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1.
Pigment Cell Melanoma Res ; 36(1): 6-18, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36148789

RESUMO

Melanin is a free-radical scavenger, antioxidant, and broadband absorber of ultraviolet (UV) radiation which protects the skin from environmental carcinogenesis. However, melanin synthesis and UV-induced reactive melanin species are also implicated in melanocyte genotoxicity. Here, we attempted to reconcile these disparate functions of melanin using a UVB-sensitive, NRAS-mutant mouse model, TpN. We crossed TpN mice heterozygous for an inactivating mutation in Tyrosinase to produce albino and black littermates on a C57BL/6J background. These animals were then exposed to a single UVB dose on postnatal day three when keratinocytes in the skin have yet to be melanized. Approximately one-third (35%) of black mice were protected from UVB-accelerated tumor formation. However, melanoma growth rates, tumor mutational burdens, and gene expression profiles were similar in melanomas from black and albino mice. Skin from albino mice contained more cyclobutane pyrimidine dimer (CPD) positive cells than black mice 1-h post-irradiation. However, this trend gradually reversed over time with CPDs becoming more prominent in black than albino melanocytes at 48 h. These results show that in the absence of epidermal pigmentation, melanocytic melanin limits the tumorigenic effects of acute UV exposure but fails to protect melanocytes from UVB-induced mutagenesis.


Assuntos
Melanoma , Neoplasias Cutâneas , Camundongos , Animais , Melaninas/metabolismo , Neoplasias Cutâneas/patologia , Camundongos Endogâmicos C57BL , Melanócitos/metabolismo , Melanoma/patologia , Raios Ultravioleta , Mutagênese
2.
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
3.
Life Sci Alliance ; 4(9)2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34210801

RESUMO

BRAF-mutant melanomas are more likely than NRAS-mutant melanomas to arise in anatomical locations protected from chronic sun damage. We hypothesized that this discrepancy in tumor location is a consequence of the differential sensitivity of BRAF and NRAS-mutant melanocytes to ultraviolet light (UV)-mediated carcinogenesis. We tested this hypothesis by comparing the mutagenic consequences of a single neonatal, ultraviolet-AI (UVA; 340-400 nm) or ultraviolet-B (UVB; 280-390 nm) exposure in mouse models heterozygous for mutant Braf or homozygous for mutant Nras Tumor onset was accelerated by UVB, but not UVA, and the resulting melanomas contained recurrent mutations affecting the RING domain of MAP3K1 and Actin-binding domain of Filamin A. Melanomas from UVB-irradiated, Braf-mutant mice averaged twice as many single-nucleotide variants and five times as many dipyrimidine variants than tumors from similarly irradiated Nras-mutant mice. A mutational signature discovered in UVB-accelerated tumors mirrored COSMIC signatures associated with human skin cancer and was more prominent in Braf- than Nras-mutant murine melanomas. These data show that a single UVB exposure yields a greater burden of mutations in murine tumors driven by oncogenic Braf.


Assuntos
Melanoma/etiologia , Proteínas Monoméricas de Ligação ao GTP/genética , Mutagênese/efeitos da radiação , Mutação/efeitos da radiação , Proteínas Proto-Oncogênicas B-raf/genética , Raios Ultravioleta/efeitos adversos , Animais , Biomarcadores Tumorais , Modelos Animais de Doenças , Suscetibilidade a Doenças , Predisposição Genética para Doença , Melanoma/metabolismo , Melanoma/patologia , Camundongos
4.
Curr Opin Genet Dev ; 66: 41-49, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33422949

RESUMO

The search for somatic cancer driver genes has largely focused on variants altering protein-coding regions of the genome but as this search has plateaued, there has been increasing interest in understanding how the non-coding portion of the genome regulates genes important for carcinogenesis. The increasing number of tumor whole genome sequences has fueled discoveries of recurrent gene regulatory mutations or 'hotspots' and has provided a comprehensive look at structural variants. One recurrent 'hotspot' is the TERT promoter region which exemplifies the variety of non-coding variants that can occur including simple somatic mutations, 'enhancer hijacking', copy number and neutral alterations, and insertion of transposable elements and viral enhancers. Integration of multiple omics datasets and functional assays are imperative for linking variants with functional effects.


