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1.
J Transl Med ; 19(1): 381, 2021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34496872

RESUMO

BACKGROUND: Tumor-derived exosomes (TEXs) are involved in tumor progression and the immune modulation process and mediate intercellular communication in the tumor microenvironment. Although exosomes are considered promising liquid biomarkers for disease diagnosis, it is difficult to discriminate TEXs and to develop TEX-based predictive biomarkers. METHODS: In this study, the gene expression profiles and clinical information were collected from The Cancer Genome Atlas (TCGA) database, IMvigor210 cohorts, and six independent Gene Expression Omnibus datasets. A TEXs-associated signature named TEXscore was established to predict overall survival in multiple cancer types and in patients undergoing immune checkpoint blockade therapies. RESULTS: Based on exosome-associated genes, we first constructed a tumor-derived exosome signature named TEXscore using a principal component analysis algorithm. In single-cell RNA-sequencing data analysis, ascending TEXscore was associated with disease progression and poor clinical outcomes. In the TCGA Pan-Cancer cohort, TEXscore was elevated in tumor samples rather than in normal tissues, thereby serving as a reliable biomarker to distinguish cancer from non-cancer sources. Moreover, high TEXscore was associated with shorter overall survival across 12 cancer types. TEXscore showed great potential in predicting immunotherapy response in melanoma, urothelial cancer, and renal cancer. The immunosuppressive microenvironment characterized by macrophages, cancer-associated fibroblasts, and myeloid-derived suppressor cells was associated with high TEXscore in the TCGA and immunotherapy cohorts. Besides, TEXscore-associated miRNAs and gene mutations were also identified. Further experimental research will facilitate the extending of TEXscore in tumor-associated exosomes. CONCLUSIONS: TEXscore capturing tumor-derived exosome features might be a robust biomarker for prognosis and treatment responses in independent cohorts.


Assuntos
Exossomos , Melanoma , Biomarcadores Tumorais/genética , Humanos , Imunoterapia , Melanoma/genética , Melanoma/terapia , Prognóstico , Análise de Célula Única , Microambiente Tumoral
2.
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
3.
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
4.
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
5.
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
6.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445551

RESUMO

Cancer-specific isoenzyme of phosphofructokinase II (PFKFB4), as our previous research has shown, may be one of the most important enzymes contributing to the intensification of glycolysis in hypoxic malignant melanoma cells. Although the PFKFB4 gene seems to play a crucial role in the progression of melanoma, so far there are no complete data on the expression of PFKFB4 at the isoform level and the influence of hypoxia on alternative splicing. Using RT-qPCR and semi-quantitative RT-PCR, we presented the PFKFB4 gene expression profile at the level of six isoforms described in the OMIM NCBI database in normoxic and hypoxic melanoma cells. Additionally, using VMD software, we analyzed the structure of isoforms at the protein level, concluding about the catalytic activity of individual isoforms. Our research has shown that five isoforms of PFKFB4 are expressed in melanoma cells, of which the D and F isoforms are highly constitutive, while the canonical B isoform seems to be the main isoform induced in hypoxia. Our results also indicate that the expression profile at the level of the PFKFB4 gene does not reflect the expression at the level of individual isoforms. Our work clearly indicates that the PFKFB4 gene expression profile should be definitely analyzed at the level of individual isoforms. Moreover, the analysis at the protein level allowed the selection of those isoforms whose functional validation should be performed to fully understand the importance of PFKFB4 expression in the metabolic adaptation of malignant melanoma cells.


Assuntos
Processamento Alternativo , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Hipóxia/fisiopatologia , Melanoma/patologia , Oxigênio/metabolismo , Fosfofrutoquinase-2/genética , Biomarcadores Tumorais/genética , Glicólise , Humanos , Melanoma/genética , Melanoma/metabolismo , Células Tumorais Cultivadas
7.
J Transl Med ; 19(1): 371, 2021 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-34454518

RESUMO

BACKGROUND: Immune cells in the tumor microenvironment have prognostic value. In preclinical models, recruitment and infiltration of these cells depends on immune cell homing (ICH) genes such as chemokines, cell adhesion molecules, and integrins. We hypothesized ICH ligands CXCL9-11 and CCL2-5 would be associated with intratumoral T-cells, while CXCL13 would be more associated with B-cell infiltrates. METHODS: Samples of human melanoma were submitted for gene expression analysis and immune cells identified by immunohistochemistry. Associations between the two were evaluated with unsupervised hierarchical clustering using correlation matrices from Spearman rank tests. Univariate analysis performed Mann-Whitney tests. RESULTS: For 119 melanoma specimens, analysis of 78 ICH genes revealed association among genes with nonspecific increase of multiple immune cell subsets: CD45+, CD8+ and CD4+ T-cells, CD20+ B-cells, CD138+ plasma cells, and CD56+ NK-cells. ICH genes most associated with these infiltrates included ITGB2, ITGAL, CCL19, CXCL13, plus receptor/ligand pairs CXCL9 and CXCL10 with CXCR3; CCL4 and CCL5 with CCR5. This top ICH gene expression signature was also associated with genes representing immune-activation and effector function. In contrast, CD163+ M2-macrophages was weakly associated with a different ICH gene signature. CONCLUSION: These data do not support our hypothesis that each immune cell subset is uniquely associated with specific ICH genes. Instead, a larger set of ICH genes identifies melanomas with concordant infiltration of B-cell and T-cell lineages, while CD163+ M2-macrophage infiltration suggesting alternate mechanisms for their recruitment. Future studies should explore the extent ICH gene signature contributes to tertiary lymphoid structures or cross-talk between homing pathways.


