Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.840
Filtrar
1.
J Cancer Res Clin Oncol ; 145(9): 2241-2250, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31342168

RESUMO

PURPOSE: The tripartite motif (TRIM)16 acts as a tumour suppressor in both squamous cell carcinoma (SCC) and melanoma. TRIM16 is known to be secreted by keratinocytes, but no studies have been reported yet to assess the relationship between TRIM16 keratinocyte expression and melanoma development. METHODS: To study the role of TRIM16 in skin cancer development, we developed a keratinocyte TRIM16-specific knockout mouse model, and used the classical two-stage skin carcinogenesis challenge method, to assess the loss of keratinocyte TRIM16 on both papilloma, SCC and melanoma development in the skin after topical carcinogen treatment. RESULTS: Heterozygous, but not homozygous, TRIM16 knockout mice exhibited an accelerated development of skin papillomas and melanomas, larger melanoma lesions and an increased potential for lymph node metastasis. CONCLUSION: This study provides the first evidence that keratinocyte loss of the putative melanoma tumour suppressor protein, TRIM16, enhances melanomagenesis. Our data also suggest that TRIM16 expression in keratinocytes is involved in cross talk between keratinocytes and melanocytes, and has a role in melanoma tumorigenesis.


Assuntos
Proteínas de Transporte/genética , Queratinócitos/metabolismo , Perda de Heterozigosidade/fisiologia , Linfonodos/metabolismo , Melanócitos/metabolismo , Melanoma/genética , Neoplasias Cutâneas/genética , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Proteínas de Transporte/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Células Cultivadas , Regulação Neoplásica da Expressão Gênica , Queratinócitos/patologia , Linfonodos/patologia , Metástase Linfática , Melanócitos/patologia , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Camundongos Knockout , Pele/metabolismo , Pele/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
3.
Graefes Arch Clin Exp Ophthalmol ; 257(8): 1783-1788, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31098751

RESUMO

PURPOSE: In primary conjunctival melanoma (CoM), one of the characteristics that is associated with an increased risk of metastases and death is a lack of tumour pigmentation. The aim of this study was to investigate whether the degree of pigmentation of CoM recurrences relates similarly to clinical outcome. METHODS: A data set of 177 patients with a CoM recurrence from the Wills Eye Hospital (USA) and the Leiden University Medical Center (The Netherlands) was analysed. The relation between clinical tumour pigmentation of the recurrences, the characteristics of the primary lesions and clinical outcome was investigated. RESULTS: In 117 (66%) of 177 patients with a CoM recurrence, tumour pigmentation was known: 71 patients (61%) had recurrences with low pigmentation. Primary lesions had low pigmentation in 39% of cases, which is significantly different (p = 0.001). However, low tumour pigmentation of recurrences correlated with low tumour pigmentation of the primary lesion (p < 0.001). No association was observed between pigmentation of the recurrences and iris colour (p = 0.66). Low pigmentation of the recurrences was not significantly associated with an increased risk for metastases (HR 1.96, p = 0.12) or death (HR 1.79, p = 0.27), whereas primary tumours with low pigmentation did show a greater risk for metastases (HR 2.82, p = 0.016) and death (HR 2.90, p = 0.037). CONCLUSIONS: CoM recurrences are more often lightly pigmented compared to primary lesions. A correlation exists between the degree of pigmentation of primary and recurrent lesions, but recurrences can appear with any degree of pigmentation. Unlike primary CoM, the level of pigmentation of CoM recurrences is not related to metastasis or death.


