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Irradiation-induced skin ulcers can be resultant from nuclear accident or reaction to radiation therapy of tumor and is intractable for healing. Human umbilical cord mesenchymal stem cells (hUC-MSCs) have been considered to be the potential therapeutic tools for tissue regeneration. However, the underlying mechanisms are still not well understood. This study aims to investigate the effects of hUC-MSCs on irradiation-induced skin ulcers healing and the related mechanisms. The ulcers were induced by irradiating the skin of adult SD rats. The ulcers of SD rats were treated with vehicle or hUC-MSCs donated from mother giving birth. The ulcer healing was measured by imaging the healing rate and the H&E staining. CD31 and VEGF expression was measured with immunohistochemistry assay. iTRAQ proteomics analysis was used to analyze the signaling pathway. The results showed that hUC-MSCs improved healing of irradiation-induced skin ulcers in vivo using a rat model of skin ulcer. Transplantation of hUC-MSCs promoted keratin generation and keratinocytes proliferation of ulcer areas. Furthermore, the results demonstrated that hUC-MSCs increased expression of CD31 and VEGF in ulcers and promoted neovascularization. iTRAQ proteomics analysis results indicated that PI3K/Akt signaling pathway involved in hUC-MSCs-mediated repairing of irradiation-induced skin ulcer. In conclusion, human umbilical cord mesenchymal stem cells promoted neovascularization and re-epithelization, and improved healing of irradiation-induced skin ulcers. This healing improvement may be conducted through activating the PI3K/Akt signaling pathway, however, which needs to be proven by the further investigations. [ABSTRACT FROM AUTHOR]

The skin is the largest outermost organ of the human body. It is vulnerable to various damages, such as ionizing radiation. Exploration of proliferation, senescence and radiosensitivity of skin cells contributes to the development of medical and cosmetic countermeasures against skin aging and toward injury protection. Human antigen R (HuR) is one of the most widely studied RNA-binding proteins and serves an important role in stabilization of mRNA and regulation of the expression of the target genes. To investigate the role of HuR in modulating proliferation, senescence and radiosensitivity of skin cells, the present study performed an in vitro study using lentivirus-mediated overexpression or silencing of HuR in human keratinocyte HaCaT cells and human skin fibroblast WS1 cells. The results indicated that overexpression of HuR promoted proliferation, whereas downregulation of HuR inhibited proliferation of HaCaT and WS1 cells. Overexpression of HuR reduced apoptosis and senescence in skin cells. RNA-Seq of skin cells with HuR overexpression or knockdown identified 77 mRNAs positively or negatively correlated with HuR expression levels. In addition, silencing of HuR induced a significant increase in radiogenic reactive oxygen species after irradiation. Overexpression of HuR increased radiotolerance of HaCaT and WS1 cells. RNA immunoprecipitation coupled with RNA-Seq identified 14 mRNAs interacting with HuR upon radiation exposure. Overall, the findings of the present study illustrated the key role of HuR in modulating proliferation, senescence and radiosensitivity of skin cells providing a new therapeutic strategy for cosmetic treatments and to combat skin injury. [ABSTRACT FROM AUTHOR]

