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Mitosis is a prognostic factor for cutaneous melanoma (CM), but accurate mitosis detection in CM tissues is difficult. Therefore, the 8th Edition of the American Joint Committee on Cancer staging system has removed the mitotic rate as a category criterion of the tumor T‐category, based on the evidence that the mitotic rate was not an independent prognostic factor for melanoma survival. As single‐nucleotide polymorphisms (SNPs) have been shown to be potential predictors for cutaneous melanoma‐specific survival (CMSS), we investigated the potential prognostic value of SNPs in mitosis‐related pathway genes in CMSS by analyzing their associations with outcomes of 850 CM patients from The University of Texas MD Anderson Cancer Center in a discovery dataset and validated the findings in another dataset of 409 CM patients from the Harvard University Nurses’ Health Study and Health Professionals Follow‐up Study. In both datasets, we identified two SNPs (SDCCAG8 rs10803138 G>A and MAGI2 rs3807694 C>T) as independent prognostic factors for CMSS, with adjusted allelic hazards ratios of 1.49 (95% confidence interval = 1.17‐1.90, P = .001) and 1.45 (1.13‐1.86, P = .003), respectively. Furthermore, their combined unfavorable alleles also predicted a poor survival in both discovery and validation datasets in a dose‐response manner (P trend = .0006 and .0001, respectively). Additional functional analysis revealed that both SDCCAG8 rs10803138 A and MAGI2 rs3807694 T alleles were associated with elevated mRNA expression levels in normal tissues. Therefore, these findings suggest that SDCCAG8 rs10803138 G>A and MAGI2 rs3807694 C>T are independent prognostic biomarkers for CMSS, possibly by regulating the mRNA expression of the corresponding genes involved in mitosis., Mitosis is a prognostic factor for cutaneous melanoma (CM), but accurate mitosis detection in CM tissues is difficult. Therefore, the 8th Edition of the American Joint Committee on Cancer staging system has removed the mitotic rate as a category criterion of the tumor T‐category, based on the evidence that the mitotic rate was not an independent prognostic factor for melanoma survival. Since single‐nucleotide polymorphisms (SNPs) have been shown to be potential predictors for cutaneous melanoma‐specific survival (CMSS), we investigated the potential prognostic value of SNPs in mitosis‐related pathway genes in CMSS by analyzing their associations with outcomes of CM patients from The University of Texas MD Anderson Cancer Center in a discovery dataset and validated the findings in another dataset of CM patients from the Harvard University Nurses’ Health Study and Health Professionals Follow‐up Study. In both datasets, we identified two SNPs (SDCCAG8 rs10803138 G>A and MAGI2 rs3807694 C>T) as independent prognostic factors for CMSS.

Ultraviolet B (UVB) is one of the most dangerous insults for skin, which can cause skin sunburn, pigment disease, photoaging, and photocarcinogenesis. This study aimed to identify pathogenic genes related to ferroptosis in the skin of humans after UVB radiation.The gene expression profiles (GSE41078, GSE54413) were downloaded from the Gene Expression Omnibus (GEO) database, and the ferroptosis-related genes (FRGs) were downloaded from the Genecards database. To identify the differentially expressed genes (DEGs) and obtain differentially expressed FRGs by intersecting DEGs with FRGs. To identify the functional annotation and potential pathways by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Differentially expressed FRGs-associated protein-protein interaction network (PPI) was performed by STRING database and Cytoscape software.A total of 628 co-expressed DEGs of the two profiles (GSE41078 and GSE54413) were identified, including 371 upregulated and 257 downregulated DEGs. A total of 32 differentially expressed FRGs were identified. The results of GO analyses showed that, in the biological processes, UVB had a great influence on the response to oxidative stress; in the molecular functions, UVB had a great influence on antioxidant activity; in the cellular components, UVB had a great influence on endocytic vesicle lumen. The key pathways of differentially expressed FRGs were identified by KEGG analyses. The most significant 12 central node genes were identified by PPI network.We identified differentially expressed FRGs candidate genes and pathways in UVB-induced skin photodamage, which could contribute to the development of new therapeutic targets for skin photodamage.

