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1.
Am J Hum Genet ; 108(9): 1611-1630, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34343493

RESUMO

Genome-wide association studies (GWASs) have identified a melanoma-associated locus on chromosome band 7p21.1 with rs117132860 as the lead SNP and a secondary independent signal marked by rs73069846. rs117132860 is also associated with tanning ability and cutaneous squamous cell carcinoma (cSCC). Because ultraviolet radiation (UVR) is a key environmental exposure for all three traits, we investigated the mechanisms by which this locus contributes to melanoma risk, focusing on cellular response to UVR. Fine-mapping of melanoma GWASs identified four independent sets of candidate causal variants. A GWAS region-focused Capture-C study of primary melanocytes identified physical interactions between two causal sets and the promoter of the aryl hydrocarbon receptor (AHR). Subsequent chromatin state annotation, eQTL, and luciferase assays identified rs117132860 as a functional variant and reinforced AHR as a likely causal gene. Because AHR plays critical roles in cellular response to dioxin and UVR, we explored links between this SNP and AHR expression after both 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and ultraviolet B (UVB) exposure. Allele-specific AHR binding to rs117132860-G was enhanced following both, consistent with predicted weakened AHR binding to the risk/poor-tanning rs117132860-A allele, and allele-preferential AHR expression driven from the protective rs117132860-G allele was observed following UVB exposure. Small deletions surrounding rs117132860 introduced via CRISPR abrogates AHR binding, reduces melanocyte cell growth, and prolongs growth arrest following UVB exposure. These data suggest AHR is a melanoma susceptibility gene at the 7p21.1 risk locus and rs117132860 is a functional variant within a UVB-responsive element, leading to allelic AHR expression and altering melanocyte growth phenotypes upon exposure.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carcinoma de Células Escamosas/genética , Cromossomos Humanos Par 7 , Loci Gênicos , Melanócitos/metabolismo , Melanoma/genética , Receptores de Hidrocarboneto Arílico/genética , Neoplasias Cutâneas/genética , Alelos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Cromatina/química , Cromatina/metabolismo , Regulação da Expressão Gênica , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Melanócitos/efeitos dos fármacos , Melanócitos/patologia , Melanócitos/efeitos da radiação , Melanoma/metabolismo , Melanoma/patologia , Dibenzodioxinas Policloradas/toxicidade , Polimorfismo de Nucleotídeo Único , Cultura Primária de Células , Regiões Promotoras Genéticas , Receptores de Hidrocarboneto Arílico/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Banho de Sol , Raios Ultravioleta/efeitos adversos
2.
Ann Clin Lab Sci ; 51(4): 470-486, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34452885

RESUMO

OBJECTIVE: Epithelium-specific ETS protein 3 (Ese-3) is a member of the ETS family that is associated with tumor progression. However, there is little knowledge about Ese-3 in skin cancer. This study was conducted to explore the effects of Ese-3 on clinical prognosis in skin cancer and the functions of HaCaT cells. MATERIALS AND METHODS: Gene expression and clinical data were collected from The Cancer Genome Atlas (TCGA), The Genotype-Tissue Expression (GTEx), and three GSE datasets (GSE15605, GSE46517, and GSE114445). Comparison of data between groups was performed by Student's t-test and chi square test. Survival analysis was performed using log-rank test. Univariate and multivariate analyses were performed using Cox proportional hazards models. Enrichment analysis was used to predict Ese-3 related functions. Cell proliferation assays, colony formation assays, and flow cytometry were used to assess cell proliferation, while Transwell assays analyzed cell migration and invasion. RESULTS: Compared with normal tissues, the Ese-3 mRNA in cutaneous malignant melanoma (CMM) patients was downregulated (P<0.0001). Ese-3 mRNA was associated with the T stage (χ 2=10.015, P=0.018), clinical stage (χ 2=4.122, P=0.042), and prognosis in CMM patients (P=0.0219) and was an independent prognostic predictor in CMM (HR=1.878, P=0.048). Enrichment analysis showed that differentially expressed proteins were associated with "protein kinase B (AKT) binding." CONCLUSION: Ese-3 inhibited the proliferation, migration, and invasion of HaCaT cells by downregulating PSIP1 and NUCKS1 expression levels to inactivate the phosphorylation of AKT.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas Nucleares/antagonistas & inibidores , Fosfoproteínas/antagonistas & inibidores , Neoplasias Cutâneas/patologia , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Idoso , Apoptose , Biomarcadores Tumorais/genética , Movimento Celular , Proliferação de Células , Feminino , Células HaCaT , Humanos , Masculino , Invasividade Neoplásica , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Prognóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Taxa de Sobrevida , Fatores de Transcrição/genética
3.
Eur J Pharm Sci ; 166: 105975, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34391880

