant growth in this field. The United States, China, and Italy led in publication volume and citation impact, with Harvard University and the University of California System among the top contributing institutions. Research output showed three phases of growth, peaking in 2020. Keyword and co-citation analyses revealed a transition from early focus on BRAF mutations and MAPK pathway activation to recent emphasis on immunotherapy, combination therapies, and non-apoptotic cell death mechanisms like ferroptosis and pyroptosis. These trends reflect the evolving priorities and innovative approaches shaping the field of resistance to BRAF and MEK inhibitors in melanoma.

Research on BRAF and MEK inhibitor resistance has evolved significantly. This analysis provides a strategic framework for future investigations, guiding the development of innovative, multi-modal approaches to improve treatment outcomes for melanoma patients.

Melanoma (MM), the deadliest form of skin cancer, originates from melanocytes. Despite advances in immunotherapy that have somewhat improved the prognosis for MM patients, high levels of resistance to treatment continue to result in poor clinical outcomes. Identifying novel biomarkers and therapeutic targets is critical for improving the prognosis and treatment of MM.

In this study, we analyzed the expression patterns of WNT signaling pathway genes in MM and explored their potential mechanisms. Using Cox regression analysis, we identified 19 prognostic-related genes. Consistency clustering was performed to evaluate the potential of these genes as classifiers for prognosis. The Least Absolute Shrinkage and Selection Operator (LASSO) algorithm was then applied to refine the gene set and construct a 13-gene prognostic model. We validated the model at multiple time points to assess its predictive performance. Additionally, correlation analyses were performed to investigate the relationships between key genes and processes, including epithelial-to-mesenchymal transition (EMT) and immune responses.

We identified that CSNK1E and RAC3 were significantly positively correlated with the EMT process, with CSNK1E showing a similar expression trend to EMT-related genes. Both genes were also negatively correlated with multiple immune cell types and immune checkpoint genes. The 13-gene prognostic model demonstrated excellent predictive performance in MM prognosis. Pan-cancer analysis further revealed heterogeneous expression patterns and prognostic potential of CSNK1E across various cancers. Wet experiments confirmed that CSNK1E promotes MM cell proliferation, invasion, and migration, and enhances malignant progression through the TGF-β signaling pathway.

Our findings suggest that CSNK1E plays a crucial role in MM progression and could serve as a potential therapeutic target. The WNT and TGF-β pathways may work synergistically in regulating the EMT process in MM, highlighting their potential as novel therapeutic targets. These insights may contribute to the development of more effective treatments for MM, particularly for overcoming resistance to current therapies.

Liposomes, especially polyethylene glycol (PEG)-modified long-circulating liposomes, have been approved for market use, due to good biocompatibility, passive tumor targeting, and sustained drug release. PEG-modified long-circulating liposomes address issues such as poor stability and rapid clearance by the reticuloendothelial system. However, they still face challenges like hindering drug uptake by tumor cells and preventing tumor penetration. Inspired by the hypoxic tumor microenvironment, we constructed a hypoxia-responsive liposome (PAO-L) to enhance the intracellular uptake and photodynamic therapy (PDT) effect of chlorin e6 (Ce6). The intelligent hypoxia-cleavable PEG-AZO-OA (PAO) was prepared by coupling PEG and octadecylamine (OA) to hypoxia-sensitive azobenzene-4,4'-dicarboxylic acid (AZO) through amide reaction. The synthesized PAO was further incorporated into Ce6-loaded liposomes to enhance the circulation stability, while promote the tumor penetration and internalization by the responsive shedding of PEG from liposome surface upon reaching the hypoxic tumor tissue. PAO-L mediated PDT significantly inhibited the growth of B16F10 and 4T1 tumors, as well as lung metastasis of 4T1 breast cancer. The excellent therapeutic effect and good tolerability make PAO-L a promising candidate for enhanced PDT.