Yutao Wang, China Medical University, ChinaThe tumor microenvironment (TME) has been shown to impact the prognosis of tumors in patients including cutaneous melanoma (CM); however, not all components of TME are important. Given the aforementioned situation, the functional immune cell contents correlated with CM patient prognosis are needed to optimize present predictive models and reflect the overall situation of TME. We developed a novel risk score named core tumor-infiltrating immune cell score (cTICscore), which showed certain advantages over existing biomarkers or TME-related signatures in predicting the prognosis of CM patients. Furthermore, we explored a new gene signature named cTILscore−related module gene score (cTMGs), based on four identified TME-associated genes (GCH1, GZMA, PSMB8, and PLAAT4) showing a close correlation with the cTICscore, which was generated by weighted gene co-expression network analysis and least absolute shrinkage and selection operator analysis to facilitate clinical application. Patients with low cTMGs had significantly better overall survival (OS, P = 0.002,< 0.001, = 0.002, and = 0.03, respectively) in the training and validating CM datasets. In addition, the area under the curve values used to predict the immune response in four CM cohorts were 0.723, 0.723, 0.754, and 0.792, respectively, and that in one gastric cohort was 0.764. Therefore, the four-gene signature, based on cTICscore, might improve prognostic information, serving as a predictive tool for CM patients receiving immunotherapy.cutaneous melanoma, tumor microenvironment, prognosis, immunotherapy, cTICscore

Background Keratinocytes can function as innate immune cells under oxidative stress and aggravate the cutaneous T-cell response that undermines melanocytes in the setting of vitiligo. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a regulator of innate immunity that exists in keratinocytes. However, the role of the NLRP3 inflammasome in the pathogenesis of vitiligo has not been investigated. Objective We sought to explicate the contribution of the activated NLRP3 inflammasome in keratinocytes to the autoimmune response in patients with vitiligo. Methods Perilesional and serum samples from patients with vitiligo were collected to examine the status of the NLRP3 inflammasome in the setting of vitiligo. Cultured keratinocytes were treated with H2O2 to investigate the mechanism for NLRP3 inflammasome activation under oxidative stress. Peripheral blood T cells were extracted from patients with vitiligo to explore the influence of the NLRP3 inflammasome on the T-cell response in patients with vitiligo. Results Expressions of NLRP3 and downstream cytokine IL-1β were consistently increased in perilesional keratinocytes of patients with vitiligo. Notably, serum IL-1β levels were increased in patients with vitiligo, correlated with disease activity and severity, and decreased after effective therapy. Furthermore, oxidative stress promoted NLRP3 inflammasome activation in keratinocytes through transient receptor potential cation channel subfamily M member 2 (TRPM2), a redox-sensitive cation channel, which was dependent on TRPM2-mediated calcium influx. More importantly, blocking TRPM2-induced NLRP3 inflammasome activation in keratinocytes impaired chemotaxis for CD8+ T cells and inhibited the production of cytokines in T cells in patients with vitiligo. Conclusion Oxidative stress–induced NLRP3 inflammasome activation in keratinocytes promotes the cutaneous T-cell response, which could be targeted for the treatment of vitiligo.