AU-rich element RNA-binding factor 1 (AUF1) is a classical RNA-binding protein. AUF1 influences the process of development, apoptosis and tumorigenesis by interacting with adenylate-uridylate rich element-bearing mRNAs. Human skin is the largest organ of the body and acts as a protective barrier against pathogens and injuries. The aim of the present study was to explore the function and potential molecular pathways of AUF1 in human skin cells. AUF1 was overexpressed in human keratinocyte HaCaT cells and human skin fibroblast WS1 cells using adenoviruses and silenced using lentiviruses. AUF1 overexpression facilitated cell proliferation, whereas AUF1 knockdown induced the opposite effect. AUF1 reduced apoptosis but did not affect cell cycle progression. Forced AUF1 expression promoted the migration of human skin cells, as demonstrated by a scratch wound healing assay. Cell senescence was alleviated in AUF1-overexpressing skin cells, while AUF1 knockdown increased cell senescence. WS1 cells with AUF1 overexpression and silencing were used for RNA-sequencing and Kyoto Encyclopedia of Genes and Genomes-based pathway analysis to identify AUF1-affected mRNAs. A total of 18 mRNAs (eight mRNAs with positive associations and 10 mRNAs with negative associations) revealed consistent associations with both AUF1 overexpression and silencing. Enriched pathways associated with AUF1 expression included 'MAPK', 'cell adhesion molecules', 'proteasome', 'cellular senescence' and 'TGF-β signaling', indicating a complex regulatory network. Overall, the results of the present study revealed that AUF1 is involved in the proliferation, migration and senescence of skin cells in vitro and may be a potential target for cosmetic and disease treatment of skin. [ABSTRACT FROM AUTHOR]

The extensive application of nuclear technology has increased the potential of uncontrolled radiation exposure to the public. Since skin is the largest organ, radiation‐induced skin injury remains a serious medical concern. Organisms evolutionally develop distinct strategies to protect against environment insults and the related research may bring novel insights into therapeutics development. Here, 26 increased peptides are identified in skin tissues of frogs (Pelophylax nigromaculatus) exposed to electron beams, among which four promoted the wound healing of irradiated skin in rats. Specifically, radiation‐induced frog skin peptide‐2 (RIFSP‐2), from histone proteolysis exerted membrane permeability property, maintained cellular homeostasis, and reduced pyroptosis of irradiated cells with decreased TBK1 phosphorylation. Subsequently, stearyl‐CoA desaturase 1 (SCD1) is identified, a critical enzyme in biogenesis of monounsaturated fatty acids (MUFAs) as a direct target of RIFSP‐2 based on streptavidin‐biotin system. The lipidomic analysis further assured the restrain of MUFAs biogenesis by RIFSP‐2 following radiation. Moreover, the decreased MUFA limited radiation‐induced and STING‐mediated inflammation response. In addition, genetic depletion or pharmacological inhibition of STING counteracted the decreased pyroptosis by RIFSP‐2 and retarded tissue repair process. Altogether, RIFSP‐2 restrains radiation‐induced activation of SCD1‐MUFA‐STING axis. Thus, the stress‐induced amphibian peptides can be a bountiful source of novel radiation mitigators. [ABSTRACT FROM AUTHOR]

Ultraviolet (UV) radiation is ubiquitous in the environment, which has been classified as an established human carcinogen. As the largest and outermost organ of the body, direct exposure of skin to sunlight or UV radiation can result in sunburn, inflammation, photo-immunosuppression, photoaging and even skin cancers. To date, there are tactics to protect the skin by preventing UV radiation and reducing the amount of UV radiation to the skin. Nevertheless, deciphering the essential regulatory mechanisms may pave the way for therapeutic interventions against UV-induced skin disorders. Additionally, UV light is considered beneficial for specific skin-related conditions in medical UV therapy. Recent evidence indicates that the biological effects of UV exposure extend beyond the skin and include the treatment of inflammatory diseases, solid tumors and certain abnormal behaviors. This review mainly focuses on the effects of UV on the skin. Moreover, novel findings of the biological effects of UV in other organs and systems are also summarized. Nevertheless, the mechanisms through which UV affects the human organism remain to be fully elucidated to achieve a more comprehensive understanding of its biological effects. [ABSTRACT FROM AUTHOR]