Assuntos
Carcinogênese/genética , Elementos de DNA Transponíveis/genética , Neoplasias/genética , Sequências Reguladoras de Ácido Nucleico/genética , Elementos Facilitadores Genéticos/genética , Genoma Humano/genética , Humanos , Mutação/genética , Neoplasias/patologia , Fases de Leitura Aberta/genética , Regiões Promotoras Genéticas/genética , Sequenciamento Completo do Genoma
5.
Nat Commun ; 11(1): 2718, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483191

RESUMO

Genome-wide association studies (GWAS) have identified ~20 melanoma susceptibility loci, most of which are not functionally characterized. Here we report an approach integrating massively-parallel reporter assays (MPRA) with cell-type-specific epigenome and expression quantitative trait loci (eQTL) to identify susceptibility genes/variants from multiple GWAS loci. From 832 high-LD variants, we identify 39 candidate functional variants from 14 loci displaying allelic transcriptional activity, a subset of which corroborates four colocalizing melanocyte cis-eQTL genes. Among these, we further characterize the locus encompassing the HIV-1 restriction gene, MX2 (Chr21q22.3), and validate a functional intronic variant, rs398206. rs398206 mediates the binding of the transcription factor, YY1, to increase MX2 levels, consistent with the cis-eQTL of MX2 in primary human melanocytes. Melanocyte-specific expression of human MX2 in a zebrafish model demonstrates accelerated melanoma formation in a BRAFV600E background. Our integrative approach streamlines GWAS follow-up studies and highlights a pleiotropic function of MX2 in melanoma susceptibility.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Melanoma/genética , Mutação , Proteínas de Resistência a Myxovirus/genética , Polimorfismo de Nucleotídeo Único , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Regulação da Expressão Gênica , Genes Reporter/genética , Células HEK293 , Humanos , Melanócitos/metabolismo , Melanoma/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Locos de Características Quantitativas/genética , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
6.
Pigment Cell Melanoma Res ; 30(5): 477-487, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28544727

RESUMO

To mitigate melanoma risk, sunscreen use is widely advocated; yet, the ability of sunscreens to prevent melanoma remains controversial. Here, we test the tenet that sunscreens limit melanoma risk by blocking ultraviolet radiation (UV)-induced DNA damage using murine models that recapitulate the genetics and spontaneous evolution of human melanoma. We find that a single, non-erythematous dose of UV dramatically accelerates melanoma onset and increases tumor multiplicity in mice carrying an endogenous, melanocyte-specific NRas61R allele. By contrast, transient UV exposure does not alter tumor onset in mice lacking p16INK4a or harboring an NRas12D allele. To block the rapid onset of melanoma cooperatively caused by UV and NRas61R , we employed a variety of aerosol sunscreens. While all sunscreens delayed melanoma formation and blocked UV-induced DNA damage, differences in aerosol output (i.e., amount applied/cm2 ) caused variability in the cancer preventative efficacy of products with identical sunburn protection factor (SPF) ratings.


Assuntos
Carcinogênese/patologia , Carcinogênese/efeitos da radiação , Melanoma/tratamento farmacológico , Melanoma/patologia , Mutação/genética , Neoplasias Cutâneas/tratamento farmacológico , Protetores Solares/uso terapêutico , Raios Ultravioleta , Proteínas ras/genética , Aerossóis , Animais , Códon/genética , Dano ao DNA , Intervalo Livre de Doença , Relação Dose-Resposta à Radiação , Camundongos Endogâmicos C57BL , Neoplasias Cutâneas/patologia , Fator de Proteção Solar
7.
Mol Cancer Ther ; 16(3): 417-427, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28148715