Assuntos
Túnica Conjuntiva/patologia , Neoplasias da Túnica Conjuntiva/diagnóstico , Melanócitos/patologia , Melanoma/diagnóstico , Recidiva Local de Neoplasia/diagnóstico , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pigmentação , Prognóstico , Fatores de Risco
4.
Anticancer Res ; 39(5): 2447-2451, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31092438

RESUMO

BACKGROUND/AIM: The insulin-like growth factor 1 (IGF1) signaling pathway as an aging mechanism related to p53 in human melanogenesis remains unclear. The aim of this study was to investigate the relationship between p53 and IGF1 signaling pathway in young, senescent and H2O2-treated cells. MATERIALS AND METHODS: The protein and gene expression in young, senescent and H2O2-treated cells were analyzed using western blot and reverse transcription polymerase chain reaction (RT-PCR) assays, respectively. RESULTS: The expression levels of (phosphoinositide 3-kinases) PI3K, v-akt murine thymoma viral oncogene homolog 1 (AKT1), mammalian target of rapamycin, ß-catenin (CTNNB1), acetylated p53 (ac-p53), p53 and p-p21 proteins, related to IGF1 and p53 signaling pathways, were higher in senescent and H2O2-treated cells than those of young cells. Furthermore, AKT reduced melanogenesis through microphthalmia-associated transcription factor (MITF) inactivation by the inhibition of CTNNB1. The gene expression levels of PI3K, TP53 and catalase (CAT) in senescent and H2O2-treated cells were increased compared to young cells. CONCLUSION: p53 protein plays a key role in the aging of melanocytes via IGF1 signaling pathways.


Assuntos
Envelhecimento/genética , Proliferação de Células/genética , Fator de Crescimento Insulin-Like I/genética , Proteína Supressora de Tumor p53/genética , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Catalase/genética , Proliferação de Células/efeitos dos fármacos , Senescência Celular/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/toxicidade , Melanócitos/metabolismo , Melanócitos/patologia , Camundongos , Fator de Transcrição Associado à Microftalmia/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos , beta Catenina/antagonistas & inibidores , beta Catenina/genética
6.
Science ; 364(6437): 283-285, 2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-31000662

RESUMO

Malignancies arising from mutation of tumor suppressors have unexplained tissue proclivity. For example, BAP1 encodes a widely expressed deubiquitinase for histone H2A, but germline mutations are predominantly associated with uveal melanomas and mesotheliomas. We show that BAP1 inactivation causes apoptosis in mouse embryonic stem cells, fibroblasts, liver, and pancreatic tissue but not in melanocytes and mesothelial cells. Ubiquitin ligase RNF2, which silences genes by monoubiquitinating H2A, promoted apoptosis in BAP1-deficient cells by suppressing expression of the prosurvival genes Bcl2 and Mcl1. In contrast, BAP1 loss in melanocytes had little impact on expression of prosurvival genes, instead inducing Mitf Thus, BAP1 appears to modulate gene expression by countering H2A ubiquitination, but its loss only promotes tumorigenesis in cells that do not engage an RNF2-dependent apoptotic program.


Assuntos
Apoptose/genética , Carcinogênese/genética , Regulação Neoplásica da Expressão Gênica , Melanoma/genética , Complexo Repressor Polycomb 1/metabolismo , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Ubiquitina-Proteína Ligases/metabolismo , Neoplasias Uveais/genética , Animais , Técnicas de Introdução de Genes , Mutação em Linhagem Germinativa , Histonas , Humanos , Melanócitos/metabolismo , Melanócitos/patologia , Melanoma/patologia , Mesotelioma/genética , Mesotelioma/patologia , Camundongos , Camundongos Mutantes , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ubiquitinação , Neoplasias Uveais/patologia
7.
Rev. bras. cir. plást ; 34(1): 151-155, jan.-mar. 2019. ilus
Artigo em Inglês, Português | LILACS | ID: biblio-994623

RESUMO

O lentigo maligno (LM) é uma forma de melanoma in situ que mais comumente se apresenta como uma mácula de crescimento lentamente progressivo, pigmentada, na face de idosos com pele danificada pelo sol. Esse melanoma in situ tem um risco (30% a 50%) de progressão para lentigo maligno melanoma. A excisão cirúrgica completa da lesão requer margens de pelo menos 10mm, mesmo para lesões in situ. Porém, quando o crescimento de LM ocorre em áreas de implicações estéticas ou funcionais (face, pescoço, solas), a excisão é frequentemente reduzida para preservar estruturas anatômicas importantes e por razões cosméticas. Além disso, as margens periféricas podem ser clinicamente mal definidas e nem sempre pigmentadas, com extensão subestimada e risco de ressecção insuficiente. A "técnica de espaguete", descrita por Gaudy Marqueste, é uma cirurgia estratégica baseada na amostragem de uma faixa de tecido "spaghettilike" para determinar as margens da lesão antes da remoção do tumor. Após a confirmação anatomopatológica de margens livres de neoplasia, a lesão principal central é ressecada, permitindo a reconstrução do defeito no mesmo procedimento, sendo uma alternativa à cirurgia micrográfica de Mohs.(AU)