As a form of skin cancer, melanoma's incidence rate is continuing to rise globally. Therefore, there is an urgent need to find new agents to improve survival in melanoma patients. Isoflavones, a class of phytoestrogens, are primarily found in soy and other legumes. Cumulating evidence demonstrates that isoflavones exhibits significant anti-tumor properties and is beneficial for the prevention and treatment of melanoma. In the present study, we aim to investigate the anti-melanoma role of tricholoma isoflavone derivative CA028. By using in vitro melanoma cell line models, A375 and A2058 and in vivo xenograft mouse model, our results indicate that melanoma proliferation, migration, and invasion are attenuated following CA028 treatment. In addition, the treatment of CA028 induced cell apoptosis of melanoma. Finally, we addressed the mechanism of CA028 against melanoma by comparative transcriptomic analysis. The results of gene ontology highlighted the involvement of CA028's targets in the cell proliferation, cell apoptosis, and migration ability of melanoma cells. Furthermore, Ingenuity Pathway Analysis constructed the network involved in the apoptotic roles of CA028 through targeting p53 signaling and death receptor signaling. For the first time, our data suggested the possible use of modified isoflavone for therapeutic applications against melanoma.

Skin cancer, a common malignancy worldwide, has increased incidence and mortality. Thus, it is a public health issue and a significant illness burden, which increases treatment costs. Chemotherapy and surgery are used to treat skin cancer. However, conventional skin cancer treatments have several limitations, demanding the development of innovative, safe, and effective methods. To overcome these limitations of conventional topical dosage forms, many nanocarriers have been developed and tested for the targeted delivery of anticancer drugs.

The main objective of the present review was to discuss the utility of various vesicular nanocarrier systems to deliver anticancer drugs following topical administration to treat skin cancer.

For this review article, we scoured the scholarly literature using Science Direct, Google Scholar, and PubMed.

The vesicular drug delivery system has been intensively explored and developed as an alternative to conventional skin cancer drug delivery systems, especially for melanoma. They improve the penetration of anticancer drugs via the skin, reaching the cancer area with enough and killing cancer cells. Vesicles minimize skin irritation and drug degradation. This improves therapy efficacy and reduces systemic toxicity.

Utilizing the vesicular drug delivery system shows promise in treating skin cancer. Therefore, further research and inquiries are necessary to explore the therapeutic potential of these substances in treating skin cancer, intending to develop a personalized, efficient, and secure therapy approach for patients with this condition.

Melanomas arise from transformed melanocytes, positioned at the dermal-epidermal junction in the basal layer of the epidermis. Melanocytes are completely surrounded by keratinocyte neighbors, with which they communicate through direct contact and paracrine signaling to maintain normal growth control and homeostasis. UV radiation from sunlight reshapes this communication network to drive a protective tanning response. However, repeated rounds of sun exposure result in accumulation of mutations in melanocytes that have been considered as primary drivers of melanoma initiation and progression. It is now clear that mutations in melanocytes are not sufficient to drive tumor formation-the tumor environment plays a critical role. This review focuses on changes in melanocyte-keratinocyte communication that contribute to melanoma initiation and progression, with a particular focus on recent mechanistic insights that lay a foundation for developing new ways to intercept melanoma development.

Melanoma is a malignant tumor with a terrible prognosis. Although so many therapies are used for melanoma, the overall survival rate is still poor globally. Novel therapies are still required. In our study, the role and potential mechanism of regorafenib in melanoma are explored. Regorafenib has the ability to limit the growth, invasion, and metastasis of melanoma cells but to upregulate apoptosis-prompting markers (cleaved-PARP and Bax). RRM2 is identified to be the downstream target of regorafenib by RNA sequencing. In addition, we discovered that RRM2 inhibition and regorafenib have comparable effects on melanoma cells. Rescue experiments showed that RRM2 is crucial in regulating regorafenib's anti-melanoma progression. Moreover, ERK/E2F3 signaling influences regorafenib's ability to suppress melanoma cell growth. Ultimately, regorafenib significantly inhibits tumor growth in vivo. In conclusion, our finding demonstrated that regorafenib promotes antitumor progression in melanoma by reducing RRM2.