Radiogenic skin injury (RSI) is a common complication during cancer radiotherapy or accidental exposure to radiation. The aim of this study is to investigate the metabolism of bile acids (BAs) and their derivatives during RSI. Rat skin tissues were irradiated by an X-ray linear accelerator. The quantification of BAs and their derivatives were performed by liquid chromatography–mass spectrometry (LC–MS)-based quantitative analysis. Key enzymes in BA biosynthesis were analyzed from single-cell RNA sequencing (scRNA-Seq) data of RSI in the human patient and animal models. The in vivo radioprotective effect of deoxycholic acid (DCA) was detected in irradiated SD rats. Twelve BA metabolites showed significant differences during the progression of RSI. Among them, the levels of cholic acid (CA), DCA, muricholic acid (MCA), chenodeoxycholic acid (CDCA), glycocholic acid (GCA), glycohyodeoxycholic acid (GHCA), 12-ketolithocholic acid (12-ketoLCA) and ursodeoxycholic acid (UDCA) were significantly elevated in irradiated skin, whereas lithocholic acid (LCA), tauro-β-muricholic acid (Tβ-MCA) and taurocholic acid (TCA) were significantly decreased. Additionally, the results of scRNA-Seq indicated that genes involved in 7a-hydroxylation process, the first step in BA synthesis, showed pronounced alterations in skin fibroblasts or keratinocytes. The alternative pathway of BA synthesis is more actively altered than the classical pathway after ionizing radiation. In the model of rat radiogenic skin damage, DCA promoted wound healing and attenuated epidermal hyperplasia. Ionizing radiation modulates the metabolism of BAs. DCA is a prospective therapeutic agent for the treatment of RSI. [ABSTRACT FROM AUTHOR]

Keloids are benign dermal tumors that arise from abnormal wound healing processes following skin lesions. Surgical excision followed by radiotherapy plays an important role in the treatment of keloids. Nevertheless, radioresistance remains a serious impediment to treatment efficacy. Investigation of the molecular response of keloids to radiation may contribute to radiosensitizing strategies. Primary keloid fibroblasts from human keloids were isolated and irradiated with X-ray. The expression profiles of messenger RNA (mRNA) in nonradiated and irradiated primary keloid fibroblasts were measured by mRNA sequencing analysis. Then, we identified common motifs and corresponding transcription factors of dysregulated mRNAs by using bioinformatic analysis of the proximal promoters. Whereafter, GO and KEGG were used to analyze the functional enrichment of the differentially expressed genes. We found that radiation not only suppressed proliferation but also increased cell senescence of primary keloid fibroblasts. There were 184 mRNAs and 204 mRNAs that showed significant changes in 4 and 8 Gy irradiated primary keloid fibroblasts, respectively. Among them, 8 upregulated and 30 downregulated mRNAs showed consistent alterations in 4 and 8 Gy irradiated primary keloid fibroblasts. More importantly, the xForkhead box O1 (FOXO1) signaling pathway was involved in the irradiation response. Pretreatment with the FOXO1 signaling inhibitor AS1842856 significantly promoted LDH release, apoptosis and senescence of primary keloid fibroblasts following irradiation. Our findings illustrated the molecular changes in human keloid fibroblasts in response to radiation, and FOXO1 pathway inhibition is expected to provide a novel strategy for the radiosensitization of keloids. [ABSTRACT FROM AUTHOR]