Lentigo maligna (LM) is a melanoma in situ that commonly presents as a macula with progressive and irregularly pigmented growth, especially in the face of elderly people with sun-damaged skin. This melanoma in situ has a risk (30-50%) of progression to lentigo maligna melanoma. Complete surgical excision of the lesion requires margins of at least 10 mm, even for lesions in situ. However, when the growth of LM occurs in areas of aesthetic or functional implications (face, neck, and soles), the excision is often reduced to preserve important anatomic structures and for cosmetic purposes. Moreover, the peripheral margins may be clinically ill-defined and not always pigmented, and thus, such cases are associated with underestimated extension and risk of insufficient resection. The "spaghetti" technique, described by Gaudy Marqueste, is a strategic surgical approach based on sampling of a range of "spaghetti-like" strips to determine the margins of the lesion prior to removal of the tumor. After the pathological confirmation of neoplasia-free margins, the main central lesion is resected, allowing reconstruction of the defect in the same procedure, as an alternative to Mohs micrographic surgery. (AU)


Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Cutâneas , Sarda Melanótica de Hutchinson/fisiopatologia , Procedimentos Cirúrgicos Reconstrutivos/métodos , Procedimentos Cirúrgicos Nasais/métodos , Melanócitos/patologia , Melanoma/complicações , Melanoma/diagnóstico , Procedimentos Cirúrgicos Reconstrutivos/métodos , Melanoma/cirurgia
8.
Int J Mol Sci ; 20(4)2019 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-30813264

RESUMO

Melanin is produced in melanocytes and stored in melanosomes, after which it is transferred to keratinocytes and, thus, determines skin color. Despite its beneficial sun-protective effects, abnormal accumulation of melanin results in esthetic problems. A range of topical hypopigmenting agents have been evaluated for their use in the treatment of pigmentary disorders with varying degrees of success. Hydroquinone (HQ), which competes with tyrosine, is the main ingredient in topical pharmacological agents. However, frequent occurrence of adverse reactions is an important factor that limits its use. Thus, efforts to discover effective topical hypopigmenting agents with less adverse effects continue. Here, we describe the potential of resveratrol to function as an effective hypopigmenting agent based on its mechanism of action. Resveratrol is not only a direct tyrosinase inhibitor but an indirect inhibitor as well. Additionally, it can affect keratinocytes, which regulate the function of melanocytes. Resveratrol regulates the inflammatory process of keratinocytes and protects them from oxidative damage. In this way, it prevents keratinocyte-induced melanocyte stimulation. Furthermore, it has a rescuing effect on the stemness of interfollicular epidermal cells that can repair signs of photoaging in the melasma, a typical pigmentary skin disorder. Overall, resveratrol is a promising potent hypopigmenting agent.


Assuntos
Hipopigmentação/tratamento farmacológico , Resveratrol/administração & dosagem , Resveratrol/uso terapêutico , Administração Tópica , Animais , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/patologia , Melanócitos/efeitos dos fármacos , Melanócitos/patologia , Melanoma/tratamento farmacológico , Melanoma/patologia , Resveratrol/farmacologia
9.
Int J Mol Sci ; 20(5)2019 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-30870978