RESUMO

Anti-cutaneous melanoma activity of the skin-delivered gambogic acid (GA) has been reported in our previous study. However, it is difficult for GA to diffuse passively through intact skin without any enhancement means. In this study, a combination of chemical enhancers (EN: azone and propylene glycol) and physical ultrasound (US) was used to improve the percutaneous permeation of GA and enhance the anti-melanoma activity. The enhancement effect of the combination of EN and US (EN-US) on GA in vitro and in vivo was studied, and the enhancement mechanism and skin irritation were also evaluated. We showed that the parameters of US application at a constant frequency (30 kHz) with a duty cycle of 100% and intensity of 1.75 W/cm2 for 20 min were optimal. In vitro, EN-US showed a considerable enhancement of the permeation of GA, and the enhancement effect was stronger than that with the use of EN or US alone. In vivo antitumor study showed that the tumor growth was significantly inhibited after percutaneous administration of GA by EN-US, more than in the intravenous injection group. The penetration enhancement mechanism revealed that EN-US not only altered the structure of lipid bilayers and keratins to reduce the barrier effect of the stratum corneum but also produced diffusion channels in the skin under the cavitation effect of US, thereby promoting the skin penetration of GA. In addition, there was no observable skin irritation in mice after treatment with EN-US. Our study demonstrated that the combination of EN and US improved the skin permeation and retention of GA to enhance the anti-melanoma activity. This method also provides technical guidance for the future development of topical and transdermal therapeutic system of GA.


Assuntos
Melanoma , Neoplasias Cutâneas , Administração Cutânea , Animais , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Camundongos , Permeabilidade , Pele/metabolismo , Absorção Cutânea , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/metabolismo , Xantonas
4.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360915

RESUMO

Patients diagnosed with melanoma have a poor prognosis due to regional invasion and metastases. The receptor tyrosine kinase epidermal growth factor receptor (EGFR) is found in a subtype of melanoma with a poor prognosis and contributes to drug resistance. Aloysia citrodora essential oil (ALOC-EO) possesses an antitumor effect. Understanding signaling pathways that contribute to the antitumor of ALOC-EO is important to identify novel tumor types that can be targeted by ALOC-EO. Here, we investigated the effects of ALOC-EO on melanoma growth and tumor cell migration. ALOC-EO blocked melanoma growth in vitro and impaired primary tumor cell growth in vivo. Mechanistically, ALOC-EO blocked heparin-binding-epidermal growth factor (HB-EGF)-induced EGFR signaling and suppressed ERK1/2 phosphorylation. Myelosuppressive drugs upregulated HB-EGF and EGFR expression in melanoma cells. Cotreatment of myelosuppressive drugs with ALOC-EO improved the antitumor activity and inhibited the expression of matrix metalloproteinase-7 and -9 and a disintegrin and metalloproteinase domain-containing protein9. In summary, our study demonstrates that ALOC-EO blocks EGFR and ERK1/2 signaling, with preclinical efficacy as a monotherapy or in combination with myelosuppressive drugs in melanoma.


Assuntos
Antineoplásicos/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/metabolismo , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Melanoma/metabolismo , Óleos Voláteis/farmacologia , Extratos Vegetais/farmacologia , Neoplasias Cutâneas/metabolismo , Verbenaceae/química , Animais , Apoptose/efeitos dos fármacos , Bortezomib/farmacologia , Doxorrubicina/farmacologia , Sinergismo Farmacológico , Humanos , Melanoma/patologia , Camundongos , Fosforilação/efeitos dos fármacos , Neoplasias Cutâneas/patologia
5.
Int J Mol Sci ; 22(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34360654

RESUMO

CD147, a transmembrane glycoprotein that belongs to the immunoglobulin superfamily, and cyclophilin A (CypA), one of the binding partners of CD147, are overexpressed in tumor cells and associated with the progression of several malignancies, including both solid and hematological malignancies. However, CD147 and CypA involvement in cutaneous T-cell lymphoma (CTCL) has not been reported. In this study, we examined CD147 and CypA expression and function using clinical samples of mycosis fungoides (MF) and Sézary syndrome (SS) and CTCL cell lines. CD147 and CypA were overexpressed by tumor cells of MF/SS, and CypA was also expressed by epidermal keratinocytes in MF/SS lesional skin. Serum CypA levels were increased and correlated with disease severity markers in MF/SS patients. Anti-CD147 antibody and/or anti-CypA antibody suppressed the proliferation of CTCL cell lines, both in vitro and in vivo, via downregulation of phosphorylated extracellular-regulated kinase 1/2 and Akt. These results suggest that CD147-CypA interactions can contribute to the proliferation of MF/SS tumor cells in both a autocrine and paracrine manner, and that the disruption of CD147-CypA interactions could be a new therapeutic strategy for the treatment of MF/SS.