Assuntos
Antígenos CD , Melanoma , Antígenos CD/genética , Antígenos de Diferenciação Mielomonocítica , Humanos , Subpopulações de Linfócitos , Macrófagos , Melanoma/genética , Receptores de Superfície Celular , Microambiente Tumoral
8.
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
9.
Klin Monbl Augenheilkd ; 238(7): 773-780, 2021 Jul.
Artigo em Inglês, Alemão | MEDLINE | ID: mdl-34376007

RESUMO

Over the last ten years, much has been learnt about the genetic characteristics and genetic evolution of uveal melanoma. It has been shown that uveal melanoma differs fundamentally from non-uveal melanoma and is an independent genetic subtype. Compared to other tumours, uveal melanoma has a low mutational burden. There are recurring chromosomal aberrations with losses of 1p, 6q, 8p and 16q, gains of 6p and 8q, and the presence of monosomy 3. GNAQ, GNA11, PLCB4, CYSLTR2, MAPKAPK5, as well as mutations in BAP1, SF3B1, SRSF2 and EIF1AX, the latter being linked to a higher risk of metastasis, have been identified as significantly mutated genes. In rare cases, a BAP1 germline mutation may also be present. In addition to higher risk of uveal melanoma, this variant is also linked with other tumours. In this case, additional work-up, genetic counselling and screening of family members should be offered. While the knowledge about the genetic characteristics of uveal melanoma is already routinely used for diagnostic and prognostic purposes, targeted genotype-dependent therapy of uveal melanoma is currently still missing.


Assuntos
Melanoma , Ubiquitina Tiolesterase , Neoplasias Uveais , Análise Mutacional de DNA , Humanos , Melanoma/diagnóstico , Melanoma/genética , Mutação , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Neoplasias Uveais/diagnóstico , Neoplasias Uveais/genética
10.
J Transl Med ; 19(1): 330, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34344410

RESUMO

BACKGROUND: Tumor microenvironment (TME) is associated with tumor progression and prognosis. Previous studies provided tools to estimate immune and stromal cell infiltration in TME. However, there is still a lack of single index to reflect both immune and stromal status associated with prognosis and immunotherapy responses. METHODS: A novel immune and stromal scoring system named ISTMEscore was developed. A total of 15 datasets were used to train and validate this system, containing 2965 samples from lung adenocarcinoma, skin cutaneous melanoma and head and neck squamous cell carcinoma. RESULTS: The patients with high immune and low stromal scores (HL) were associated with low ratio of T cell co-inhibitory/stimulatory molecules and low levels of angiogenesis markers, while the patients with low immune and high stromal scores (LH) had the opposite characteristics. The HL patients had immune-centered networks, while the patients with low immune and low stromal scores (LL) had desert-like networks. Moreover, copy number alteration burden was decreased in the HL patients. For the clinical characteristics, our TME classification was an independent prognostic factor. In the 5 cohorts with immunotherapy, the LH patients were linked to the lowest response rate. CONCLUSIONS: ISTMEscore system could reflect the TME status and predict the prognosis. Compared to previous TME scores, our ISTMEscore was superior in the prediction of prognosis and immunotherapy response.


Assuntos
Neoplasias de Cabeça e Pescoço , Neoplasias Pulmonares , Melanoma , Neoplasias Cutâneas , Biomarcadores Tumorais , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Melanoma/genética , Prognóstico , Microambiente Tumoral
11.
Mol Biol (Mosk) ; 55(4): 667-675, 2021.
Artigo em Russo | MEDLINE | ID: mdl-34432784

RESUMO

MicroRNAs epigenetically regulate physiological and pathological processes. Previously, we found that miR-204-5p is expressed at low levels in melanoma cells, and an increase in its level leads to a change in proliferation, migration, and invasion of these cancer cells. Now, using bioinformatics analysis, it has been shown that the target of miR-204-5p is FOXC1 transcription factor, which is implicated in carcinogenesis. Using the luciferase reporter assay, it was found that miR-204-5p suppresses expression of the FOXC1 gene by binding to its 3' non-coding region. Transfection of small interfering RNA (siRNA) targeting FOXC1 into melanoma cells caused a decrease in miR-204-5p levels, which is consistent with the generally accepted concept of feedback regulation of miRNA expression by target genes. According to the results of the MTT test and fluorescence microscopy, the proliferation level of melanoma cells under the influence of siRNA to FOXC1 decreased 72 h after transfection. Changes in the ratio of cells by cell cycle phase were analyzed using flow cytometry. Regulatory relationships between FOXC1 and miR-204-5p, and an inhibitory effect of FOXC1 knockdown on melanoma cell proliferation were revealed. Based on the results, it can be assumed that miR-204-5p regulates proliferation of melanoma cells by affecting FOXC1 expression.