RESUMO

Melanoma-derived small extracellular vesicles (sEVs) participate in tumor pathogenesis. Tumor pathogenesis is highly dependent on inflammatory processes. Given the potential for melanoma sEVs to carry tumor biomarkers, we explored the hypothesis that they may contain inflammation-related mRNA content. Biophysical characterization showed that human primary melanocyte-derived sEVs trended toward being smaller and having less negative (more neutral) zeta potential than human melanoma sEVs (A-375, SKMEL-28, and C-32). Using primary melanocyte sEVs as the control population, RT-qPCR array results demonstrated similarities and differences in gene expression between melanoma sEV types. Upregulation of pro-angiogenic chemokine ligand CXCL1, CXCL2, and CXCL8 mRNAs in A-375 and SKMEL-28 melanoma sEVs was the most consistent finding. This paralleled increased production of CXCL1, CXCL2, and CXCL8 proteins by A-375 and SKMEL-28 sEV source cells. Overall, the use of primary melanocyte sEVs as a control sEV reference population facilitated the detection of inflammation-related melanoma sEV mRNA content.


Assuntos
Vesículas Extracelulares/genética , Inflamação/genética , Melanócitos/patologia , Melanoma/genética , RNA Mensageiro/genética , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Quimiocinas CXC/genética , Humanos , Regulação para Cima/genética
10.
J Cutan Pathol ; 46(6): 442-446, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30785652

RESUMO

Matrical carcinoma with melanocytic hyperplasia (MCMH), previously referred to as malignant melanocytic matricoma, is a rare variant of the uncommon pilomatrical carcinoma, occurring most often on the head/neck and upper backs of middle-aged men. Nodular lesions may resemble pigmented basal cell carcinoma or melanoma clinically. We present a case of MCMH in a Hispanic patient with history of melanoma. Histopathological clues to appropriate diagnosis include basaloid cells, numerous atypical mitotic figures, matrical differentiation, shadow cells, strong diffuse nuclear and cytoplasmic expression of ß-catenin, and interspersed pigmented dendritic melanocytes.


Assuntos
Carcinoma Basocelular , Carcinoma de Apêndice Cutâneo , Doenças do Cabelo , Melanócitos , Melanoma , Neoplasias Cutâneas , Idoso de 80 Anos ou mais , Carcinoma Basocelular/diagnóstico , Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/patologia , Carcinoma de Apêndice Cutâneo/diagnóstico , Carcinoma de Apêndice Cutâneo/metabolismo , Carcinoma de Apêndice Cutâneo/patologia , Diagnóstico Diferencial , Doenças do Cabelo/diagnóstico por imagem , Doenças do Cabelo/metabolismo , Doenças do Cabelo/patologia , Humanos , Masculino , Melanócitos/metabolismo , Melanócitos/patologia , Melanoma/diagnóstico , Melanoma/metabolismo , Melanoma/patologia , México , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
11.
J Cutan Pathol ; 46(5): 383-388, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30719746

RESUMO

A 36-year-old man presented with a subcutaneous nodule on the right upper arm. A small nodule had developed 8 years earlier, and grew in size, accompanied by a tingling sensation and numbness. In addition, he had a bluish irregular patch on the right hand since birth, which crossed from the palm to the dorsal hand. Skin biopsies from the hand showed a heavily pigmented melanocyte proliferation in the dermis with perieccrine, perivascular, and perineural involvement, and a diagnosis of congenital plaque-type blue nevus was made. The tumor on the arm was located closely along the median nerve, and was observed as a large black pedunculated round tumor. Histopathologically, the tumor on the arm consisted of densely packed tissue with nevoid cells without atypia in the larger nodular part, and heavily pigmented spindle and epithelioid melanocytes in the slender stalk area, which was diagnosed as cellular blue nevus with pigmented epithelioid melanocytoma-like pattern. Next-generation sequencing revealed GNAQ mutations in the hand lesion, and in the lesions on the arm. This case suggests that the areas of skin following the same neural distribution of a congenital plaque-type blue nevus on the extremities should be followed up for secondary changes.