Assuntos
Basigina/metabolismo , Proliferação de Células , Ciclofilina A/metabolismo , Linfoma Cutâneo de Células T/patologia , Micose Fungoide/patologia , Síndrome de Sézary/patologia , Neoplasias Cutâneas/patologia , Basigina/genética , Estudos de Casos e Controles , Ciclofilina A/genética , Feminino , Humanos , Linfoma Cutâneo de Células T/genética , Linfoma Cutâneo de Células T/metabolismo , Masculino , Pessoa de Meia-Idade , Micose Fungoide/genética , Micose Fungoide/metabolismo , Índice de Gravidade de Doença , Síndrome de Sézary/genética , Síndrome de Sézary/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo
6.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299325

RESUMO

Extramammary Paget's disease (EMPD) is a rare skin cancer arising in the apocrine gland-rich areas. Most EMPD tumors are dormant, but metastatic lesions are associated with poor outcomes owing to the lack of effective systemic therapies. Trophoblast cell surface antigen 2 (Trop2), a surface glycoprotein, has drawn attention as a potential therapeutic target for solid tumors. Sacituzumab govitecan, an antibody-drug conjugate of Trop2, has recently entered clinical use for the treatment of various solid cancers. However, little is known about the role of Trop2 in EMPD. In this study, we immunohistochemically examined Trop2 expression in 116 EMPD tissue samples and 10 normal skin tissues. In normal skin, Trop2 was expressed in the epidermal keratinocytes, inner root sheaths, and infundibulum/isthmus epithelium of hair follicles, eccrine/apocrine glands, and sebaceous glands. Most EMPD tissues exhibited homogeneous and strong Trop2 expression, and high Trop2 expression was significantly associated with worse disease-free survival (p = 0.0343). These results suggest the potential use of Trop2-targeted therapy for EMPD and improve our understanding of the skin-related adverse effects of current Trop2-targeted therapies such as sacituzumab govitecan.


Assuntos
Antígenos de Neoplasias/biossíntese , Moléculas de Adesão Celular/biossíntese , Doença de Paget Extramamária/metabolismo , Neoplasias Cutâneas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Glândulas Apócrinas/metabolismo , Biomarcadores Tumorais , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Feminino , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Folículo Piloso/metabolismo , Humanos , Imunoconjugados/farmacologia , Queratinócitos/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Doença de Paget Extramamária/tratamento farmacológico , Doença de Paget Extramamária/genética , Doença de Paget Extramamária/patologia , Glândulas Sebáceas/metabolismo , Pele/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia
7.
Neurology ; 97(7 Suppl 1): S4-S14, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34230208

RESUMO

OBJECTIVE: As part of an evaluation of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration patient representative program, we surveyed REiNS members to (1) identify facilitators and barriers to involving patient representatives and (2) understand whether and how involving patient representatives affected recommendations for clinical trial outcomes. METHODS: We administered an anonymous online survey to all REiNS members. Facilitators and barriers to patient representative involvement were solicited using a modified free listing technique; responses were inductively grouped into higher-order categories and ranked based on saliency score (Smith s). Open-ended questions assessed patient representative expectations for engagement, perceived benefits/costs of patient engagement, and patient representative contributions; responses were analyzed using conventional content analysis. RESULTS: A total of 63/172 (37%) members responded, including 18/30 (60%) patient representatives. Providing sufficient opportunities to meaningfully engage in research tasks and cultivating a respectful, inclusive atmosphere were key facilitators to patient representatives' satisfaction and ability to make an impact. Respondents perceived that patient representatives directly (through their input on research tasks) and indirectly (through effects on other stakeholders' knowledge and communication style) improved the organization's research, leading to selection of more meaningful, relevant, and feasible clinical trial outcome measures. Ongoing challenges to patient engagement include difficulty scheduling meetings and concerns about the level of scientific knowledge patient representatives needed to effectively engage. CONCLUSIONS: Involving patient representatives in REiNS improved perceived quality of neurofibromatosis clinical trial outcome measures. Negotiating sufficient opportunities to engage, fostering an inclusive atmosphere, and navigating time pressures are key to effective patient engagement.


Assuntos
Neurilemoma/metabolismo , Neurilemoma/terapia , Neurofibromatoses/metabolismo , Neurofibromatoses/terapia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/terapia , Ensaios Clínicos como Assunto , Comunicação , Humanos , Neurofibromatose 1/metabolismo , Avaliação de Resultados em Cuidados de Saúde , Participação do Paciente/métodos
8.
Am J Hum Genet ; 108(9): 1631-1646, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34293285