It has long been widely acknowledged that ultraviolet (UV) light is an environment risk factor that can lead to cancer, particularly skin cancer. However, it is worth noting that UV radiation holds potential for cancer treatment as a relatively high-energy electromagnetic wave. With the help of nanomaterials, the role of UV radiation has caught increasing attention in cancer treatment. In this review, we briefly summarized types of UV-induced cancers, including malignant melanoma, squamous cell carcinoma, basal cell carcinoma, Merkel cell carcinoma. Importantly, we discussed the primary mechanisms underlying UV carcinogenesis, including mutations by DNA damage, immunosuppression, inflammation and epigenetic alterations. Historically limited by its shallow penetration depth, the introduction of nanomaterials has dramatically transformed the utilization of UV light in cancer treatment. The direct effect of UV light itself generally leads to the suppression of cancer cell growth and the initiation of apoptosis and ferroptosis. It can also be utilized to activate photosensitizers for reactive oxygen species (ROS) production, sensitize radiotherapy and achieve controlled drug release. Finally, we comprehensively weigh the significant risks and limitations associated with the therapeutic use of UV radiation. And the contradictory effect of UV exposure in promoting and inhibiting tumor has been discussed. This review provides clues for potential clinical therapy as well as future study directions in the UV radiation field. The precise delivery and control of UV light or nanomaterials and the wavelength as well as dose effects of UV light are needed for a thorough understanding of UV radiation.

Background and Objectives: The relationship between hepatitis C virus (HCV) infection and melanoma remains poorly understood. This study aimed to investigate the association between HCV and melanoma, assess outcomes in patients with both conditions, and explore potential molecular mechanisms connecting the two diseases. Materials and Methods: We conducted a retrospective cohort study of 142 melanoma patients, including 29 with HCV-related cirrhosis, and analyzed their clinical outcomes. For external validation, we used the TriNetX Global Collaborative Network database, comprising 219,960 propensity-matched patients per group. An in silico analysis was performed to identify the molecular pathways linking HCV and melanoma. Results: In the retrospective cohort, HCV-positive melanoma patients showed an increased risk of early relapse (41.4% vs. 18.6%, p = 0.014), recurrence (65.5% vs. 39.8%, p = 0.020), and mortality (65.5% vs. 23.0%, p < 0.001) compared to HCV-negative patients. TriNetX data analysis revealed that HCV-positive patients had a 53% lower risk of developing melanoma (RR = 0.470, 95% CI: 0.443-0.498, p < 0.001). However, HCV-positive melanoma patients had higher all-cause mortality (HR = 1.360, 95% CI: 1.189-1.556, p < 0.001). An in silico analysis identified key molecular players, including IL-6 and CTLA4, in the HCV-melanoma network. Conclusions: While HCV infection may be associated with a lower risk of melanoma development, HCV-positive patients who develop melanoma have poorer outcomes. The identified molecular pathways provide potential targets for future research and therapeutic interventions.

Cell culture methods are indispensable strategies for studies in biological sciences and for drug discovery and testing. Most cell cultures have been developed using two-dimensional (2D) culture methods, but three-dimensional (3D) culture techniques enable the establishment of in vitro models that replicate various pathogenic conditions and they provide valuable insights into the pathophysiology of various diseases as well as more precise results in tests for drug efficacy. However, one difficulty in the use of 3D cultures is selection of the appropriate 3D cell culture technique for the study purpose among the various techniques ranging from the simplest single cell type-derived spheroid culture to the more sophisticated organoid cultures. In the simplest single cell type-derived spheroid cultures, there are also various scaffold-assisted methods such as hydrogel-assisted cultures, biofilm-assisted cultures, particle-assisted cultures, and magnet particle-assisted cultures, as well as non-assisted methods, such as static suspension cultures, floating cultures, and hanging drop cultures. Since each method can be differently influenced by various factors such as gravity force, buoyant force, centrifugal force, and magnetic force, in addition to non-physiological scaffolds, each method has its own advantages and disadvantages, and the methods have different suitable applications. We have been focusing on the use of a hanging drop culture method for modeling various non-cancerous and cancerous diseases because this technique is affected only by gravity force and buoyant force and is thus the simplest method among the various single cell type-derived spheroid culture methods. We have found that the biological natures of spheroids generated even by the simplest method of hanging drop cultures are completely different from those of 2D cultured cells. In this review, we focus on the biological aspects of single cell type-derived spheroid culture and its applications in in vitro models for various diseases.