Assuntos
Melanócitos , Nevo Azul , Neoplasias Cutâneas , Adulto , Braço/patologia , Humanos , Masculino , Melanócitos/metabolismo , Melanócitos/patologia , Nevo Azul/metabolismo , Nevo Azul/patologia , Pele/metabolismo , Pele/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
12.
Arch Dermatol Res ; 311(3): 183-191, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30778667

RESUMO

Little is known about the anti-pigmenting effects of whitening agents on solar lentigos (SLs), which comprise ~ 60% of hyperpigmented facial lesions of Asian subjects. Lotions with or without 6% L-ascorbate-2-phosphate trisodium salt (APS) [test lotion (TL) and placebo lotion (PL), respectively] were applied twice daily for 24 weeks in a double-blind half-face study of 27 Japanese females with SLs on both sides of their faces. Pigmentation scores were evaluated using a photo-scale and the skin colors were assessed using a color difference meter and a mexameter for SLs and the non-lesional surrounding skin (NLS). Although the pigmentation scores were not significantly different between the TL and PL-treated SLs after 24 weeks, the L values of TL-treated SLs and NLS increased significantly with a significantly higher △L value in SLs than in NLS. In contrast, the L values of PL-treated SLs and NLS remained unchanged after the treatment. The number of subjects with > 2.0 △L was 7 of 27 (TL) and 0 of 27 (PL) in SLs and 3 of 27 (TL) and 0 of 27 (PS) in NLS. In contrast, the melanin index in TL-treated SLs and NLS significantly decreased with a significantly higher △melanin index in SLs than in NLS. Similarly, the melanin index of PL-treated SLs and NLS were significantly decreased with a significantly higher △melanin index in SLs than in NLS. These findings strongly indicate that APS has a weak but significant anti-pigmenting effect on SLs and a significant whitening effect even on normally pigmented healthy skin.


Assuntos
Ácido Ascórbico/análogos & derivados , Lentigo/tratamento farmacológico , Melaninas/metabolismo , Melanócitos/efeitos dos fármacos , Preparações Clareadoras de Pele/administração & dosagem , Pigmentação da Pele/efeitos dos fármacos , Administração Cutânea , Ácido Ascórbico/administração & dosagem , Ácido Ascórbico/efeitos adversos , Grupo com Ancestrais do Continente Asiático , Método Duplo-Cego , Feminino , Humanos , Japão , Lentigo/diagnóstico , Lentigo/etnologia , Lentigo/metabolismo , Melanócitos/metabolismo , Melanócitos/patologia , Preparações Clareadoras de Pele/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
13.
Am J Dermatopathol ; 41(3): 167-179, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30801340

RESUMO

The presence of multiple BAP1-negative melanocytic neoplasms is a hallmark of familial cancer susceptibility syndrome caused by germline mutations in BAP1. Melanocytic tumors lacking BAP1 expression may also present as sporadic lesions in patients lacking a germline BAP1 mutation. Here, we report histomorphologic and clinical characteristics of cutaneous melanomas with loss of BAP1 expression in 4 patients with no known history of BAP1-associated cancer susceptibility syndrome. The lesions were nodular melanomas composed predominantly of intradermal large epithelioid (Spitzoid) melanocytes with nuclear pseudoinclusions as well as scattered multinucleated cells, arising in association with a typical intradermal nevus. Of the 4 patients, only 1 had recurrence. This patient had multiple recurrences with in-transit and regional lymph node metastases. To the best of our knowledge, this is the first reported series of cutaneous melanomas with loss of BAP1 expression arising in patients without a family history of cancer.


Assuntos
Biomarcadores Tumorais/análise , Melanoma/enzimologia , Neoplasias Cutâneas/enzimologia , Proteínas Supressoras de Tumor/análise , Ubiquitina Tiolesterase/análise , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Metástase Linfática , Masculino , Melanócitos/patologia , Melanoma/genética , Melanoma/secundário , Melanoma/cirurgia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia , Resultado do Tratamento , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética
14.
Mol Cells ; 42(2): 151-160, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30703869