Vitiligo is a complex disorder characterized by patchy loss of skin pigmentation due to abnormal melanocyte function. Overwhelming evidences have suggested that oxidative stress plays a major role in the loss of melanocytes thereby mediating the onset and progression of vitiligo. The nuclear factor erythroid 2-like factor 2 (Nrf2) is a master regulator of cellular redox homeostasis and the activation of Nrf2 signaling pathway is impaired in the vitiligo melanocytes. Baicalein, as flavonoid extracted from the Scutellaria baicalensis, has been proved to possess the ability to activate Nrf2 signaling pathway in other cell types and mouse model. Our previous data found that baicalein exerts a cytoprotective role in H2O2-induced apoptosis in human melanocytes cell line (PIG1). Based on these founding, we hypothesized that baicalein activates Nrf2 signaling pathway, alleviates H2O2-induced mitochondrial dysfunction and cellular damage, thereby protecting human vitiligo melanocytes from oxidative stress. In the present study, we found that baicalein effectively inhibited H2O2-induced cytotoxicity and apoptosis in human vitiligo melanocytes (PIG3V). Further results demonstrated that baicalein promoted Nrf2 nucleus translocation as well as up-regulated the expression of Nrf2 and its target gene, heme oxygenase-1 (HO-1). Moreover, the protective effects of baicalein against H2O2-induced cellular damage and apoptosis as well as mitochondrial dysfunction were abolished by Nrf2 knockdown. Additionally, we observed that Nrf2 knockdown suppressed proliferation and increased the sensitivity of PIG3V cells to H2O2 treatment. Finally, we explored the mechanism of baicalein associated with Nrf2 activation and found that the phosphorylation of Nrf2 as well as ERK1/2and PI3K/AKT signaling were not involved in the baicalein-induced activation of Nrf2. Taken together, these data clearly suggest that baicalein enhances cellular antioxidant defense capacity of human vitiligo melanocytes through the activation of the Nrf2 signaling pathway, providing beneficial evidence for the application of baicalein in the vitiligo treatment.

Cutaneous squamous cell carcinoma (CSCC), an epidermal keratinocyte-derived skin tumor, is one of the most leading causes of cancer-associated morbidity and mortality worldwide. Long noncoding RNAs have emerged as key regulators of tumor development and progression. Recent studies have identified LINC00319, a long intergenic noncoding RNA, as an oncogene in lung cancer. However, the biological role of LINC00319 in CSCC remains largely unknown. The current study aimed to explore the role of LINC00319 in CSCC and uncover the molecular mechanisms. In current study, we found that LINC00319 was significantly upregulated in both CSCC tissues and cell lines. Besides, the χ2 test showed that increased expression of LINC00319 was associated with larger tumor size, advanced TNM stage, and lymphovascular invasion. Gain-of-function and loss-of-function approaches were applied to investigate the effects of LINC00319 on CSCC cells. Functional studies demonstrated that LINC00319 promoted CSCC cell proliferation, accelerated cell cycle progression, facilitated cell migration and invasion, and inhibited cell apoptosis. Mechanistic studies revealed that LINC00319 exerts its oncogenic functions in CSCC via miR-1207-5p-mediated regulation of cyclin-dependent kinase 3. Taken together, upregulation of LINC00319 implies a potential link with poor prognosis and reflects CSCC progression. Collectively, this study may provide some evidence for LINC00319 as a candidate target in CSCC treatment.

In vitiligo, cutaneous depigmentation is accompanied by increased T cell cytolytic activity targeting melanocytes, indicating that autoimmune tolerance is disrupted. The inhibited amount and function of Tregs have been indicated to be involved in the autoimmune intolerance in vitiligo, however, with the conclusion still controversial and the involved mechanism unknown. In this study, we explored the molecular and cellular alterations accounting for the impaired Treg response in vitiligo. Our results showed that the amount of Tregs was drastically reduced in peripheral blood of active vitiligo patients. Furthermore, the immunoregulatory function of Tregs was attenuated, with lower expression of CTLA4, IL‐10 and TGF‐β. Moreover, the expression of HO‐1, a functional modulator of Tregs, was decreased in vitiligo Tregs, and the concentrations of HO‐1 metabolites, including bilirubin, CoHb and iron, were correspondingly decreased in serum of vitiligo patients. In addition, we treated the Tregs from vitiligo patients with Hemin, an agonist of HO‐1, and found that enhanced HO‐1 expression restored the function of Tregs by up‐regulating IL‐10 expression. Our study demonstrates the essential role of HO‐1 in the impaired Treg response in vitiligo and indicates the potential of HO‐1 as a therapeutic target in vitiligo management.