The genome of living cells is constantly challenged by DNA lesions that interfere with cellular processes such as transcription and replication. A manifold of mechanisms act in concert to ensure adequate DNA repair, gene expression, and genome stability. Bulky DNA lesions, such as those induced by UV light or the DNA-damaging agent 4-nitroquinoline oxide, act as transcriptional and replicational roadblocks and thus represent a major threat to cell metabolism. When located on the transcribed strand of active genes, these lesions are handled by transcription-coupled nucleotide excision repair (TC-NER), a yet incompletely understood NER sub-pathway. Here, using a genetic screen in the yeast Saccharomyces cerevisiae, we identified histone variant H2A.Z as an important component to safeguard transcription and DNA integrity following UV irradiation. In the absence of H2A.Z, repair by TC-NER is severely impaired and RNA polymerase II clearance reduced, leading to an increase in double-strand breaks. Thus, H2A.Z is needed for proficient TC-NER and plays a major role in the maintenance of genome stability upon UV irradiation.

Cancer is a serious global public health issue, and a great deal of research has been made to treat cancer. Of these, discovery of promising compounds that effectively fight cancer always has been the main point of interest in pharmaceutical research. Carnosic acid (CA) is a phenolic diterpenoid compound widely present in Lamiaceae plants such as Rosemary (Rosmarinus officinalis L.). In recent years, there has been increasing evidence that CA has significant anti-cancer activity, such as leukaemia, colorectal cancer, breast cancer, lung cancer, liver cancer, pancreatic cancer, stomach cancer, lymphoma, prostate cancer, oral cancer, etc. The potential mechanisms involved by CA, including inhibiting cell proliferation, inhibiting metastasis, inducing cell apoptosis, stimulating autophagy, regulating the immune system, reducing inflammation, regulating the gut microbiota, and enhancing the effects of other anti-cancer drugs. This article reviews the biosynthesis, pharmacokinetics and metabolism, safety and toxicity, as well as the molecular mechanisms and signaling pathways of the anticancer activity of CA. This will contribute to the development of CA or CA-containing functional foods for the prevention and treatment of cancer, providing important advances in the advancement of cancer treatment strategies.

Background and Objectives: Amelanotic/hypomelanotic melanomas (AHMs) account for 2-8% of all cutaneous melanomas. Due to their clinical appearance and the lack of specific dermoscopic indicators, AHMs are challenging to diagnose, particularly in thinner cutaneous lesions. The aim of our study was to evaluate the clinicopathological and dermoscopic features of thin AHMs. Identifying the baseline clinical-pathological features and dermoscopic aspects of thin AHMs is crucial to better understand this entity. Materials and Methods: We divided the AHM cohort into two groups based on Breslow thickness: thin (≤1.00 mm) and thick (>1.00 mm). This stratification helped identify any significant clinicopathological differences between the groups. For dermoscopic analysis, we employed the "pattern analysis" approach, which involves a simultaneous and subjective assessment of different criteria. Results: Out of the 2.800 melanomas analyzed for Breslow thickness, 153 were identified as AHMs. Among these, 65 patients presented with thin AHMs and 88 with thick AHMs. Red hair color and phototype II were more prevalent in patients with thin AHMs. The trunk was the most common anatomic site for thin AHMs. Patients with thin AHMs showed a higher number of multiple melanomas. Dermoscopic analysis revealed no significant difference between thin AHMs and thick AHMs, except for a more frequent occurrence of residual reticulum in thin AHMs. Conclusions: Thin AHMs typically affect individuals with lower phototypes and red hair color. These aspects can be related to the higher presence of pheomelanin, which provides limited protection against sun damage. This also correlates with the fact that the trunk, a site commonly exposed to intermittent sun exposure, is the primary anatomical location for thin AHMs. Multiple primary melanomas are more common in patients with thin AHMs, likely due to an intrinsic predisposition as well as greater periodic dermatologic follow-ups in this class of patients. Apart from the presence of residual reticulum, no other significant dermoscopic differences were observed, complicating the differential diagnosis between thin and thick AHMs based on dermoscopy alone.

