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1.
Clin Plast Surg ; 48(4): 551-560, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34503716

RESUMO

Melanoma is the most lethal type of skin cancer, originating from the uncontrolled proliferation of melanocytes. The transformation of normal melanocytes into malignant tumor cells has been a focus of research seeking to better understand melanoma's pathogenesis and develop new therapeutic targets. Over the past few decades, a conglomeration of studies has pinpointed several driver mutations and their associated signaling pathways. In this review, we summarize the key signaling pathways and the driver mutations involved in melanoma tumorigenesis and also discuss the potential underlying mechanisms.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Melanócitos , Melanoma/genética , Transdução de Sinais , Neoplasias Cutâneas/genética
2.
Clin Plast Surg ; 48(4): 587-598, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34503719

RESUMO

Conventional histopathology is the primary means of melanoma diagnosis. Both architectural and cytologic features aid in discrimination of melanocytic nevi from melanoma. Communication between the clinician and pathologist regarding the history, examination, differential diagnosis, prior biopsy findings, method of sampling, and specimen orientation is critical to an accurate diagnosis. A melanoma pathology report includes multiple prognostic indicators to guide surgical and medical management. In challenging cases, immunohistochemistry and molecular diagnostics may be of benefit.


Assuntos
Melanoma , Nevo Pigmentado , Neoplasias Cutâneas , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica , Melanoma/diagnóstico , Melanoma/genética , Nevo Pigmentado/diagnóstico , Nevo Pigmentado/genética , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética
3.
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
4.
Nat Commun ; 12(1): 5056, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417458

RESUMO

Melanoma cells rely on developmental programs during tumor initiation and progression. Here we show that the embryonic stem cell (ESC) factor Sall4 is re-expressed in the Tyr::NrasQ61K; Cdkn2a-/- melanoma model and that its expression is necessary for primary melanoma formation. Surprisingly, while Sall4 loss prevents tumor formation, it promotes micrometastases to distant organs in this melanoma-prone mouse model. Transcriptional profiling and in vitro assays using human melanoma cells demonstrate that SALL4 loss induces a phenotype switch and the acquisition of an invasive phenotype. We show that SALL4 negatively regulates invasiveness through interaction with the histone deacetylase (HDAC) 2 and direct co-binding to a set of invasiveness genes. Consequently, SALL4 knock down, as well as HDAC inhibition, promote the expression of an invasive signature, while inhibition of histone acetylation partially reverts the invasiveness program induced by SALL4 loss. Thus, SALL4 appears to regulate phenotype switching in melanoma through an HDAC2-mediated mechanism.


Assuntos
Epigênese Genética , Melanoma/genética , Melanoma/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Fator de Células-Tronco/metabolismo , Fatores de Transcrição/metabolismo , Acetilação , Animais , Sequência de Bases , Carcinogênese/genética , Carcinogênese/patologia , Adesão Celular/genética , Linhagem Celular Tumoral , Linhagem da Célula , Proliferação de Células , Proteínas de Ligação a DNA/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Histona Desacetilase 2/metabolismo , Histonas/metabolismo , Humanos , Melanócitos/metabolismo , Melanócitos/patologia , Camundongos Nus , Camundongos Transgênicos , Invasividade Neoplásica , Micrometástase de Neoplasia , Ligação Proteica , Carga Tumoral
5.
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
6.
Int J Mol Sci ; 22(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34360727

RESUMO

Hereditary leiomyomatosis and renal cell carcinoma (HL (RCC)) entails cutaneous and uterine leiomyomatosis with aggressive type 2 papillary RCC-like histology. HLRCC is caused by pathogenic variants in the FH gene, which encodes fumarate hydratase (FH). Here, we describe an episode of young-onset RCC caused by a genomic FH deletion that was diagnosed via clinical sequencing. A 35-year-old woman was diagnosed with RCC and multiple metastases: histopathological analyses supported a diagnosis of FH-deficient RCC. Although the patient had neither skin tumors nor a family history of HLRCC, an aggressive clinical course at her age and pathological diagnosis of FH-deficient RCC suggested a germline FH variant. After counseling, the patient provided written informed consent for germline genetic testing. She was simultaneously subjected to paired tumor profiling tests targeting the exome to identify a therapeutic target. Although conventional germline sequencing did not detect FH variants, exome sequencing revealed a heterozygous germline FH deletion. As such, paired tumor profiling, not conventional sequencing, was required to identify this genetic deletion. RCC caused by a germline FH deletion has hitherto not been described in Japan, and the FH deletion detected in this patient was presumed to be of maternal European origin. Although the genotype-phenotype correlation in HLRCC-related tumors is unclear, the patient's family was advised to undergo genetic counseling to consider additional RCC screening.