RESUMO

Selinexor, a selective inhibitor of nuclear export (SINE) compound targeting exportin-1, has previously been shown to inhibit melanoma cell growth in vivo We hypothesized that combining selinexor with antibodies that block or disrupt T-cell checkpoint molecule signaling would exert superior antimelanoma activity. In vitro, selinexor increased PDCD1 and CTLA4 gene expression in leukocytes and induced CD274 gene expression in human melanoma cell lines. Mice bearing syngeneic B16F10 melanoma tumors demonstrated a significant reduction in tumor growth rate in response to the combination of selinexor and anti-PD-1 or anti-PD-L1 antibodies (P < 0.05). Similar results were obtained in B16F10-bearing mice treated with selinexor combined with anti-CTLA4 antibody. Immunophenotypic analysis of splenocytes by flow cytometry revealed that selinexor alone or in combination with anti-PD-L1 antibody significantly increased the frequency of both natural killer cells (P ≤ 0.050) and CD4+ T cells with a Th1 phenotype (P ≤ 0.050). Further experiments indicated that the antitumor effect of selinexor in combination with anti-PD-1 therapy persisted under an alternative dosing schedule but was lost when selinexor was administered daily. These data indicate that the efficacy of selinexor against melanoma may be enhanced by disrupting immune checkpoint activity. Mol Cancer Ther; 16(3); 417-27. ©2017 AACRSee related article by Tyler et al., p. 428.


Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Hidrazinas/farmacologia , Carioferinas/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Triazóis/farmacologia , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno CTLA-4/antagonistas & inibidores , Linhagem Celular Tumoral , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Humanos , Imunomodulação/efeitos dos fármacos , Melanoma Experimental , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Linfócitos T/imunologia , Proteína Exportina 1
8.
Mol Cancer Res ; 15(3): 237-249, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28039358

RESUMO

Senescent cells within the tumor microenvironment (TME) adopt a proinflammatory, senescence-associated secretory phenotype (SASP) that promotes cancer initiation, progression, and therapeutic resistance. Here, exposure to palbociclib (PD-0332991), a CDK4/6 inhibitor, induces senescence and a robust SASP in normal fibroblasts. Senescence caused by prolonged CDK4/6 inhibition is DNA damage-independent and associated with Mdm2 downregulation, whereas the SASP elicited by these cells is largely reliant upon NF-κB activation. Based upon these observations, it was hypothesized that the exposure of nontransformed stromal cells to PD-0332991 would promote tumor growth. Ongoing clinical trials of CDK4/6 inhibitors in melanoma prompted a validation of this hypothesis using a suite of genetically defined melanoma cells (i.e., Ras mutant, Braf mutant, and Ras/Braf wild-type). When cultured in the presence of CDK4/6i-induced senescent fibroblasts, melanoma cell lines exhibited genotype-dependent proliferative responses. However, in vivo, PD-0332991-treated fibroblasts enhanced the growth of all melanoma lines tested and promoted the recruitment of Gr-1-positive immune cells. These data indicate that prolonged CDK4/6 inhibitor treatment causes normal fibroblasts to enter senescence and adopt a robust SASP. Such senescent cells suppress the antitumor immune response and promote melanoma growth in immunocompetent, in vivo models.Implications: The ability of prolonged CDK4/6 inhibitor treatment to induce cellular senescence and a robust SASP in primary cells may hinder therapeutic efficacy and promote long-term, gerontogenic consequences that should be considered in clinical trials aiming to treat melanoma and other cancer types. Mol Cancer Res; 15(3); 237-49. ©2016 AACR.


Assuntos
Antineoplásicos/farmacologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Melanoma Experimental/tratamento farmacológico , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Animais , Linhagem Celular Tumoral , Senescência Celular/efeitos dos fármacos , Humanos , Melanoma Experimental/enzimologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Células Estromais/efeitos dos fármacos , Células Estromais/enzimologia , Células Estromais/patologia , Microambiente Tumoral
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