Aging is a multifaceted process influenced by hereditary factors, lifestyle, and environmental elements. As time progresses, the human body experiences degenerative changes in major functions. The external and internal signs of aging manifest in various ways, including skin dryness, wrinkles, musculoskeletal disorders, cardiovascular diseases, diabetes, neurodegenerative disorders, and cancer. Additionally, cancer, like aging, is a complex disease that arises from the accumulation of various genetic and epigenetic alterations. Circadian clock dysregulation has recently been identified as an important risk factor for aging and cancer development. Natural compounds and herbal medicines have gained significant attention for their potential in preventing age-related diseases and inhibiting cancer progression. These compounds demonstrate antioxidant, anti-inflammatory, anti-proliferative, pro-apoptotic, anti-metastatic, and anti-angiogenic effects as well as circadian clock regulation. This review explores age-related diseases, cancers, and the potential of specific natural compounds in targeting the key features of these conditions.

IBI310 is a recombinant fully human IgG1 antibody against cytotoxic T lymphocyte antigen 4. This study was conducted to evaluate IBI310 monotherapy or combination therapy with sintilimab in the patients with advanced melanoma or urothelial carcinoma (UC). Patients in phase 1a received IBI310 at 0.3/1/2/3 mg/kg intravenously (IV) every 3 weeks (Q3W) following the accelerated titration and 3 + 3 escalation design. Patients in phase 1b received IBI310 (1/2/3 mg/kg IV, Q3W) plus sintilimab (200 mg IV, Q3W) for four cycles, followed by sintilimab maintenance therapy. The phase 1b expansion of IBI310 plus sintilimab was performed in patients with advanced melanoma or UC. Overall, 53 patients were enrolled, including 10 patients with melanoma in phase 1a, 34 with melanoma, and 9 with UC in phase 1b. Overall, 94.3% of patients (50/53) experienced at least one treatment-related adverse event (TRAE) with most being grade 1-2; 26.4% of patients (14/53) experienced grade 3 or higher TRAEs. In phase 1a, the disease control rate (DCR) was 50.0% (95% confidence interval [CI], 18.7%-81.3%). In phase 1b, the objective response rate (ORR) and DCR were 17.6% (95% CI, 6.8%-34.5%) and 44.1% (95% CI, 27.2%-62.1%), respectively, for melanoma, and were 22.2% (95% CI, 2.8%-60.0%) and 66.7% (95% CI, 29.9%-92.5%), respectively, for UC. IBI310 monotherapy or combination therapy with sintilimab was well tolerated with favorable antitumor activity across patients with advanced melanoma and UC.

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.

Developmental signaling pathways associated with growth factors such as TGFb are commonly dysregulated in melanoma. Here we identified a human TGFb enhancer specifically activated in melanoma cells treated with TGFB1 ligand. We generated stable transgenic zebrafish with this TGFb Induced Enhancer driving green fluorescent protein (TIE:EGFP). TIE:EGFP was not expressed in normal melanocytes or early melanomas but was expressed in spatially distinct regions of advanced melanomas. Single-cell RNA-sequencing revealed that TIE:EGFP+ melanoma cells down-regulated interferon response while up-regulating a novel set of chronic TGFb target genes. ChIP-sequencing demonstrated that AP-1 factor binding is required for activation of chronic TGFb response. Overexpression of SATB2, a chromatin remodeler associated with tumor spreading, showed activation of TGFb signaling in early melanomas. Confocal imaging and flow cytometric analysis showed that macrophages localize to TIE:EGFP+ regions and preferentially phagocytose TIE:EGFP+ melanoma cells compared to TIE:EGFP- melanoma cells. This work identifies a TGFb induced immune response and demonstrates the need for the development of chronic TGFb biomarkers to predict patient response to TGFb inhibitors.