Assuntos
Melanoma , MicroRNAs , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Fatores de Transcrição Forkhead , Humanos , Melanoma/genética , MicroRNAs/genética
12.
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
13.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299025

RESUMO

Several studies have demonstrated that melanoma-derived extracellular vesicles (EVs) are involved in lymph node metastasis; however, the molecular mechanisms involved are not completely defined. Here, we found that EMILIN-1 is proteolyzed and secreted in small EVs (sEVs) as a novel mechanism to reduce its intracellular levels favoring metastasis in mouse melanoma lymph node metastatic cells. Interestingly, we observed that EMILIN-1 has intrinsic tumor and metastasis suppressive-like properties reducing effective migration, cell viability, primary tumor growth, and metastasis. Overall, our analysis suggests that the inactivation of EMILIN-1 by proteolysis and secretion in sEVs reduce its intrinsic tumor suppressive activities in melanoma favoring tumor progression and metastasis.


Assuntos
Movimento Celular/genética , Proliferação de Células/genética , Vesículas Extracelulares/metabolismo , Melanoma/metabolismo , Glicoproteínas de Membrana/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Biologia Computacional , Metástase Linfática/genética , Masculino , Espectrometria de Massas , Melanoma/genética , Melanoma/patologia , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteólise , RNA-Seq , Reação em Cadeia da Polimerase em Tempo Real , Estatísticas não Paramétricas , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Genes (Basel) ; 12(6)2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200642

RESUMO

FENDRR (Fetal-lethal non-coding developmental regulatory RNA, LncRNA FOXF1-AS1) is a recently identified tumor suppressor long non-coding (LncRNA) RNA, and its expression has been linked with epigenetic modulation of the target genes involved in tumor immunity. In this study, we aimed to understand the role of FENDRR in predicting immune-responsiveness and the inflammatory tumor environment. Briefly, FENDRR expression and its relationship to immune activation signals were assessed in murine cell lines. Data suggested that tumor cells (e.g., C26 colon, 4T1 breast) that typically upregulate immune activation genes and the MHC class I molecule exhibited high FENDRR expression levels. Conversely, tumor cells with a generalized downregulation of immune-related gene expression (e.g., B16F10 melanoma) demonstrated low to undetectable FENDRR levels. Mechanistically, the modulation of FENDRR expression enhanced the inflammatory and WNT signaling pathways in tumors. Our early data suggest that FENDRR can play an important role in the development of immune-relevant phenotypes in tumors, and thereby improve cancer immunotherapy.


Assuntos
Neoplasias do Colo/genética , Melanoma/genética , RNA Longo não Codificante/genética , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Linhagem Celular Tumoral , Neoplasias do Colo/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Melanoma/imunologia , Camundongos , Camundongos Endogâmicos C57BL , RNA Longo não Codificante/metabolismo , Via de Sinalização Wnt
15.
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
16.
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
17.
J Transl Med ; 19(1): 296, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34238310

RESUMO

BACKGROUND: Immunotherapy is a revolutionary strategy in cancer therapy, but the resistance of which is one of the important challenges. Detecting the regulation of immune cells and biomarkers concerning immune checkpoint blockade (ICB) therapy is of great significance. METHODS: Here, we firstly constructed regulation networks for 11 immune cell clusters by integrating biological pathway data and single cell sequencing data in metastatic melanoma with or without ICB therapy. We then dissected these regulation networks and identified differently expressed genes between responders and non-responders. Finally, we trained and validated a logistic regression model based on ligands and receptors in the regulation network to predict ICB therapy response. RESULTS: We discovered the regulation of genes across eleven immune cell stats. Functional analysis indicated that these stat-specific networks consensually enriched in immune response corrected pathways and highlighted antigen processing and presentation as a core pathway in immune cell regulation. Furthermore, some famous ligands like SIRPA, ITGAM, CD247and receptors like CD14, IL2 and HLA-G were differently expressed between cells of responders and non-responders. A predictive model of gene sets containing ligands and receptors performed accuracy prediction with AUCs above 0.7 in a validation dataset suggesting that they may be server as biomarkers for predicting immunotherapy response. CONCLUSIONS: In summary, our study presented the gene-gene regulation landscape across 11 immune cell clusters and analysis of these networks revealed several important aspects and immunotherapy response biomarkers, which may provide novel insights into immune related mechanisms and immunotherapy response prediction.


Assuntos
Biomarcadores Tumorais , Melanoma , Biomarcadores Tumorais/genética , Humanos , Imunoterapia , Melanoma/genética , Melanoma/terapia
18.
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
19.
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
20.
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
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