Radiation-induced skin injury is a serious concern during radiotherapy and accidental exposure to radiation. This study aims to investigate the molecular events in early response to ionizing radiation of skin tissues and underlying mechanism. Mice and rats were irradiated with an electron beam. Skin tissues were used for liquid chromatography-mass spectrometry (LC-MS)-based metabolomics, mRNA-Seq and single-cell RNA sequencing (scRNA-Seq). Human keratinocytes (HaCaT) and skin fibroblasts (WS1) were used for functional studies. The integrated analysis of metabolomics and transcriptomics showed that 6 key fatty acid-associated metabolites, 9 key fatty acid-associated genes and multiple fatty acid-associated pathways were most obviously enriched and increased in the irradiated skins. Among them, acyl-CoA dehydrogenase very long chain (ACADVL) was investigated in greater detail due to its most obvious expression difference and significance in fatty acid metabolism. ScRNA-Seq of rat skin from irradiated individuals revealed that ACADVL was expressed in all subpopulations of skin tissues, with variations at different timepoints after radiation. Immunohistochemistry confirmed an increased ACADVL expression in the epidermis from human sample and various animal models, including monkeys, rats and mice. The knockdown of ACADVL increased the radiosensitivity of human keratinocytes and human skin fibroblasts. Silencing of ACADVL facilitated the expression of apoptosis and pyroptosis-related proteins following ionizing radiation. This study illustrated that cutaneous fatty acid metabolism was altered in the early response of ionizing radiation, and fatty acid metabolism-associated ACADVL is involved in radiation-induced cell death. ● Cutaneous fatty acid metabolism was altered in the early response of ionizing radiation. ● Fatty acid metabolism-associated ACADVL is involved in radiation-induced cell death. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the dynamic change of CD34 level during the survival process of narrow pedicle flaps. Methods: Twenty-five white pigs were randomly and equally divided into 5 experimental groups. Five different type of narrow pedicle with different length-to-width ratio were employed, and each type of narrow pedicle was covered with 5 different size random flaps and which was classified into A, B, C, D and E for 5 groups. Group A was control group. Each type narrow pedicle with 5 different skin flaps were implanted onto the back of the pigs along the midline of back with a reverse direction. A 0.3 cm×0.3 cm full thickness skin flap in the middle of distal segment was collected and on 3rd, 5th, 7th and 14th days of post-operation. The expression of CD34 was measured by immunohistochemistry and enzyme-linked immunosorbent (ELISA). Results: Histological examination showed that with the increasing of length-to-width ratio of the narrow pedicle skin flaps, the expression of CD34 increased in the skin flaps. Increased level of CD34 was found on 3rd day post-operation, and the peak expression was found on 7th day. Persistent high level of CD34 was found until 14th day. Conclusion: Increased CD34 level in the distal skin flap, there is the association between CD34 level and ischemia injury. Moreover, CD34 expression plays an important role during the repair processes of pedicle flaps. [ABSTRACT FROM AUTHOR]

The article titled "A Frog Skin-Derived Peptide Targeting SCD1 Exerts Radioprotective Effects Against Skin Injury by Inhibiting STING-Mediated Inflammation" discusses the discovery of a peptide called RIFSP-2 that provides protection against ionizing radiation. The researchers identified this peptide in the skin of a clear black-spot frog, which is depicted on the cover of the journal. The frog skin, containing the RIFSP-2 peptide, can block the rays released by ionizing radiation, indicating its potential for radioprotection. The study was conducted by a team of authors and provides valuable insights into the development of treatments for skin injury caused by radiation. [Extracted from the article]

[Display omitted] • MnO 2 /PDA@Cu nanosheets: Cu added to MnO 2 via PDA. • MnO 2 /PDA@Cu-HA microneedle: delivers agents to wounds. • MnO 2 /PDA@Cu-HA: fights bacteria, clears ROS, promotes vascularization. • MnO 2 /PDA@Cu-HA: speeds up wound healing. Effective treatment of infected diabetic wound (IDW) requires delivering therapeutic agents to both wound surface and deep layers, as well as improving the wound microenvironment through antibacterial actions, clearing excessive reactive oxygen species (ROS), and promoting vascular regeneration. Here, we present a novel inorganic nanosheet called MnO 2 /PDA@Cu, consisting of manganese dioxide (MnO 2) with copper (Cu) ions loaded on its surface through in-situ polymerization, using polydopamine (PDA) as an intermediate. We then encapsulated the MnO 2 /PDA@Cu nanosheet into a methacrylated hyaluronic acid (HA) soluble microneedle patch, creating a photodynamic-controllable multifunctional MnO 2 /PDA@Cu-HA microneedle. We used this microneedle to treat IDWs in a rat full-thickness skin defect model. Results demonstrated that the MnO 2 /PDA@Cu-HA microneedle effectively delivered therapeutic agents to both wound surface and deep layers, where PDA's photodynamic therapy swiftly combated bacteria under 808 nm near-infrared irradiation. Simultaneously, MnO 2 acted as a nanoenzyme, mitigating ROS levels and providing oxygen for wound healing. In addition, the photothermal effect of PDA further facilitated the release of Cu, promoting vascularization. The MnO 2 /PDA@Cu-HA microneedle significantly accelerated wound closure, re-epithelialization, and collagen deposition, enhancing IDW healing. In conclusion, our synthesized MnO 2 /PDA@Cu-HA microneedle represents a photodynamic-controllable multifunctional platform for IDW treatment, offering a promising approach for effective wound management. [ABSTRACT FROM AUTHOR]