The mortality rate associated with cutaneous melanoma (SKCM) remains alarmingly high, highlighting the urgent need for a deeper understanding of its molecular underpinnings. In our study, we leveraged bulk transcriptome sequencing data from the SKCM cohort available in public databases such as TCGA and GEO. We utilized distinct datasets for training and validation purposes and also incorporated mutation and clinical data from TCGA, along with single-cell sequencing data from GEO. Through dimensionality reduction, we annotated cell subtypes within the single-cell data and analyzed the expression of tumor-related pathways across these subtypes. We identified differentially expressed genes (DEGs) in the training set, which were further refined using the Least Absolute Shrinkage and Selection Operator (LASSO) machine learning algorithm, employing tenfold cross-validation. This enabled the construction of a prognostic model, whose diagnostic efficacy we subsequently validated. We conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses on the DEGs, and performed immunological profiling on two risk groups to elucidate the relationship between model genes and the immune responses relevant to SKCM diagnosis, treatment, and prognosis. We also knocked down the GMR6 expression level in the melanoma cells and verified its effect on cancer through multiple experiments. The results indicate that the GMR6 gene plays a role in promoting the proliferation, invasion, and migration of cancer cells in human melanoma. Our findings offer novel insights and a theoretical framework that could enhance prognosis, treatment, and drug development strategies for SKCM, potentially leading to more precise therapeutic interventions.

Melanoma is the most lethal type of skin cancer with an increasing cutaneous cancer‑related mortality rate worldwide. Despite therapeutic advances in targeted therapy and immunotherapy, the overall survival of patients with melanoma remains unsatisfactory. Thus, a further understanding of the pathogenesis of melanoma may aid towards the development of therapeutic strategies. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) is a key enzyme that converts lysophosphatidylcholine into phosphatidylcholine in lipid remodeling. In the present study, LPCAT1 was found to play a pro‑proliferative role in melanoma. Firstly, the expression of LPCAT1 was found to be upregulated in tissues from patients with melanoma compared with that in benign nevi. Subsequently, LPCAT1 knockdown was performed, utilizing short hairpin RNA, which induced melanoma cell cycle arrest at the G1/S transition and promoted cell death. Moreover, LPCAT1 facilitated melanoma cell growth in an Akt‑dependent manner. In summary, the results of the present study indicate that targeting LPCAT1 may impede cell proliferation by inhibiting Akt signaling, thus providing a promising therapeutic strategy for melanoma in clinical practice.

The incidence of skin-related neoplasms has generally increased in recent years. Melanoma arises from malignant mutations in melanocytes in the basal layer of the epidermis and is a fatal skin cancer that seriously threatens human health. Isoflavones are polyphenolic compounds widely present in legumes and have drawn scientists' attention, because they have good efficacy against a variety of cancers, including melanoma, without significant toxic side effects and resistance. In this review article, we summarize the research progress of isoflavones in melanoma, including anti-melanoma roles and mechanisms of isoflavones via inhibition of tyrosinase activity, melanogenesis, melanoma cell growth, invasion of melanoma cells, and induction of apoptosis in melanoma cells. This information is important for the prevention, clinical treatment, and prognosis and survival of melanoma.