RESUMO

Although expression quantitative trait loci (eQTLs) have been powerful in identifying susceptibility genes from genome-wide association study (GWAS) findings, most trait-associated loci are not explained by eQTLs alone. Alternative QTLs, including DNA methylation QTLs (meQTLs), are emerging, but cell-type-specific meQTLs using cells of disease origin have been lacking. Here, we established an meQTL dataset by using primary melanocytes from 106 individuals and identified 1,497,502 significant cis-meQTLs. Multi-QTL colocalization with meQTLs, eQTLs, and mRNA splice-junction QTLs from the same individuals together with imputed methylome-wide and transcriptome-wide association studies identified candidate susceptibility genes at 63% of melanoma GWAS loci. Among the three molecular QTLs, meQTLs were the single largest contributor. To compare melanocyte meQTLs with those from malignant melanomas, we performed meQTL analysis on skin cutaneous melanomas from The Cancer Genome Atlas (n = 444). A substantial proportion of meQTL probes (45.9%) in primary melanocytes is preserved in melanomas, while a smaller fraction of eQTL genes is preserved (12.7%). Integration of melanocyte multi-QTLs and melanoma meQTLs identified candidate susceptibility genes at 72% of melanoma GWAS loci. Beyond GWAS annotation, meQTL-eQTL colocalization in melanocytes suggested that 841 unique genes potentially share a causal variant with a nearby methylation probe in melanocytes. Finally, melanocyte trans-meQTLs identified a hotspot for rs12203592, a cis-eQTL of a transcription factor, IRF4, with 131 candidate target CpGs. Motif enrichment and IRF4 ChIP-seq analysis demonstrated that these target CpGs are enriched in IRF4 binding sites, suggesting an IRF4-mediated regulatory network. Our study highlights the utility of cell-type-specific meQTLs.


Assuntos
Redes Reguladoras de Genes , Fatores Reguladores de Interferon/genética , Melanócitos/metabolismo , Melanoma/genética , Locos de Características Quantitativas , Neoplasias Cutâneas/genética , Alelos , Atlas como Assunto , Cromatina/química , Cromatina/metabolismo , Mapeamento Cromossômico , Metilação de DNA , Regulação da Expressão Gênica , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Fatores Reguladores de Interferon/metabolismo , Masculino , Melanócitos/patologia , Melanoma/metabolismo , Melanoma/patologia , Cultura Primária de Células , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Transcriptoma
9.
Anticancer Res ; 41(7): 3439-3448, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230139

RESUMO

BACKGROUND/AIM: The role of immune cells and PD-L1 in cutaneous squamous carcinogenesis is unclear. This study examines T-cell populations, Langerhans cells (LCs) and PD-L1 in invasive squamous cell carcinoma (inSCC), adjacent precursors and normal skin (NS) to investigate their participation in tumorigenesis. MATERIALS AND METHODS: Cases of cutaneous inSCC with adjacent precursors (n=125) were selected. In situ SCC (isSCC) and actinic keratosis (AK) were observed in 53 and 123 cases, respectively, whereas NS was present in 123 lesions. Immunohistochemistry was performed for CD3, CD8, Foxp3, CD1a and PD-L1. RESULTS: T-cells, LCs and PD-L1 gradually increase during the evolution from AK to isSCC and inSCC, with statistical significance between all lesions, except for CD3+ and CD8+ cells between isSCC and inSCC. Epithelial PD-L1 expression correlates with tumor diameter and thickness. CONCLUSION: The progressive increase of T-cells, LCs and PD-L1 in cutaneous squamous carcinogenesis provides rationale for immunotherapy and identification of predictive biomarkers.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/metabolismo , Células de Langerhans/metabolismo , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/metabolismo , Subpopulações de Linfócitos T/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Complexo CD3/imunologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Imuno-Histoquímica/métodos , Células de Langerhans/imunologia , Células de Langerhans/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Cutâneas/patologia , Subpopulações de Linfócitos T/imunologia , Microambiente Tumoral/imunologia
10.
Int J Mol Sci ; 22(13)2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34281234

RESUMO

Genetic splice variants have become of central interest in recent years, as they play an important role in different cancers. Little is known about splice variants in melanoma. Here, we analyzed a genome-wide transcriptomic dataset of benign melanocytic nevi and primary melanomas (n = 80) for the expression of specific splice variants. Using kallisto, a map for differentially expressed splice variants in melanoma vs. benign melanocytic nevi was generated. Among the top genes with differentially expressed splice variants were Ras-related in brain 6B (RAB6B), a member of the RAS family of GTPases, Macrophage Scavenger Receptor 1 (MSR1), Collagen Type XI Alpha 2 Chain (COLL11A2), and LY6/PLAUR Domain Containing 1 (LYPD1). The Gene Ontology terms of differentially expressed splice variants showed no enrichment for functional gene sets of melanoma vs. nevus lesions, but between type 1 (pigmentation type) and type 2 (immune response type) melanocytic lesions. A number of genes such as Checkpoint Kinase 1 (CHEK1) showed an association of mutational patterns and occurrence of splice variants in melanoma. Moreover, mutations in genes of the splicing machinery were common in both benign nevi and melanomas, suggesting a common mechanism starting early in melanoma development. Mutations in some of these genes of the splicing machinery, such as Serine and Arginine Rich Splicing Factor A3 and B3 (SF3A3, SF3B3), were significantly enriched in melanomas as compared to benign nevi. Taken together, a map of splice variants in melanoma is presented that shows a multitude of differentially expressed splice genes between benign nevi and primary melanomas. The underlying mechanisms may involve mutations in genes of the splicing machinery.