• Dysregulated transcripts of irradiated human skin keratinocytes were identified by Microarray-based expression profiling. • These dysregulated transcripts were implicated in multiple pathways including type I interferon-mediated pathways. • Interferon α inducible protein 6 (IFI6) is induced by radiation in human skin cells and confers radio protection. • IFI6 is translocated into nucleus and regulating the transcriptional activity of HSF1. 5. A certain amount of potential HSF1-targeted genes upregulated by IFI6 overexpression post radiation is involved. Radiation-induced skin injury is one of the main adverse effects and a dose-limiting factor of radiotherapy without feasible treatment. The underlying mechanism of this disease is still limited. To investigate the potential molecular pathways and mechanisms of radiation-induced skin injury. mRNA expression profiles were determined by Affymetrix Human HTA2.0 microarray. IFI6 overexpression and knockdown were mediated by lentivirus. The functional changes of skin cells were measured by flow cytometry, ROS probe and Edu probe. Protein distribution was detected by immunofluorescence experiment, and IFI6-interacting proteins were detected by immunoprecipitation (IP) combined with mass spectrometry. The global gene changes in IFI6-overexpressed skin cells after irradiation were detected by RNA-seq. mRNA expression profiling showed 50 upregulated and 13 down regulated genes and interferon alpha inducible protein 6 (IFI6) was top upregulated. Overexpression of IFI6 promoted cell proliferation and reduced cell apoptosis as well as ROS production following radiation, and conversely, increased the radiosensitivity of HaCaT and human skin fibroblast (WS1). IFI6 was translocated into nucleus in irradiated skin cells and the interacting relationship with mitochondrial single-stranded DNA-binding protein 1 (SSBP1), which could enhance the transcriptional activity of heat shock transcription factor 1 (HSF1). IFI6 augmented HSF1 activity following radiation in HaCaT and WS1 cells. RNA-seq analysis showed IFI6 modulated virus infection and cellular response to stress pathways, which may help to further explore how IFI6 regulate the transcriptional activity of HSF1. This study reveals that IFI6 is induced by ionizing radiation and confers radioprotection in skin cells. [ABSTRACT FROM AUTHOR]

• Radiation modulates the expression of lipid metabolism-related genes and decreases skin fat mass with altered lipid metabolite profiles. • Increased skin adipose mass induced by a high-fat diet confers resistance against radiogenic skin injury. • Fatty acid binding protein 4 (FABP4) from skin adipocytes could be incorporated into skin cells and promote DNA damage repair. Radiation-induced skin injury is a serious concern during radiotherapy and radiation accidents. Skin fat represents the dominant architectural component of the human skin. However, the interplay between skin fat and the progression of radiation-induced skin injury remains largely unexplored. This study aims to elucidate the interplay between skin fat and the progression of radiation-induced skin injury. SD rats were irradiated with an electron beam. mRNA profiles were determined by RNA-Seq. The skin lipid mass was monitored by magnetic resonance imaging (MRI) and lipid profiles were measured by liquid chromatography-mass spectrometry (LC–MS). Human mature adipocytes isolated from dermal and subcutaneous white adipose tissues (WATs) were co-cultured with human keratinocytes (HaCaT) and skin fibroblasts (WS1) in the transwell culture system. Cell migration ability was measured by migration assay. Radiation modulated cutaneous lipid metabolism by downregulating multiple pathways. Moreover, radiation decreased skin fat mass with altered lipid metabolite profiles. The rats fed with a high-fat diet showed resistance to radiogenic skin injury compared with that with a control diet, indicating that skin lipid plays a radioprotective role. Mature adipocytes promoted the migration but not the proliferation of co-cultured skin keratinocytes and fibroblasts. Palmitic acid, the most abundant fatty acid in skin tissues, facilitated the migration of WS1 cells. Moreover, fatty acid-binding protein 4 (FABP4) could be incorporated into skin cells and promote DNA damage repair in irradiated skin fibroblasts. Radiation induces cutaneous lipid remolding, and skin adipocytes confer a protective role against radiation-induced skin injury. [ABSTRACT FROM AUTHOR]