Assuntos
Fumarato Hidratase/deficiência , Deleção de Genes , Mutação em Linhagem Germinativa , Leiomiomatose/genética , Erros Inatos do Metabolismo/genética , Hipotonia Muscular/genética , Síndromes Neoplásicas Hereditárias/genética , Transtornos Psicomotores/genética , Neoplasias Cutâneas/genética , Neoplasias Uterinas/genética , Adulto , Feminino , Fumarato Hidratase/genética , Testes Genéticos , Humanos
7.
Artigo em Inglês | MEDLINE | ID: mdl-34360236

RESUMO

BACKGROUND AND AIM: Over the last decades, the incidence of melanoma has been steadily growing, with 4.2% of the population worldwide affected by cutaneous melanoma (CM) in 2020 and with a higher incidence and mortality in men than in women. We investigated both the risk factors for CM development and the prognostic and predictive factors for survival, stratifying for both sex and gender. METHODS: We conducted a systematic review of studies indexed in PUB-MED, EMBASE, and Scopus until 4 February 2021. We included reviews, meta-analyses, and pooled analyses investigating differences between women and men in CM risk factors and in prognostic and predictive factors for CM survival. DATA SYNTHESIS: Twenty-four studies were included, and relevant data extracted. Of these, 13 studies concerned potential risk factors, six concerned predictive factors, and five addressed prognostic factors of melanoma. DISCUSSION: The systematic review revealed no significant differences in genetic predisposition to CM between males and females, while there appear to be several gender disparities regarding CM risk factors, partly attributable to different lifestyles and behavioral habits between men and women. There is currently no clear evidence of whether the mutational landscapes of CM differ by sex/gender. Prognosis is justified by a complex combination of phenotypes and immune functions, while reported differences between genders in predicting the effectiveness of new treatments are inconsistent. Overall, the results emerging from the literature reveal the importance of considering the sex/gender variable in all studies and pave the way for including it towards precision medicine. CONCLUSIONS: Men and women differ genetically, biologically, and by social construct. Our systematic review shows that, although fundamental, the variable sex/gender is not among the ones collected and analyzed.


Assuntos
Melanoma , Neoplasias Cutâneas , Feminino , Humanos , Masculino , Melanoma/epidemiologia , Melanoma/genética , Mutação , Prognóstico , Fatores de Risco , Fatores Sexuais , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/genética
8.
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
9.
Crit Rev Oncol Hematol ; 164: 103425, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34245855

RESUMO

Melanoma is considered the most lethal skin cancer and its incidence has increased during the past decades. About 10 % of cases are classified as hereditary melanoma. Genetic predisposition usually manifests itself clinically as early onset and multiple cutaneous melanomas. Several genes have been identified as involved to melanoma susceptibility, some of them still with unknown clinical relevance. Beyond melanoma, the affected families are also more prone to develop other malignancies, such as pancreatic cancer. The identification of risk families and involved genes is of great importance, since different forms of oncological surveillance are recommended. However, well established guidelines to standardize both the selection of individuals and the genetic panel to be requested are still lacking. Given the importance of the genetic counseling and testing in the context of clinical suspicion of hereditary melanoma, this paper aims to review the literature regarding genetic panel indications worldwide.