Melanoma ranks as the fifth most common solid cancer in adults worldwide and is responsible for a significant proportion of skin-tumor-related deaths. The advent of immune checkpoint inhibition with anti-programmed death protein-1 (PD-1) antibodies has revolutionized the adjuvant treatment of high-risk, completely resected stage III/IV melanoma. However, not all patients benefit equally. Current strategies for improving outcomes involve adjuvant treatment in earlier disease stages (IIB/C) as well as perioperative treatment approaches. Interfering with T-cell exhaustion to counteract cancer immune evasion and the immunogenic nature of melanoma is key for anti-PD-1 effectiveness. Yet, the biological rationale for the efficacy of adjuvant treatment in clinically tumor-free patients remains to be fully elucidated. High-dose intermittent sun exposure (sunburn) is a well-known primary risk factor for melanomagenesis. Also, ultraviolet radiation (UVR)-induced immunosuppression may impair anti-cancer immune surveillance. In this review, we summarize the current knowledge about adjuvant anti-PD-1 blockade, including a characterization of the main cell types most likely responsible for its efficacy. In conclusion, we propose that local and systemic immunosuppression, to some extent UVR-mediated, can be restored by adjuvant anti-PD-1 therapy, consequently boosting anti-melanoma immune surveillance and the elimination of residual melanoma cell clones.

Ultraviolet radiation (UVR) is primarily recognized for its detrimental effects such as cancerogenesis, skin aging, eye damage, and autoimmune disorders. With exception of ultraviolet B (UVB) requirement in the production of vitamin D3, the positive role of UVR in modulation of homeostasis is underappreciated. Skin exposure to UVR triggers local responses secondary to the induction of chemical, hormonal, immune, and neural signals that are defined by the chromophores and extent of UVR penetration into skin compartments. These responses are not random and are coordinated by the cutaneous neuro-immuno-endocrine system, which counteracts the action of external stressors and accommodates local homeostasis to the changing environment. The UVR induces electrical, chemical, and biological signals to be sent to the brain, endocrine and immune systems, as well as other central organs, which in concert regulate body homeostasis. To achieve its central homeostatic goal, the UVR-induced signals are precisely computed locally with transmission through nerves or humoral signals release into the circulation to activate and/or modulate coordinating central centers or organs. Such modulatory effects will be dependent on UVA and UVB wavelengths. This leads to immunosuppression, the activation of brain and endocrine coordinating centers, and the modification of different organ functions. Therefore, it is imperative to understand the underlying mechanisms of UVR electromagnetic energy penetration deep into the body, with its impact on the brain and internal organs. Photo-neuro-immuno-endocrinology can offer novel therapeutic approaches in addiction and mood disorders; autoimmune, neurodegenerative, and chronic pain-generating disorders; or pathologies involving endocrine, cardiovascular, gastrointestinal, or reproductive systems.

Malignant melanoma is the most aggressive form of skin cancer with a rather poor prognosis. Standard chemotherapy often results in severe side effects on normal (healthy) cells finally being difficult to tolerate for the patients. Shown by us earlier, cerium oxide nanoparticles (CNP, nanoceria) selectively killed A375 melanoma cells while not being cytotoxic at identical concentrations on non-cancerous cells. In conclusion, the redox-active CNP exhibited both prooxidative as well as antioxidative properties. In that context, CNP induced mitochondrial dysfunction in the studied melanoma cells via generation of reactive oxygene species (primarily hydrogen peroxide (H2O2)), but that does not account for 100% of the toxicity.

Cancer cells often show an increased glycolytic rate (Warburg effect), therefore we focused on CNP mediated changes of the glucose metabolism.

It has been shown before that glyceraldehyde 3-phosphate dehydrogenase (GAPDH) activity is regulated via oxidation of a cysteine in the active center of the enzyme with a subsequent loss of activity. Upon CNP treatment, formation of cellular lactate and GAPDH activity were significantly lowered. The treatment of melanoma cells and melanocytes with the GAPDH inhibitor heptelidic acid (HA) decreased viability to a much higher extent in the cancer cells than in the studied normal (healthy) cells, highlighting and supporting the important role of GAPDH in cancer cells.

We identified glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as a target protein for CNP mediated thiol oxidation.