Assuntos
Processamento Alternativo , Melanoma/metabolismo , Nevo Pigmentado/metabolismo , Neoplasias Cutâneas/metabolismo , Transcriptoma , Estudos de Casos e Controles , Humanos , Melanoma/classificação , Melanoma/genética , Mutação , Isoformas de Proteínas/genética , Neoplasias Cutâneas/classificação , Neoplasias Cutâneas/genética
11.
Molecules ; 26(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208349

RESUMO

A new 11 amino acid linear peptide named roseabol A (1) and the known compound 13-oxo-trans-9,10-epoxy-11(E)-octadecenoic acid (2) were isolated from the fungus Clonostachys rosea. Combined NMR and MS analysis revealed that roseabol A (1) contained amino acid residues characteristic of the peptaibol family of peptides such as isovaline, α-aminoisobutyric acid, hydroxyproline, leucinol, and an N-terminal isovaleric acid moiety. The amino acid sequence was established by a combination of NMR studies and tandem MS fragmentation analyses, and the absolute configurations of the constituent amino acids of 1 were determined by the advanced Marfey's method. Compound 2 showed inhibitory activity against Merkel cell carcinoma, a rare and difficult-to-treat type of skin cancer, with an IC50 value of 16.5 µM.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Célula de Merkel/tratamento farmacológico , Hypocreales/química , Peptaibols/química , Peptaibols/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Sequência de Aminoácidos , Antineoplásicos/química , Carcinoma de Célula de Merkel/química , Carcinoma de Célula de Merkel/metabolismo , Linhagem Celular Tumoral , Humanos , Espectroscopia de Ressonância Magnética/métodos , Estrutura Molecular , Neoplasias Cutâneas/química , Neoplasias Cutâneas/metabolismo
12.
Int J Mol Sci ; 22(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34298962

RESUMO

We studied CD34+ stromal cells/telocytes (CD34+SCs/TCs) in pathologic skin, after briefly examining them in normal conditions. We confirm previous studies by other authors in the normal dermis regarding CD34+SC/TC characteristics and distribution around vessels, nerves and cutaneous annexes, highlighting their practical absence in the papillary dermis and presence in the bulge region of perifollicular groups of very small CD34+ stromal cells. In non-tumoral skin pathology, we studied examples of the principal histologic patterns in which CD34+SCs/TCs have (1) a fundamental pathophysiological role, including (a) fibrosing/sclerosing diseases, such as systemic sclerosis, with loss of CD34+SCs/TCs and presence of stromal cells co-expressing CD34 and αSMA, and (b) metabolic degenerative processes, including basophilic degeneration of collagen, with stromal cells/telocytes in close association with degenerative fibrils, and cutaneous myxoid cysts with spindle-shaped, stellate and bulky vacuolated CD34+ stromal cells, and (2) a secondary reactive role, encompassing dermatitis-e.g., interface (erythema multiforme), acantholytic (pemphigus, Hailey-Hailey disease), lichenoid (lichen planus), subepidermal vesicular (bullous pemphigoid), psoriasiform (psoriasis), granulomatous (granuloma annulare)-vasculitis (leukocytoclastic and lymphocytic vasculitis), folliculitis, perifolliculitis and inflammation of the sweat and sebaceous glands (perifolliculitis and rosacea) and infectious dermatitis (verruca vulgaris). In skin tumor and tumor-like conditions, we studied examples of those in which CD34+ stromal cells are (1) the neoplastic component (dermatofibrosarcoma protuberans, sclerotic fibroma and solitary fibrous tumor), (2) a neoplastic component with varying presentation (fibroepithelial polyp and superficial myxofibrosarcoma) and (3) a reactive component in other tumor/tumor-like cell lines, such as those deriving from vessel periendothelial cells (myopericytoma), epithelial cells (trichoepithelioma, nevus sebaceous of Jadassohn and seborrheic keratosis), Merkel cells (Merkel cell carcinoma), melanocytes (dermal melanocytic nevi) and Schwann cells (neurofibroma and granular cell tumor).