Assuntos
Melanoma , Síndromes Neoplásicas Hereditárias , Neoplasias Pancreáticas , Neoplasias Cutâneas , Aconselhamento Genético , Predisposição Genética para Doença , Humanos , Melanoma/diagnóstico , Melanoma/epidemiologia , Melanoma/genética , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/genética
10.
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
11.
Front Immunol ; 12: 622563, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220795

RESUMO

Purpose: To identify CD8+ T cell-related factors and the co-expression network in melanoma and illustrate the interactions among CD8+ T cell-related genes in the melanoma tumor microenvironment. Method: We obtained melanoma and paracancerous tissue mRNA matrices from TCGA-SKCM and GSE65904. The CIBERSORT algorithm was used to assess CD8+ T cell proportions, and the "estimate" package was used to assess melanoma tumor microenvironment purity. Weighted gene co-expression network analysis was used to identify the most related co-expression modules in TCGA-SKCM and GSE65904. Subsequently, a co-expression network was built based on the joint results in the two cohorts. Subsequently, we identified the core genes of the two most relevant modules of CD8+T lymphocytes according to the module correlation, and constructed the signature using ssGSEA. Later, we compared the signature with the existing classical pathways and gene sets, and confirmed the important prognostic significance of the signature in this paper. Results: Nine co-expressed genes were identified as CD8+ T cell-related genes enriched in the cellular response to interferon-gamma process and antigen processing and presentation of peptide antigen. In the low expression level group, inflammation and immune responses were weaker. Single-cell sequencing and immunohistochemistry indicated that these nine genes were highly expressed in CD8+ T cells group. Conclusion: We identified nine-gene signature, and the signature is considered as the biomarker for T lymphocyte response and clinical response to immune checkpoint inhibitors for melanoma.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Melanoma/genética , Neoplasias Cutâneas/genética , Biomarcadores Farmacológicos , Movimento Celular , Conjuntos de Dados como Assunto , Redes Reguladoras de Genes , Humanos , Interferon gama/metabolismo , Ativação Linfocitária , Melanoma/tratamento farmacológico , Prognóstico , Análise de Célula Única , Neoplasias Cutâneas/tratamento farmacológico , Transcriptoma , Microambiente Tumoral
12.
Neurology ; 97(7 Suppl 1): S91-S98, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34230207

RESUMO

OBJECTIVE: Because clinically validated biomarkers for neurofibromatosis 1 (NF1) and neurofibromatosis 2 (NF2) have not been identified, we aimed to determine whether genotype-phenotype correlations are useful in clinical trials in NF1 and NF2. METHODS: The Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) Biomarker Group first performed a systematic literature search and reviewed existing data on genetic biomarkers in NF1 and NF2 and in in malignant peripheral nerve sheath tumors. The group then met during a series of consensus meetings to develop a joint report. RESULTS: We found that in NF2, the genetic severity score is clearly of potential clinical use. In NF1, despite over 3,000 constitutional variants having been described in the NF1 gene, only 4 actionable genotype-phenotype correlations exist. The diagnosis and treatment decision of these tumors should ideally include histopathology and compilation of some of the genetic markers. CONCLUSION: We summarized emerging clinical use of genotype-phenotype correlations in neurofibromatosis.


Assuntos
Estudos de Associação Genética , Neurofibromatoses/diagnóstico , Neurofibromatoses/genética , Biomarcadores/análise , Genes da Neurofibromatose 1/fisiologia , Humanos , Neurilemoma/diagnóstico , Neurilemoma/genética , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/genética , Neurofibromatose 2/diagnóstico , Neurofibromatose 2/genética , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética
13.
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
14.
Int J Mol Sci ; 22(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34298873

RESUMO

Solid tumors are complex systems characterized by dynamic interactions between neoplastic cells, non-tumoral cells, and extracellular components. Among all the stromal cells that populate tumor microenvironment, fibroblasts are the most abundant elements and are critically involved in disease progression. Cancer-associated fibroblasts (CAFs) have pleiotropic functions in tumor growth and extracellular matrix remodeling implicated in local invasion and distant metastasis. CAFs additionally participate in the inflammatory response of the tumor site by releasing a variety of chemokines and cytokines. It is becoming clear that understanding the dynamic, mutual melanoma-fibroblast relationship would enable treatment options to be amplified. To better characterize melanoma-associated fibroblasts, here we analyzed low-passage primary CAFs derived from advanced-stage primary skin melanomas, focusing on the immuno-phenotype. Furthermore, we assessed the expression of several CAF markers and the production of growth factors. To deepen the study of CAF-melanoma cell crosstalk, we employed CAF-derived supernatants and trans-well co-culture systems to evaluate the influences of CAFs on (i) the motogenic ability of melanoma cells, (ii) the chemotherapy-induced cytotoxicity, and (iii) the release of mediators active in modulating tumor growth and spread.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Melanoma/genética , Neoplasias Cutâneas/genética , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Técnicas de Cocultura , Citocinas/genética , Matriz Extracelular/genética , Perfilação da Expressão Gênica/métodos , Humanos , Inflamação/genética , Células Estromais/metabolismo
15.
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
16.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203771