Human skin is daily exposed to oxidative stresses in the environment such as physical stimulation, chemical pollutants and pathogenic microorganisms, which are likely to cause skin diseases. As important post-translational modifications, protein ubiquitination and deubiquitination play crucial roles in maintaining cellular homeostasis by the proteolytic removal of oxidized proteins. We have previously reported that the expression of ubiquitin-specific protease 47 (USP47), a kind of deubiquitinating enzymes (DUBs), was significantly elevated in response to oxidative stress. However, the role of USP47 in cutaneous oxidative injury remains unclear. Usp47 wild-type (Usp47 +/+ ) mice and Usp47 knockout (Usp47 −/− ) mice were used to establish two animal models of oxidative skin damage: (1) radiation- and (2) imiquimod (IMQ)-induced skin injury. Loss of Usp47 consistently aggravated mouse skin damage in vivo. Subsequently, we screened 63 upregulated and 170 downregulated proteins between the skin tissues of wild-type and Usp47 −/− mice after 35 Gy electron beam radiation using proteomic analysis. Among the dysregulated proteins, nicotinamide nucleotide transhydrogenase (NNT), which has been reported as a significant regulator of oxidative stress and redox homeostasis, was further investigated in detail. Results showed that NNT was regulated by USP47 through direct ubiquitination mediated degradation and involved in the pathogenesis of cutaneous oxidative injury. Knockdown of NNT expression dramatically limited the energy production ability, with elevated mitochondrial reactive oxygen species (ROS) accumulation and increased mitochondrial membrane potential in irradiated HaCaT cells. Taken together, our present findings illustrate the critical role of USP47 in oxidative skin damage by modulating NNT degradation and mitochondrial homeostasis. • Loss of Usp47 aggravates radiation- and imiquimod-induced skin injury in vivo. • USP47 stabilizes NNT by inhibiting proteasome-mediated degradation. • NNT is decreased in radiation-induced skin oxidative injury. • USP47 attenuates skin oxidative injury by modulating NNT expression. [ABSTRACT FROM AUTHOR]

[Display omitted] • We developed a multifunctional core-shell nanofiber loaded with CTS in the shell layer, Cu and DWJM in the core layer. • Initial released CTS exerts antibacterial activity and sustain released Cu drives cell migration and neovascularization. • DWJM accelerated the deposition of collagen and these three bioactive agents synergistically enhanced DW healing. Infected diabetic wound (DW) healing entails a series of temporally and spatially regulated stages including antibacterial responses, revascularization, and collagen deposition, underscoring the need for the controlled sequential delivery of appropriate compounds when treating these wounds. Here, we designed a multifunctional core–shell CTS@PLCL/DWJM@Cu nanofiber loaded with three bioactive agents, including chitosan (CTS), copper (Cu), and decellularized Wharton's jelly matrix (DWJM). We used this platform to facilitate regulated antibacterial, angiogenic, and collagen deposition activity in the context of DW healing. These CTS@PLCL/DWJM@Cu nanofibers exhibited satisfactory mechanical properties, excellent absorption, acceptable biodegradability, a high level of biocompatibility, elevated adhesive rates, and the ability to sequentially mediate controlled sequential CTS and Cu release. Further in vitro analyses revealed that the initial release of the CTS shell was sufficient to exert antibacterial activity, after which the sustained release of the Cu core promoted cellular migration, neovascularization, and enhanced angiogenesis-related gene expression. In vivo, DWJM further accelerated the deposition of collagen. Together, the sequential antibacterial, angiogenic, and collagen deposition activities synergistically enhanced DW healing. We thus posit that the core–shell CTS@PLCL/DWJM@Cu nanofiber holds great promise for use as a dressing material capable of promoting the appropriate stages of DW healing in a regulated, sequential manner. [ABSTRACT FROM AUTHOR]