Assuntos
Antígenos CD34/metabolismo , Dermatite/metabolismo , Derme/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Cutâneas/metabolismo , Telócitos/metabolismo , Animais , Dermatite/patologia , Derme/patologia , Humanos , Neoplasias Cutâneas/patologia , Telócitos/patologia
13.
Int J Mol Sci ; 22(13)2021 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-34199056

RESUMO

Palmoplantar keratodermas (PPKs) are characterized by thickness of stratum corneum and epidermal hyperkeratosis localized in palms and soles. PPKs can be epidermolytic (EPPK) or non epidermolytic (NEPPK). Specific mutations of keratin 16 (K16) and keratin 1 (K1) have been associated to EPPK, and NEPPK. Cases of mosaicism in PPKs due to somatic keratin mutations have also been described in scientific literature. We evaluated a patient presenting hyperkeratosis localized monolaterally in the right palmar area, characterized by linear yellowish hyperkeratotic lesions following the Blaschko lines. No other relatives of the patient showed any dermatological disease. Light and confocal histological analysis confirmed the presence of epidermolityic hyperkeratosis. Genetic analysis performed demonstrates the heterozygous deletion NM_006121.4:r.274_472del for a total of 198 nucleotides, in KRT1 cDNA obtained by a palmar lesional skin biopsy, corresponding to the protein mutation NP_006112.3:p.Gly71_Gly137del. DNA extracted from peripheral blood lymphocytes did not display the presence of the mutation. These results suggest a somatic mutation causing an alteration in K1 N-terminal variable domain (V1). The deleted sequence involves the ISIS subdomain, containing a lysine residue already described as fundamental for epidermal transglutaminases in the crosslinking of IF cytoskeleton. Moreover, a computational analysis of the wild-type and V1-mutated K1/K10 keratin dimers, suggests an unusual interaction between these keratin filaments. The mutation taster in silico analysis also returned a high probability for a deleterious mutation. These data demonstrate once again the importance of the head domain (V1) of K1 in the formation of a functional keratinocyte cytoskeleton. Moreover, this is a further demonstration of the presence of somatic mutations arising in later stages of the embryogenesis, generating a mosaic phenotype.


Assuntos
Queratina-10/química , Queratina-1/química , Queratina-1/genética , Nevo/etiologia , Domínios e Motivos de Interação entre Proteínas , Deleção de Sequência , Neoplasias Cutâneas/etiologia , Sequência de Aminoácidos , Sequência de Bases , Biópsia , Análise Mutacional de DNA , Imunofluorescência , Humanos , Imuno-Histoquímica , Queratina-1/metabolismo , Queratina-10/metabolismo , Modelos Moleculares , Nevo/metabolismo , Nevo/patologia , Conformação Proteica , Multimerização Proteica , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Relação Estrutura-Atividade
14.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209674

RESUMO

Pre-mRNA processing factor 4B (PRP4) has previously been shown to induce epithelial-mesenchymal transition (EMT) and drug resistance in cancer cell lines. As melanin plays an important photoprotective role in the risk of sun-induced skin cancers, we have investigated whether PRP4 can induce drug resistance and regulate melanin biosynthesis in a murine melanoma (B16F10) cell line. Cells were incubated with a crucial melanogenesis stimulator, alpha-melanocyte-stimulating hormone, followed by transfection with PRP4. This resulted in the inhibition of the production of melanin via the downregulation of adenylyl cyclase-cyclic adenosine 3',5'-monophosphate (AC)-(cAMP)-tyrosinase synthesis signaling pathway. Inhibition of melanin production by PRP4 leads to the promotion of carcinogenesis and induced drug resistance in B16F10 cells. Additionally, PRP4 overexpression upregulated the expression of ß-arrestin 1 and desensitized the extracellular calcium-sensing receptor (CaSR), which in turn, inhibited the influx of extracellular Ca2+ ions. The decreased influx of Ca2+ was confirmed by a decreased expression level of calmodulin. We have demonstrated that transient receptor potential cation channel subfamily C member 1 was involved in the influx of CaSR-induced Ca2+ via a decreasing level of its expression. Furthermore, PRP4 overexpression downregulated the expression of AC, decreased the synthesis of cAMP, and modulated the actin cytoskeleton by inhibiting the expression of Ras homolog family member A (RhoA). Our investigation suggests that PRP4 inhibits the production of melanin in B16F10 cells, blocks the influx of Ca2+ through desensitization of CaSR, and modulates the actin cytoskeleton through downregulating the AC-cAMP pathway; taken together, these observations collectively lead to the promotion of skin carcinogenesis.