RESUMO

Melanoma develops from malignant transformations of the pigment-producing melanocytes. If located in the basal layer of the skin epidermis, melanoma is referred to as cutaneous, which is more frequent. However, as melanocytes are be found in the eyes, ears, gastrointestinal tract, genitalia, urinary system, and meninges, cases of mucosal melanoma or other types (e.g., ocular) may occur. The incidence and morbidity of cutaneous melanoma (cM) are constantly increasing worldwide. Australia and New Zealand are world leaders in this regard with a morbidity rate of 54/100,000 and a mortality rate of 5.6/100,000 for 2015. The aim of this review is to consolidate and present the data related to the aetiology and pathogenesis of cutaneous melanoma, thus rendering them easier to understand. In this article we will discuss these problems and the possible impacts on treatment for this disease.


Assuntos
Melanoma/etiologia , Neoplasias Cutâneas/etiologia , Animais , Predisposição Genética para Doença , Humanos , Melanoma/genética , Melanoma/patologia , Fatores de Risco , Transdução de Sinais/efeitos da radiação , Pele/patologia , Pele/efeitos da radiação , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia
17.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199609

RESUMO

The acid-sensing ion channels ASIC1 and ASIC2, as well as the transient receptor potential vanilloid channels TRPV1 and TRPV4, are proton-gated cation channels that can be activated by low extracellular pH (pHe), which is a hallmark of the tumor microenvironment in solid tumors. However, the role of these channels in the development of skin tumors is still unclear. In this study, we investigated the expression profiles of ASIC1, ASIC2, TRPV1 and TRPV4 in malignant melanoma (MM), squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and in nevus cell nevi (NCN). We conducted immunohistochemistry using paraffin-embedded tissue samples from patients and found that most skin tumors express ASIC1/2 and TRPV1/4. Striking results were that BCCs are often negative for ASIC2, while nearly all SCCs express this marker. Epidermal MM sometimes seem to lack ASIC1 in contrast to NCN. Dermal portions of MM show strong expression of TRPV1 more frequently than dermal NCN portions. Some NCN show a decreasing ASIC1/2 expression in deeper dermal tumor tissue, while MM seem to not lose ASIC1/2 in deeper dermal portions. ASIC1, ASIC2, TRPV1 and TRPV4 in skin tumors might be involved in tumor progression, thus being potential diagnostic and therapeutic targets.


Assuntos
Canais Iônicos Sensíveis a Ácido/genética , Neoplasias Cutâneas/genética , Canais de Cátion TRPV/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Basocelular/classificação , Carcinoma Basocelular/genética , Carcinoma Basocelular/patologia , Carcinoma de Células Escamosas/classificação , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Melanoma/classificação , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Nevo/classificação , Nevo/genética , Nevo/patologia , Neoplasias Cutâneas/classificação , Neoplasias Cutâneas/patologia
18.
Anticancer Res ; 41(8): 4021-4026, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281868

RESUMO

BACKGROUND/AIM: The G8790A (rs2285666) functional polymorphism of the angiotensin-converting enzyme 2 (ACE2) gene influences alternative mRNA splicing and quantitatively affects the enzyme's production. Specifically, the presence of the A allele has been associated with higher ACE2 plasma levels. In this study, we investigated the possible association of the functional polymorphism ACE2-G8790A with the pathogenesis of basal cell carcinoma (BCC). PATIENTS AND METHODS: A total of 190 DNA samples were studied, including 91 BCC patients and 99 controls of Greek origin. Molecular genotyping for the ACE2 G8790A polymorphism was carried out by PCR amplification, followed by AluI enzyme digestion and agarose gel electrophoresis of the DNA fragments. RESULTS: The allelic and genotypic frequencies presented no statistical difference between the patient and the control group. CONCLUSION: There is no association between the ACE2 G8790A polymorphism and pathogenesis of BCC.