B7-H3 is a type I membrane protein that has contradictory co-stimulatory and co-inhibitory effects in adaptive and anti-tumour immunity. B7-H3 is up-regulated in many malignant tumours, including breast cancer. Therefore, we hypothesise that B7-H3, which has an immunosuppressive role, suppresses anti-tumour immunity. The aim of this study was to clarify the role of B7-H3 in the tumor microenvironment in breast cancer, explore the possibility of B7-H3 as a target for clinical immunotherapy, and provide reference for clinical work. We knocked down B7-H3 with siRNA in MCF7 breast cancer cells, which we termed MCF7-B7-H3-KD cells, and the expression of B7-H3 was assessed by flow cytometry. GAPDH (glyceraldehyde-3-phosphate dehydrogenase) knockdown was used as a control (MCF7-Gapdh). MCF7-B7-H3-KD and MCF7-Gapdh cells were co-cultured with peripheral blood mononuclear cells (PBMCs) and CD3+ T cells from healthy donors to assess the effect of B7-H3 loss. PBMCs cultured with MCF7-Gapdh cells showed decreased activation, proliferation, and function of CD8+ T cells, but there was no effect on the proliferation of CD4+ T cells. However, when MCF7-B7-H3-KD cells were co-cultured with PBMCs, the proliferation ability of CD4+ T cells and CD8+ T cells was significantly higher than that observed in MCF7-Gapdh cell co-culture. Additionally, co-culture with MCF7-Gapdh cells decreased the expression of IFN-γ (Interferon-γ). However, after co-culture with MCF7-B7-H3-KD cells, there was an increase in IFN-γ. We further found that this inhibitory effect on IFN-γ was because of decreased mTOR (the mammalian target of rapamycin) phosphorylation in T cells. Treatment of T cells co-cultured with MCF7-B7-H3-KD cells with an mTOR inhibitor blocked the secretion of IFN-γ. B7-H3 on tumour cells inhibits the proliferation of CD4+ and CD8+ T cells and inhibits the release of IFN-γ by decreasing mTOR signalling. A better understanding of these complex immune regulatory mechanisms should facilitate the generation of more powerful and selective tools to manipulate cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Melanoma has the highest mortality rate of all skin tumors, and metastases are the major cause of death from it. The molecular mechanism leading to melanoma metastasis is currently unclear.Methods: With the goal of revealing the underlying mechanism, three data sets with accession numbers GSE8401, GSE46517 and GSE7956 were downloaded from the Gene Expression Omnibus (GEO) database. After identifying the differentially expressed gene (DEG) of primary melanoma and metastatic melanoma, three kinds of analyses were performed, namely functional annotation, protein-protein interaction (PPI) network and module construction, and co-expression and drug-gene interaction prediction analysis.Results: A total of 41 up-regulated genes and 79 down-regulated genes was selected for subsequent analyses. Results of pathway enrichment analysis showed that extracellular matrix organization and proteoglycans in cancer are closely related to melanoma metastasis. In addition, seven pivotal genes were identified from PPI network, including CXCL8, THBS1, COL3A1, TIMP3, KIT, DCN, and IGFBP5, which have all been verified in the TCGA database and clinical specimens, but only CXCL8, THBS1 and KIT had significant differences in expression.Conclusions: To conclude, CXCL8, THBS1 and KIT may be the hub genes in the metastasis of melanoma and thus may be regarded as therapeutic targets in the future. [ABSTRACT FROM AUTHOR]