The sex-determining region Y-related high-mobility group box transcription factor 4 (SOX4) plays a fundamental role during embryogenesis and controls cell fate and differentiation. Recently, increased SOX4 expression has been reported in various cancer types, contributing to the progression and survival of cancer cells. However, the distinct functions and downstream targets of SOX4 remain to be fully elucidated. In this study, we initially found elevated SOX4 expression in melanoma. SOX4 regulates apoptosis and cell cycle arrest, affects glucose consumption and lactate production, and consequently, promotes melanoma cell proliferation. Moreover, we found that SOX4 rewires glucose metabolism by regulating the expression of glucose transporter type 1, hexokinase 2, and lactate dehydrogenase A at the transcriptional level. Mechanistically, SOX4 knockdown reduced activation of acutely transforming retrovirus AKT8 in rodent T-cell lymphoma and mTORC1, leading to an attenuated malignant phenotype. We also identified p70 ribosomal S6 kinase and eukaryotic initiation factor 4E-binding protein 1 as key substrates involved in the regulation of mTORC1 in melanoma cells. In conclusion, our study demonstrates the essential role of SOX4 in melanoma glycolytic metabolism through the acutely transforming retrovirus AKT8 in rodent T-cell lymphoma signaling pathway and highlights its potential as a therapeutic target in melanoma management.

Diffuse large B-cell lymphoma (DLBCL) is a clinically aggressive B-cell non-Hodgkin’s lymphoma (NHL) with high treatment difficulty and high relapse rate. The bromodomain and extra-terminal (BET) proteins play significant roles in supporting the transcription of known DLBCL oncogene MYC, which provides a way for the development of targeted therapeutic agents to address this kind of malignant tumor. Here, we reported a novel benzoxazinone derivative YLT-LL-11 as potential BRD4 inhibitor and further investigated the biological activities against DLBCL. The results suggested that YLT-LL-11 inhibited cell growth against a panel of human hematopoietic malignancies cell lines in a dose- and time-dependent manner. In addition, flow cytometry and Western blotting assays showed that YLT-LL-11 inhibited the proliferation of a DLBCL cell line OCI-LY10 via inducing G0/G1 cell cycle arrest with regulation of the cyclin-dependent kinases (CDKs) expression. Furthermore, YLT-LL-11 facilitated OCI-LY10 cell apoptosis by up-regulation of pro-apoptotic protein BAX and down-regulation of anti-apoptotic protein Bcl-2. Taken together, these results revealed that BRD4 inhibitor YLT-LL-11 can down-regulate growth-associated transcription factors MYC in DLBCL thus resulted in cell growth inhibition and apoptosis.

Oxidative stress plays important roles in the pathogenesis of vitiligo. The removal of hydrogen peroxided (HIn the present study, we investigated the potential protective effect of BBR against oxidative stress on an immortalized normal human melanocyte cell line PIG1.Generally, PIG1 cells were pretreated with various concentrations of BBR for 1 h followed by exposure to 1.0 mM HOur results showed that cell viability rose and intracellular ROS generation, cell apoptosis of melanocytes decreased significantly in response to HThe results above suggest that BBR can protect melanocytes against oxidative stress via its anti-oxidative activity. Also, we found H

The prevention of hydrogen peroxide (H

In vitiligo, melanocytes are particularly vulnerable to oxidative stress owing to the pro-oxidant state generated during melanin synthesis and to the genetic antioxidant defects. Autophagy is a controlled self-digestion process which can protect cells against oxidative damage. However, the exact role of autophagy in vitiligo melanocytes in response to oxidative stress and the mechanism involved are still not clear. To determine the implications of autophagy for melanocyte survival in response to oxidative stress, we first detected the autophagic flux in normal melanocytes exposure to H2O2, and found that autophagy was significantly enhanced in normal melanocytes, for protecting cells against H2O2-induced oxidative damage. Nevertheless, vitiligo melanocytes exhibited dysregulated autophagy and hypersensitivity to H2O2-induced oxidative injury. In addition, we confirmed that the impairment of Nrf2-p62 pathway is responsible for the defects of autophagy in vitiligo melanocytes. Noteworthily, upregulation of the Nrf2-p62 pathway or p62 reduced H2O2-induced oxidative damage of vitiligo melanocytes. Therefore, our data demonstrated that dysregulated autophagy owing to the impairment of Nrf2-p62 pathway increase the sensitivity of vitiligo melanocytes to oxidative stress, thus promote the development of vitiligo. Upregulation of p62-dependent autophagy may be applied to vitiligo treatment in the future.