RESUMO

Ultraviolet (UV) radiation of the sunlight, especially UVA and UVB, is the primary environmental cause of skin damage, including topical inflammation, premature skin aging, and skin cancer. Previous reports show that activation of nuclear factor-κB (NF-κB) in human skin fibroblasts and keratinocytes after UV exposure induces the expression and release of proinflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α), and subsequently leads to the production of matrix metalloproteases (MMPs) and growth factor basic fibroblast growth factor (bFGF). Here, we demonstrated that TNFR2-SKEE and TNFR2-SKE, oligopeptides from TNF receptor-associated factor 2 (TRAF2)-binding site of TNF receptor 2 (TNFR2), strongly inhibited the interaction of TNFR1 as well as TNFR2 with TRAF2. In particular, TNFR2-SKE suppressed UVB- or TNF-α-induced nuclear translocalization of activated NF-κB in mouse fibroblasts. It decreased the expression of bFGF, MMPs, and COX2, which were upregulated by TNF-α, and increased procollagen production, which was reduced by TNF-α. Furthermore, TNFR2-SKE inhibited the UVB-induced proliferation of keratinocytes and melanocytes in the mouse skin and the infiltration of immune cells into inflamed tissues. These results suggest that TNFR2-SKE may possess the clinical potency to alleviate UV-induced photoaging in human skin.


Assuntos
Peptídeos/farmacologia , Receptores Tipo II do Fator de Necrose Tumoral/antagonistas & inibidores , Envelhecimento da Pele/efeitos dos fármacos , Envelhecimento da Pele/efeitos da radiação , Raios Ultravioleta , Animais , Proliferação de Células/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hiperplasia , Inflamação/patologia , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Melanócitos/efeitos dos fármacos , Melanócitos/metabolismo , Melanócitos/patologia , Camundongos , NF-kappa B/metabolismo , Células NIH 3T3 , Ligação Proteica/efeitos dos fármacos , Receptores Tipo I de Fatores de Necrose Tumoral/antagonistas & inibidores , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Pele/efeitos dos fármacos , Pele/patologia , Pele/efeitos da radiação , Fator 2 Associado a Receptor de TNF/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
15.
Oncogene ; 38(19): 3585-3597, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30664687

RESUMO

Although antioxidants promote melanoma metastasis, the role of reactive oxygen species (ROS) in other stages of melanoma progression is controversial. Moreover, genes regulating ROS have not been functionally characterized throughout the entire tumor progression in mouse models of cancer. To address this question, we crossed mice-bearing knock-out of Klf9, an ubiquitous transcriptional regulator of oxidative stress, with two conditional melanocytic mouse models: BrafCA mice, where BrafV600E causes premalignant melanocytic hyperplasia, and BrafCA/Pten-/- mice, where BrafV600E and loss of Pten induce primary melanomas and metastases. Klf9 deficiency inhibited premalignant melanocytic hyperplasia in BrafCA mice but did not affect formation and growth of BrafCA/Pten-/- primary melanomas. It also, as expected, promoted BrafCA/Pten-/- metastasis. Treatment with antioxidant N-acetyl cysteine phenocopied loss of Klf9 including suppression of melanocytic hyperplasia. We were interested in a different role of Klf9 in regulation of cell proliferation in BrafCA and BrafCA/Pten-/- melanocytic cells. Mechanistically, we demonstrated that BRAFV600E signaling transcriptionally upregulated KLF9 and that KLF9-dependent ROS were required for full-scale activation of ERK1/2 and induction of cell proliferation by BRAFV600E. PTEN depletion in BRAFV600E-melanocytes did not further activate ERK1/2 and cell proliferation, but rendered these phenotypes insensitive to KLF9 and ROS. Our data identified an essential role of KLF9-dependent ROS in BRAFV600E signaling in premalignant melanocytes, offered an explanation to variable role of ROS in premalignant and transformed melanocytic cells and suggested a novel mechanism for suppression of premalignant growth by topical antioxidants.