Assuntos
Citoesqueleto de Actina/metabolismo , Cálcio/metabolismo , Melaninas/biossíntese , Ribonucleoproteína Nuclear Pequena U4-U6/metabolismo , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/metabolismo , Animais , Antineoplásicos , Calmodulina/genética , Calmodulina/metabolismo , Proteínas de Transporte , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Espaço Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Espaço Intracelular/metabolismo , Melanoma Experimental , Camundongos , Ligação Proteica , Ribonucleoproteína Nuclear Pequena U4-U6/genética , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/patologia
15.
Molecules ; 26(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34066283

RESUMO

Tyrosinases belong to the functional copper-containing proteins family, and their structure contains two copper atoms, in the active site, which are coordinated by three histidine residues. The biosynthesis of melanin in melanocytes has two stages depending on the actions of the natural substrates L-DOPA and L-tyrosine. The dysregulation of tyrosinase is involved in skin cancer initiation. In the present study, using molecular modeling tools, we analyzed the inhibition activity of tyrosinase activity using kojic acid (KA) derivatives designed from aromatic aldehydes and malononitrile. All derivatives showed conformational affinity to the enzyme active site, and a favorable distance to chelate the copper ion, which is essential for enzyme function. Molecular dynamics simulations revealed that the derivatives formed promising complexes, presenting stable conformations with deviations between 0.2 and 0.35 Å. In addition, the investigated KA derivatives showed favorable binding free energies. The most stable KA derivatives showed the following binding free energies: -17.65 kcal mol-1 (D6), -18.07 kcal mol-1 (D2), -18.13 (D5) kcal mol-1, and -10.31 kcal mol-1 (D4). Our results suggest that these derivatives could be potent competitive inhibitors of the natural substrates of L-DOPA (-12.84 kcal mol-1) and L-tyrosine (-9.04 kcal mol-1) in melanogenesis.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular/métodos , Simulação de Dinâmica Molecular , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/química , Pironas/química , Pironas/farmacologia , Domínio Catalítico , Humanos , Levodopa/metabolismo , Melaninas/biossíntese , Melanócitos/metabolismo , Melanoma/metabolismo , Estrutura Molecular , Monofenol Mono-Oxigenase/metabolismo , Neoplasias Cutâneas/metabolismo , Relação Estrutura-Atividade , Tirosina/metabolismo
16.
Life Sci ; 283: 119759, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34171381

RESUMO

AIMS: Skin cancer is the most widespread cancer worldwide, mainly caused by exposure to ultraviolet radiation (UV) in sunlight. Utilizing topical preventive agents in routinely daily used cosmetics may prevent UV-related skin damages and skin cancers. γ-Oryzanol (GO) is a natural component derived from rice bran oil, with potential antioxidant and skin anti-aging properties. MAIN METHODS: We biologically thorough studied the antioxidant and anticancer effects of GO in vitro to found the effective signaling pathways, then evaluated the sun protection factor of prepared formulation, and finally investigated the long-term preventive effects of GO-loaded nanoethosomes (GO-NEs) against UVB-induced skin cancer in mice. KEY FINDINGS: GO-NEs could effectively prevent UVB-induced skin cancer. SIGNIFICANCE: Our results suggest that GO-NEs could be utilized as an innovative ingredient in cosmetics.


Assuntos
Nanoestruturas , Fenilpropionatos , Neoplasias Cutâneas/prevenção & controle , Protetores Solares , Raios Ultravioleta/efeitos adversos , Animais , Linhagem Celular Tumoral , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nanoestruturas/química , Nanoestruturas/uso terapêutico , Fenilpropionatos/química , Fenilpropionatos/farmacologia , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Protetores Solares/química , Protetores Solares/farmacologia
17.
Nat Immunol ; 22(7): 851-864, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099918

RESUMO

Group 2 innate lymphoid cells (ILC2s) are essential to maintain tissue homeostasis. In cancer, ILC2s can harbor both pro-tumorigenic and anti-tumorigenic functions, but we know little about their underlying mechanisms or whether they could be clinically relevant or targeted to improve patient outcomes. Here, we found that high ILC2 infiltration in human melanoma was associated with a good clinical prognosis. ILC2s are critical producers of the cytokine granulocyte-macrophage colony-stimulating factor, which coordinates the recruitment and activation of eosinophils to enhance antitumor responses. Tumor-infiltrating ILC2s expressed programmed cell death protein-1, which limited their intratumoral accumulation, proliferation and antitumor effector functions. This inhibition could be overcome in vivo by combining interleukin-33-driven ILC2 activation with programmed cell death protein-1 blockade to significantly increase antitumor responses. Together, our results identified ILC2s as a critical immune cell type involved in melanoma immunity and revealed a potential synergistic approach to harness ILC2 function for antitumor immunotherapies.