Assuntos
Enzima de Conversão de Angiotensina 2/genética , Carcinoma Basocelular/genética , Neoplasias Cutâneas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Fatores de Risco , Adulto Jovem
19.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201751

RESUMO

Cylindromatosis (CYLD) is a deubiquitinase (DUB) enzyme that was initially characterized as a tumor suppressor of adnexal skin tumors in patients with CYLD syndrome. Later, it was also shown that the expression of functionally inactive mutated forms of CYLD promoted tumor development and progression of non-melanoma skin cancer (NMSC). However, the ability of wild-type CYLD to inhibit skin tumorigenesis in vivo in immunocompetent mice has not been proved. Herein, we generated transgenic mice that express the wild type form of CYLD under the control of the keratin 5 (K5) promoter (K5-CYLDwt mice) and analyzed the skin properties of these transgenic mice by WB and immunohistochemistry, studied the survival and proliferating characteristics of primary keratinocytes, and performed chemical skin carcinogenesis experiments. As a result, we found a reduced activation of the nuclear factor kappa B (NF-κB) pathway in the skin of K5-CYLDwt mice in response to tumor necrosis factor-α (TNF-α); accordingly, when subjected to insults, K5-CYLDwt keratinocytes are prone to apoptosis and are protected from excessive hyperproliferation. Skin carcinogenesis assays showed inhibition of tumor development in K5-CYLDwt mice. As a mechanism of this tumor suppressor activity, we found that a moderate increase in CYLD expression levels reduced NF-κB activation, which favored the differentiation of tumor epidermal cells and inhibited its proliferation; moreover, it decreased tumor angiogenesis and inflammation. Altogether, our results suggest that increased levels of CYLD may be useful for anti-skin cancer therapy.


Assuntos
Carcinoma de Células Escamosas/patologia , Enzima Desubiquitinante CYLD/genética , Neoplasias Cutâneas/patologia , Animais , Carcinoma de Células Escamosas/irrigação sanguínea , Carcinoma de Células Escamosas/genética , Diferenciação Celular/genética , Proliferação de Células/genética , Células Cultivadas , Enzima Desubiquitinante CYLD/metabolismo , Genes Supressores de Tumor , Imunocompetência , Queratinócitos/efeitos dos fármacos , Queratinócitos/patologia , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Transgênicos , NF-kappa B/metabolismo , Neovascularização Patológica/genética , Ésteres de Forbol/toxicidade , Neoplasias Cutâneas/irrigação sanguínea , Neoplasias Cutâneas/genética , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
20.
Br J Dermatol ; 185(1): e4-e33, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34216011

RESUMO

Linked Article: Meyer et al. Br J Dermatol 2021; 185:147-152. Ceramide kinase-like protein (CERKL) was originally described in retinal tissue in the eye. It has been shown to protect cells from oxidative stress, which is a process that kills cells; and mutations (faults) in CERKL cause an inherited disease called retinitis pigmentosa that leads to loss of vision. We set out to investigate CERKL in normal skin and in a type of skin cancer called cutaneous squamous cell carcinoma (cSCC). CERKL levels were low in normal skin but significantly increased in cSCC and also in actinic keratoses (areas of sun-damaged skin that sometimes can develop into skin cancer). Because of their fast metabolism, cancer cells have high levels of oxidative stress. CERKL appears to enable these cSCC cells to survive, because when we inactivated CERKL, the cSCC cells died. In conclusion, these findings suggest that CERKL may be important in disease progression in cSCC. Since CERKL is not expressed in normal skin cells, further investigation of CERKL could lead to novel strategies for prevention and treatment of cSCC.


Assuntos
Carcinoma de Células Escamosas , Retinite Pigmentosa , Neoplasias Cutâneas , Carcinoma de Células Escamosas/genética , Humanos , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Neoplasias Cutâneas/genética
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