Assuntos
Fatores de Transcrição Kruppel-Like/metabolismo , Melanoma/patologia , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Cutâneas/patologia , Acetilcisteína/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Humanos , Fatores de Transcrição Kruppel-Like/genética , Melanócitos/efeitos dos fármacos , Melanócitos/metabolismo , Melanócitos/patologia , Melanoma/genética , Melanoma/metabolismo , Melanoma Experimental/induzido quimicamente , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos Knockout , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Neoplasias Cutâneas/metabolismo
16.
Methods Mol Biol ; 1916: 249-261, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30535702

RESUMO

The expression of Yamanaka factors (Oct3/4, Klf-4, Sox-2, c-Myc) can reprogram cancer cells to a pluripotent stage. This may cause the removal of their epigenetic memory and result in altered tumorigenicity. Various studies in the literature have shown that cancer cell reprogramming is a potential tool to study disease progression or discover novel therapeutic or diagnostic markers in cancer research. In this chapter, we aim to introduce the cancer cell reprogramming protocol in detail by using human melanocytes and melanoma cell lines, and Sendai viral vectors encoding Yamanaka factors have been used to reprogram cells. Representative results are discussed and important notes have been summarized in order to point out important steps during cancer cell reprogramming.


Assuntos
Carcinogênese/genética , Reprogramação Celular/genética , Melanoma/genética , Biologia Molecular/métodos , Diferenciação Celular/genética , Humanos , Fatores de Transcrição Kruppel-Like/genética , Melanócitos/patologia , Melanoma/patologia , Proteínas de Transporte de Cátions Orgânicos/genética , Proteínas Proto-Oncogênicas c-myc/genética , Fatores de Transcrição SOXB1/genética , Transfecção/métodos
17.
Pigment Cell Melanoma Res ; 32(3): 441-447, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30548435

RESUMO

Exposure to excess ultraviolet (UV) A radiation induces the degradation/modification of both eumelanin and pheomelanin that may be deleterious to pigmented tissues. Although the spectral distribution of solar energy comprises nearly half of visible light (VL), few studies have been conducted to examine the role of VL in the photodegradation of both types of melanin, either VL alone or in combination with UVA. In this study, we examined the effects of physiological doses of VL (150 to 300 J cm-2 ) alone or in combination with a physiological dose of UVA (20 J cm-2 ) in normal human epidermal melanocytes. The degradation/modification of melanin structures was evaluated by our chemical degradation-high performance liquid chromatography methods. The results show that VL accelerates UVA-induced changes in the structural features of both eumelanin and pheomelanin, although VL or UVA alone induced only minor changes in melanin structure. The differential spectral method provides support for the additive effects of VL.


Assuntos
Epiderme/patologia , Luz/efeitos adversos , Melaninas/metabolismo , Melanócitos/patologia , Raios Ultravioleta/efeitos adversos , Células Cultivadas , Epiderme/metabolismo , Epiderme/efeitos da radiação , Humanos , Melaninas/efeitos da radiação , Melanócitos/metabolismo , Melanócitos/efeitos da radiação
18.
J Clin Neurosci ; 62: 248-253, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30580915

RESUMO

Intradural Extramedullary Spinal Melanocytoma (IESM) is an extremely uncommon tumour arising from the spinal leptomeninges; both from a gross pathology and microscopic point of view it can mimick its malignant counterpart, the Melanoma. Such tumours are usually solitary, with a lower proliferating rate and without obvious SC invasion. Their common differential diagnoses include Spinal Schwannoma and Spinal Meningiomas since they share a significant amount of radiological similarities. It is a relatively benign condition which is, to date, with no more than 24 previously reported cases, yet widely unexplored and poorly understood. We report the detailed clinical history of a 60 years old individual suffering from IESM and, by means of a thorough Literature review, the most relevant features concerning the epidemiological issues, the clinical course, the radiological appearance, the surgical results and the typical gross and microscopic pathology of a cohort of previously reported cases of IESM are extensively discussed and systematically investigated through statistical analyses in order to add to the relevant Literature a dedicated work concerning this rare and enigmatic condition.