Assuntos
Anticorpos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Inibidores de Checkpoint Imunológico/farmacologia , Interleucina-33/farmacologia , Linfócitos/efeitos dos fármacos , Melanoma Experimental/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Quimiotaxia de Leucócito/efeitos dos fármacos , Citotoxicidade Imunológica/efeitos dos fármacos , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Eosinófilos/metabolismo , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Linfócitos/imunologia , Linfócitos/metabolismo , Masculino , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/metabolismo
18.
Cell Death Dis ; 12(7): 643, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162829

RESUMO

Among the principal causative factors for the development of complications related to aging is a diet rich in fats and sugars, also known as the Western diet. This diet advocates numerous changes that might increase the susceptibility to initiate cancer and/or to create a tissue microenvironment more conducive to the growth of malignant cells, thus favoring the progression of cancer and metastasis. Hypercaloric diets in general lead to oxidative stress generating reactive oxygen species and induce endoplasmic reticulum stress. Our results demonstrate that mice bearing tumors fed with a Western diet presented bigger tumor mass with increased insulin sensitivity in these tissues. Several markers of insulin signaling, such as AKT phosphorylation and mTOR pathway, are promoted in tumors of Western diet-fed animals. This process is associated with increased macrophage infiltration, activation of unfolded protein response pathway, and initiation of epithelial-mesenchymal transition (EMT) process in these tumor tissues. Summing up, we propose that the Western diet accelerates the aging-related processes favoring tumor development.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Dieta Ocidental/efeitos adversos , Transição Epitelial-Mesenquimal , Mediadores da Inflamação/metabolismo , Melanoma Experimental/metabolismo , Neoplasias Cutâneas/metabolismo , Resposta a Proteínas não Dobradas , Fatores Etários , Animais , Linhagem Celular Tumoral , Proliferação de Células , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Fatores de Tempo , Carga Tumoral , Microambiente Tumoral , Resposta a Proteínas não Dobradas/genética
19.
J Photochem Photobiol B ; 221: 112235, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34126589

RESUMO

The investigation of in-vitro response of cell cultures derived from tumor material of individual patients with similar tumor localizations to photodynamic treatment is presented. Tumor types included in the research were renal cell carcinoma, melanoma and alveolar, synovial, lypo- and osteo- sarcomas. Long-term observations of treatment-induced morphological changes in cells were performed by means of digital holographic microscopy. A substantial variance in response of cells of individual patients with similar tumor types and localizations to photodynamic treatment with the same dose has been observed. These peculiarities are indicative of the demand to personalized protocols of photodynamic treatment. The elevated resistance of cells of some patients to treatment at high doses highlights potential limitations of photodynamic therapy for some patients. Digital holographic microscopy is shown to be an informative label-free noninvasive tool allowing for long-term monitoring of cell samples in vitro and providing quantitative information on necrosis rate and loss of cellular dry mass. The developed methodology can be generalized for analysis of cellular response to various therapies.


Assuntos
Proliferação de Células/efeitos dos fármacos , Holografia/métodos , Fármacos Fotossensibilizantes/farmacologia , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Humanos , Melanoma/metabolismo , Melanoma/patologia , Microscopia de Fluorescência , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Fármacos Fotossensibilizantes/química , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Células Tumorais Cultivadas
20.
Cancer Sci ; 112(9): 3455-3468, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34159686

RESUMO

Clinical reports indicate that gastric cancer (GC) has a high mortality rate, but its pathological mechanism remains poorly understood. This work integrated bioinformatics analysis with experimental verification to explore novel biomarkers of gastric cancer. First, weighted gene coexpression network analysis was applied to screen significant genes correlated with GC development. Gene set enrichment analysis was also used to unearth the most relevant biological functions of significant genes. As a result, we discovered homeobox C9 (HOXC9) as a novel oncogene in GC, primarily through negatively regulating immune response. High expression of HOXC9 predicted a poor prognosis in GC patients, and knocking down HOXC9 efficiently enhanced the interferon-gamma (IFNγ)-dependent apoptosis in two GC cell lines as well as organoids from patients. Furthermore, cleaved caspase-3/7 and phosphorylated signal transducer and activator of transcription 1 (p-STAT1) were also significantly enhanced in HOXC9 knockdown cells and organoids treated with IFNγ. Mechanistically, we found that HOXC9 inhibited the death-associated protein kinase 1 (DAPK1) and its downstream retinoic acid-inducible gene-I (RIG1) to generate GC IFNγ resistance. In summary, we identified and confirmed that HOXC9 generates IFNγ resistance in GC by inhibiting the DAPK1/RIG1/p-STAT1 axis.


Assuntos
Proteínas Quinases Associadas com Morte Celular/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Homeodomínio/metabolismo , Interferon gama/farmacologia , Receptores do Ácido Retinoico/metabolismo , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais/genética , Neoplasias Gástricas/metabolismo , Regulação para Cima/genética , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Estudos de Coortes , Bases de Dados Genéticas , Proteínas Quinases Associadas com Morte Celular/genética , Técnicas de Silenciamento de Genes , Proteínas de Homeodomínio/genética , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Oncogenes , Receptores do Ácido Retinoico/genética , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/metabolismo , Neoplasias Gástricas/patologia , Transfecção
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