Assuntos
Melanócitos/patologia , Neoplasias Meníngeas/patologia , Meningioma/patologia , Neoplasias da Medula Espinal/patologia , Diagnóstico Diferencial , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade
19.
Arch Dermatol Res ; 311(2): 99-107, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30547366

RESUMO

The histopathological differentiation of melanocytic nevi from malignant melanoma (MM) is based on well-known criteria, and is straightforward in the vast majority of cases. However, there are few cases of melanocytic lesions (ML), the diagnosis of which is very challenging or even impossible. Here we have studied several morphological characteristics with particular focus on elastic fibers (EF) to identify features, helpful for the distinction between nevi and MM. In a monocentric retrospective study we have analyzed 14 morphological histological characteristics in 30 MMs and 90 nevi, encompassing 30 compound/dermal nevi, 30 junctional nevi, 30 dysplastic nevi. All consecutive cases were retrieved from the archives of our tertiary referral centre during the 6-month study period. Nine characteristics including loss of EF in the ML, loss of EF in lesional fibrosis, pushing of the EF, UV-elastosis, loss of rete ridges of the epidermis, regression of the ML, atrophy of the epidermis, pigment incontinence, and concentric eosinophilic fibroplasia (CEF) showed a statistical significant difference (p < 0.05 and at least an OR > 2) distinguishing nevi from MM. Loss of EF was found in 73.1% of MM cases, but in less than 2.5% of nevi. We identified nine morphological characteristics that are helpful to differentiate melanocytic nevi from MM. A loss of the EF in a ML appeared to be highly associated with MM.


Assuntos
Tecido Elástico/patologia , Eosinófilos/patologia , Epiderme/patologia , Melanócitos/patologia , Melanoma/diagnóstico , Nevo Pigmentado/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Atrofia , Diagnóstico Diferencial , Feminino , Fibrose , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
20.
J Dermatol Sci ; 92(3): 222-229, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30527375

RESUMO

BACKGROUND: 5-HT1A receptor was participated in fluoxetine induced melanogenesis in melanocytes and in normal C57BL/6 mice, but we know little about whether other 5-HT receptors are involved in regulation of fluoxetine promotes pigmentation. OBJECTIVE: To investigate the role of 5-HT receptors in regulation of fluoxetine ameliorates chronic unpredictable mild stress (CUMS) and chronic restraint stress (CRS) induce hypopigmentation in C57BL/6 mice. METHODS: CUMS and CRS were used to induce depigmentation in mice and evaluate the effect of fluoxetine. Western blot, immunohistochemistry and Q-PCR assay were used to determine the levels of protein and mRNA. Masson Fontana staining was used for melanin staining and FITC-Phalloidin staining was used to detect the expression of F-actin. Zebrafish and B16F10 cells were used for the mechanism research. RESULTS: Fluoxetine (2.6 mg/kg, ig) ameliorated hypopigmentation induced by CUMS and CRS in mice, significantly increased the mRNA and protein levels of 5-HT1 A and 5-HT2 A receptors in mice and B16F10 cells. The effect of fluoxetine on melanogenesis in B16F10 cells and zebrafish were inhibited by WAY100635 (a selective 5-HT1 A receptor antagonist) and ketanserin (a 5-HT2 A receptor antagonist), respectively. Activation of p38 MAPK signaling pathways was contributed to fluoxetine induced melanogenesis and inhibited by WAY100635, but not ketanserin. However, ketanserin selectively weakened the action of fluoxetine promoted migration and up-regulated Rab27a protein expression in B16F10 cells. CONCLUSIONS: 5-HT1 A and 2 A receptors contribute to melanogenesis and migration property of fluoxetine. The newly revealed mechanism indicates that fluoxetine and its analogues may be a potential drug for treatment of depigmentation disorders.


Assuntos
Fluoxetina/farmacologia , Transtornos da Pigmentação/patologia , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Estresse Psicológico/complicações , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Modelos Animais de Doenças , Fluoxetina/uso terapêutico , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Melaninas/biossíntese , Melanócitos/efeitos dos fármacos , Melanócitos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Transtornos da Pigmentação/tratamento farmacológico , Transtornos da Pigmentação/etiologia , Serotonina/metabolismo , Inibidores de Captação de Serotonina/uso terapêutico , Pigmentação da Pele/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Proteínas rab27 de Ligação ao GTP/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA