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1.
Oncogene ; 39(21): 4170-4182, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32277233

RESUMO

Nonmelanoma skin cancer (NMSC) such as cutaneous squamous cell carcinoma (cSCC) is caused by solar ultraviolet (SUV) exposure and is the most common cancer in the United States. T-LAK cell-originated protein kinase (TOPK), a serine-threonine kinase is activated by SUV irradiation and involved in skin carcinogenesis. Strategies with research focusing on the TOPK signaling pathway and targeted therapy in skin carcinogenesis may helpful for the discovery of additional treatments against skin cancer. In this study, we found that TOPK can directly bind to and phosphorylate c-Jun (as one of the core member of AP-1) at Ser63 and Ser73 after SSL exposure in a JNKs-independent manner. TOPK knocking down, or HI-TOPK-032 (TOPK specific inhibitor) attenuated colony formation and cell proliferation of skin cancer cells. Phosphorylated levels of c-Jun were overexpressed in human AK and cSCC compared with normal skin tissues, and HI-TOPK-032 inhibited the phosphorylation of c-Jun in SCC cell line in a dose-dependent manner. Furthermore, HI-TOPK-032 decreased SSL-induced AP-1 transactivation activity. Moreover, acute SSL-induced inflammation was attenuated by the topical application of HI-TOPK-032 in SKH1 hairless mice. Importantly, HI-TOPK-032 suppressed chronic SSL-induced skin carcinogenesis and c-Jun phosphorylation levels in SKH1 hairless mice. Our results demonstrate that TOPK can phosphorylate and activate c-Jun at Ser63 and Ser73 in the process of skin carcinogenesis and HI-TOPK-032 could be used as a potential chemopreventive drug against cSCC development.


Assuntos
Carcinogênese , Indolizinas/farmacologia , Quinases de Proteína Quinase Ativadas por Mitógeno , Proteínas de Neoplasias , Inibidores de Proteínas Quinases/farmacologia , Quinoxalinas/farmacologia , Neoplasias Cutâneas , Luz Solar/efeitos adversos , Raios Ultravioleta/efeitos adversos , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/efeitos da radiação , Humanos , Camundongos , Camundongos Pelados , Camundongos Knockout , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia
2.
Oncogene ; 39(21): 4241-4256, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32286519

RESUMO

T-cell protein tyrosine phosphatase (TC-PTP), encoded by Ptpn2, has been shown to function as a tumor suppressor during skin carcinogenesis. In the current study, we generated a novel epidermal-specific TC-PTP-overexpressing (K5HA.Ptpn2) mouse model to show that TC-PTP contributes to the attenuation of chemically induced skin carcinogenesis through the synergistic regulation of STAT1, STAT3, STAT5, and PI3K/AKT signaling. We found overexpression of TC-PTP increased epidermal sensitivity to DMBA-induced apoptosis and it decreased TPA-mediated hyperproliferation, coinciding with reduced epidermal thickness. Inhibition of STAT1, STAT3, STAT5, or AKT reversed the effects of TC-PTP overexpression on epidermal survival and proliferation. Mice overexpressing TC-PTP in the epidermis developed significantly reduced numbers of tumors during skin carcinogenesis and presented a prolonged latency of tumor initiation. Examination of human papillomas and squamous cell carcinomas (SCCs) revealed that TC-PTP expression was significantly reduced and TC-PTP expression was inversely correlated with the increased grade of SCCs. Our findings demonstrate that TC-PTP is a potential therapeutic target for the prevention of human skin cancer given that it is a major negative regulator of oncogenic signaling.


Assuntos
Carcinoma de Células Escamosas/enzimologia , Epiderme/metabolismo , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/metabolismo , Papiloma/enzimologia , Proteína Tirosina Fosfatase não Receptora Tipo 2/biossíntese , Transdução de Sinais , Neoplasias Cutâneas/enzimologia , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Proliferação de Células , Sobrevivência Celular , Epiderme/patologia , Humanos , Camundongos , Camundongos Transgênicos , Proteínas de Neoplasias/genética , Papiloma/genética , Papiloma/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia
3.
Appl Immunohistochem Mol Morphol ; 28(2): 130-138, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32044881

RESUMO

Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that mediates multiple cellular functions such as survival, invasion, and migration. FAK has been found to be over-expressed in various human cancers, including melanoma. FAK molecule has several tyrosine, serine, and threonine phosphorylation sites which have an important regulatory role. Tyrosine phosphorylation of FAK has been extensively studied, however little is known about the role of serine phosphorylation. We sought to examine the frequency and extent of serine-910 phosphorylated FAK (P-FAKSer910) expression in a spectrum of melanocytic proliferations as well as it's correlation with other histopathologic predictors and its effect on patient's survival. Clinicopathologic features and immunohistochemical expression of P-FAKSer910 were evaluated in 147 melanocytic proliferations: 73 primary melanoma (PM), 19 metastatic melanoma (MetM), 2 melanoma in situ, and 53 melanocytic nevi (MN). Higher cytoplasmic intensity predicted better overall survival (OS) in PM (χ=5.69; P=0.034) and was associated with 48% decrease in death risk (HR, 0.52; 95% CI, 0.28-0.95; P=0.036). In contrast, increased nuclear intensity was significantly associated with better disease-free survival (DFS) when stratified by tumor stage Log-rank test, trend of survival (χ=5.83, P=0.015) and independently on multivariate analysis when subcategorized into 3-tier categories (HR, 0.43; 95% CI, 0.18-0.98; P=0.045). Also, Clark's level and tumor-infiltrating lymphocytes (TILS) were independent predictors of DFS. Cytoplasmic intensity correlated inversely with American Joint Commission on Cancer stage in primary melanoma cases as well with vascularity in both primary and metastatic melanoma. Nuclear intensity independently correlated negatively with angioinvasion and TILS when subcategorized to 3 tier system. We found American Joint Commission on Cancer tumor stage, Clark's level, depth, ulceration, TILS, mitosis, angioinvasion, and tumor vascularity predictors of both DFS and OS. There was no significant difference in cytoplasmic or nuclear expression among the major categories of melanocytic proliferation. In this pilot immunohistochemistry-based study, we found P-FAKSer910 expression in melanoma by cytoplasmic intensity to correlate with better OS while nuclear intensity correlated with better DFS.


Assuntos
Quinase 1 de Adesão Focal/biossíntese , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Melanoma , Neoplasias Cutâneas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Quinase 1 de Adesão Focal/genética , Seguimentos , Humanos , Masculino , Melanoma/enzimologia , Melanoma/genética , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Fosforilação , Serina/genética , Serina/metabolismo , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Taxa de Sobrevida
4.
Curr Opin Oncol ; 32(2): 85-90, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31895121

RESUMO

PURPOSE OF REVIEW: Better understanding of the biology of BRAF-mutated melanoma has led to the development of highly effective therapy, BRAF and MEK inhibitors, targeting abnormally activated protein kinases for patient with BRAF-mutated melanoma. The purpose of this article was to review the recent published data on BRAF and MEK inhibitors in melanoma in the metastatic, adjuvant and neoadjuvant setting to facilitate the management of melanoma patients in clinical practice. RECENT FINDINGS: The spectacular outcomes of targeted therapy in advanced melanoma patients have led to their development in the adjuvant setting with substantial improvements in recurrence-free and overall survival. The neoadjuvant strategy is already used in many cancers to decrease tumor load, improve resectability and prevent relapse. Targeted therapy in the neoadjuvant setting is a therapeutic approach being explored in subsequent studies. SUMMARY: We hope that this review will help clinicians to manage melanoma patients in routine practice.


Assuntos
MAP Quinase Quinase Quinases/antagonistas & inibidores , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Quimioterapia Adjuvante , Ensaios Clínicos Fase III como Assunto , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Melanoma/enzimologia , Melanoma/patologia , Melanoma/cirurgia , Terapia de Alvo Molecular , Terapia Neoadjuvante , Metástase Neoplásica , Estadiamento de Neoplasias , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia
5.
J Am Acad Dermatol ; 82(4): 846-853, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31437542

RESUMO

BACKGROUND: Inositol polyphosphate-5-phosphatase (INPP5A) has been shown to play a role in the progression of actinic keratosis to cutaneous squamous cell carcinoma (cSCC) and the progression of localized disease to metastatic disease. Currently, no cSCC biomarkers are able to risk stratify recurrent and metastatic disease. OBJECTIVE: To determine the prognostic value of INPP5A expression in cSCC recurrent and metastatic disease. METHODS: We conducted a multicenter, single-institutional, retrospective cohort study within the Mayo Clinic Health System on the use of immunohistochemical staining to examine cSCC INPP5A protein expression in primary tumors and recurrent and metastatic disease. Dermatologists and dermatopathologists were blinded to outcome. RESULTS: Low staining expression of INPP5A in recurrent and metastatic disease tumors was associated with poor overall survival (OS) (31.0 months for low versus 62.0 months for high expression; P = .0272). A composite risk score (calculated as score of primary tumor + score of recurrent or metastatic disease tumor, with tumors with high expression scoring a zero and low expression a 1, score range 0-2) of 0 was predictive of improved OS compared with a composite risk score of ≥1 (hazard ratio 0.42, 95% confidence interval 0.21-0.84; P = .0113). LIMITATIONS: This is a multicenter but single institution study of a white population. CONCLUSION: Loss of INPP5A expression predicts poor OS in recurrent and metastatic disease of cSCC.


Assuntos
Carcinoma de Células Escamosas/enzimologia , Inositol Polifosfato 5-Fosfatases/genética , Recidiva Local de Neoplasia/enzimologia , Neoplasias Cutâneas/enzimologia , Idoso , Biomarcadores/análise , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Progressão da Doença , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Inositol Polifosfato 5-Fosfatases/análise , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia
6.
J Clin Pathol ; 73(2): 116-119, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31506288

RESUMO

Beyond targeted therapy for patients with BRAF-mutated melanomas and immunotherapy in patients lacking BRAF mutations, anti-MEK therapy has been proposed in patients with advanced melanomas harbouring BRAF fusions. BRAF fusions diagnosis in patients with advanced melanomas is the subject of the present study. Using BRAF fluorescent in situ hybridisation (FISH), we searched for BRAF fusions in 74 samples of 66 patients with advanced BRAF/NRAS/KIT wild-type melanomas. We identified 2/66 (3%) patients with BRAF fusions in a brain metastasis of one patient and in a lymph node metastasis and in a cutaneous metastasis for the second patient with 90%-95% of tumour nuclei containing isolated 3'-BRAF FISH signals. As a result, we conclude that BRAF FISH in patients with advanced BRAF/NRAS/KIT wild-type melanomas is a valuable and easy-to-perform test to diagnose BRAF fusions and to identify patients who could benefit of anti-MEK targeted therapy.


Assuntos
Biomarcadores Tumorais/genética , GTP Fosfo-Hidrolases/genética , Fusão Gênica , Hibridização in Situ Fluorescente , Melanoma/genética , Proteínas de Membrana/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-kit/genética , Neoplasias Cutâneas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Feminino , Humanos , Masculino , Melanoma/tratamento farmacológico , Melanoma/enzimologia , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Terapia de Alvo Molecular , Seleção de Pacientes , Medicina de Precisão , Valor Preditivo dos Testes , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/enzimologia
7.
Appl Immunohistochem Mol Morphol ; 28(1): 36-41, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30095463

RESUMO

Telomerase is reactivated in most cancers and is possibly an early driver event in melanoma. Our aim was to test a novel in situ hybridization technique, RNAscope, for the detection of human telomerase reverse transcriptase (hTERT) mRNA in archival formalin-fixed, paraffin-embedded (FFPE) tissue and to compare the mRNA expression of melanomas and benign naevi. Furthermore, we wanted to see if hTERT mRNA could be a diagnostic or prognostic marker of melanoma. In situ hybridization for the detection of hTERT mRNA was performed on FFPE tissue of 17 melanomas and 13 benign naevi. We found a significant difference in the expression of hTERT mRNA between melanomas and benign naevi (P<0.001) and the expression of hTERT mRNA correlated with Breslow thickness (ρ=0.56, P=0.0205) and the Ki67 proliferation index (ρ=0.72, P=0.001). This study showed that RNAscope was a reliable in situ hybridization method for the detection of hTERT mRNA in FFPE tissue of melanomas and benign naevi. hTERT mRNA was more abundantly expressed in melanomas compared with benign naevi, but cannot be used solely as a diagnostic marker due to an overlap in expression. The hTERT mRNA expression in melanomas correlated with the prognostic markers Breslow thickness and the Ki67 index indicating a prognostic potential of hTERT mRNA.


Assuntos
Melanoma , Proteínas de Neoplasias/metabolismo , Nevo , RNA Mensageiro/metabolismo , RNA Neoplásico/metabolismo , Neoplasias Cutâneas , Telomerase/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Melanoma/enzimologia , Melanoma/patologia , Pessoa de Meia-Idade , Nevo/enzimologia , Nevo/patologia , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/patologia
8.
J Cutan Pathol ; 47(2): 139-145, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31677173

RESUMO

BACKGROUND: The spread and invasion of malignant melanoma cells involve degradation and reorganization of the extracellular matrix by the activation of several matrix metalloproteinases (MMPs). This study analyzed the expression of MMP-1, MMP-2, and MMP-13 proteins in primary nodular melanoma (NM) and dysplastic nevi (DN) as a significant risk factor for melanoma development. The secondary goal was to analyze the correlation of MMPs protein expression in NM with tumor invasion, BRAF V600 mutation status, and overall survival. METHODS: Immunohistochemistry for MMP-1, MMP-2, and MMP-13 was performed on nodular melanoma (n = 52) and dysplastic nevi (n = 28) on tissue microarray (TMA). BRAF V600 mutation analysis on NM samples was performed by the Sanger sequencing method. RESULTS: A high level of MMPs expression in NM samples (>30%) compared with DN (<8%) was statistically significant (P < 0.001). BRAF V600 mutations were detected in 15 of 39 (38.5%) NM samples. This study revealed an interesting finding that MMP-1 and MMP-13 protein expression in the BRAF V600 mutated melanomas were significantly lower than in the BRAF V600 wild type (P < 0.05). CONCLUSION: Cox analysis revealed that Clark categories, Breslow thickness, and MMP-1 high protein expression are predictive factors for shorter overall survival (P < 0.05).


Assuntos
Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Metaloproteinase 13 da Matriz/biossíntese , Metaloproteinase 1 da Matriz/biossíntese , Metaloproteinase 2 da Matriz/biossíntese , Melanoma , Proteínas de Neoplasias/biossíntese , Neoplasias Cutâneas , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Melanoma/enzimologia , Melanoma/patologia , Pessoa de Meia-Idade , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/patologia
9.
Diagn Cytopathol ; 48(4): 376-379, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31846216

RESUMO

Primary auricular melanoma is rarely reported. Approximately, it accounts for 1% to 4% of all cutaneous melanoma. Early literature suggested that melanoma of the ear is more aggressive than other melanomas, with a propensity for spreading to both regional lymph nodes and distant sites. Here, we present a case of cytological pleural metastasis from auricular melanoma in a 43-year-old woman. Immunohistochemical staining showed that the tumors cells were positive for S-100 protein and Melan-A. The mutation of the v-raf murine sarcoma viral oncogene homolog B (BRAF)V600E was demonstrated on Sanger sequencing. To our knowledge, this is the first report describing the cytomorphology of metastatic auricular melanoma in pleural effusion.


Assuntos
Neoplasias da Orelha , Melanoma , Mutação de Sentido Incorreto , Derrame Pleural Maligno , Proteínas Proto-Oncogênicas B-raf , Neoplasias Cutâneas , Adulto , Substituição de Aminoácidos , Neoplasias da Orelha/enzimologia , Neoplasias da Orelha/genética , Neoplasias da Orelha/patologia , Feminino , Humanos , Melanoma/enzimologia , Melanoma/genética , Melanoma/patologia , Metástase Neoplásica , Derrame Pleural Maligno/enzimologia , Derrame Pleural Maligno/genética , Derrame Pleural Maligno/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia
10.
Curr Opin Oncol ; 32(2): 79-84, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31833955

RESUMO

PURPOSE OF REVIEW: Melanoma treatment have been revolutionized since 2010 by the development of immune checkpoint inhibitors, and, for BRAF-mutated melanoma, targeted therapies based on BRAF and MEK inhibitors, which is a model of effective targeted therapy in cancer. However, patients with BRAF wild type cannot benefit for such treatments. In this review, we will focus on the current clinical development of targeted therapies beyond BRAF, in NRAS-mutated and KIT-altered melanoma. RECENT FINDINGS: In NRAS-mutated melanoma, targeted therapies based on MEK inhibition are being developed as monotherapy or in combination with MAPK, PI3K or CDK4/6 inhibitor. Targeted therapies of KIT-altered melanoma patients is based in KIT inhibitor (mostly imatinib, nilotinib), although for both melanoma subtypes, results are for now disappointing as compared with BRAF and MEK inhibitors in BRAF-mutated melanoma. SUMMARY: Combined therapeutic targeted strategies are awaited in NRAS-mutated and KIT-altered melanoma and could provide additional benefit.


Assuntos
GTP Fosfo-Hidrolases/antagonistas & inibidores , Melanoma/tratamento farmacológico , Proteínas de Membrana/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Ensaios Clínicos Fase III como Assunto , GTP Fosfo-Hidrolases/genética , Humanos , Melanoma/enzimologia , Melanoma/genética , Proteínas de Membrana/genética , Terapia de Alvo Molecular , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-kit/genética , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/genética
11.
Histopathology ; 76(3): 354-365, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31564060

RESUMO

AIMS: Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is caused by germline mutations in the Fumarate hydratase (FH) gene. In young women, the syndrome often presents with symptomatic uterine leiomyomas, leading to myomectomy or hysterectomy. In this study, we aimed to investigate the incidence and mutational profiles of FH-negative leiomyomas from young patients, thus allowing for early identification and triage of syndromic patients for surveillance. METHODS AND RESULTS: We evaluated 153 cases of uterine leiomyomas from women aged up to 30 years for loss of FH expression by tissue microarray (TMA)-based immunohistochemical staining. Mutational analysis of tumours with loss of FH was carried out by polymerase chain reaction (PCR) amplification of 10 exons within the FH gene and subsequent Sanger sequencing. The status of promoter methylation was assessed by bisulphite sequencing. Loss of FH protein expression was detected in seven (4.6%) of 153 tested uterine leiomyomas from young patients. All FH-negative leiomyomas displayed staghorn vasculature and fibrillary/neurophil-like cytoplasm. We found that six (86%) of seven FH-negative tumours detected by immunohistochemistry harboured FH mutations, 50% of which contained germline mutations. In particular, the germline mutational rate in FH gene was 2.0% (three of 153 cases). Bisulphite sequencing analysis failed to detect promoter methylation in any of the seven tumours. CONCLUSION: Our study showed a relatively high rate of FH germline mutation in FH-negative uterine leiomyomas from patients aged up to 30 years. While genetic mutations confer protein expression loss, epigenetic regulation of the FH gene appears to be unrelated to this phenotype.


Assuntos
Fumarato Hidratase/genética , Leiomioma/genética , Leiomiomatose/genética , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Cutâneas/genética , Neoplasias Uterinas/genética , Adolescente , Adulto , Análise Mutacional de DNA , Feminino , Fumarato Hidratase/metabolismo , Mutação em Linhagem Germinativa , Humanos , Imuno-Histoquímica , Leiomioma/enzimologia , Leiomioma/patologia , Leiomiomatose/enzimologia , Leiomiomatose/patologia , Mutação , Síndromes Neoplásicas Hereditárias/enzimologia , Síndromes Neoplásicas Hereditárias/patologia , Prevalência , Estudos Retrospectivos , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/patologia , Análise Serial de Tecidos , Neoplasias Uterinas/enzimologia , Neoplasias Uterinas/patologia , Adulto Jovem
12.
G Ital Dermatol Venereol ; 154(6): 681-695, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31859467

RESUMO

Cutaneous T cell lymphoma (CTCL) is a non-Hodgkin's lymphoma with a heterogenous presentation and highly variable disease course. The most common subtypes of CTCL are mycosis fungoides (MF) and Sézary Syndrome (SS). Treatment varies based on the stage of the disease with skin directed therapies typically utilized for early stage disease, and systemic therapies employed for more advanced disease. There are few highly effective treatments available, and systemic therapies have limited response rates. Histone deacetylase inhibitors have emerged as mainstream treatments for MF/SS over the past several years. Here, we discuss the mechanism of action of histone deacetylase inhibitors in relation to the pathogenesis of MF/SS, evaluate the clinical trials that led to Food and Drug Administration approval of two of the histone deacetylase inhibitors for MF/SS and describe the results for those still under investigation. Additionally, we discuss the potential for combination therapies in order to optimize outcomes of treatment with histone deacetylase inhibitors.


Assuntos
Inibidores de Histona Desacetilases/administração & dosagem , Linfoma Cutâneo de Células T/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Animais , Inibidores de Histona Desacetilases/farmacologia , Humanos , Linfoma Cutâneo de Células T/enzimologia , Linfoma Cutâneo de Células T/patologia , Micose Fungoide/tratamento farmacológico , Micose Fungoide/enzimologia , Micose Fungoide/patologia , Estadiamento de Neoplasias , Síndrome de Sézary/tratamento farmacológico , Síndrome de Sézary/enzimologia , Síndrome de Sézary/patologia , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/patologia
13.
Target Oncol ; 14(6): 729-742, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31754963

RESUMO

BACKGROUND: Although BRAF/MEK inhibitors are generally considered to be equally effective whether given before or after immunotherapy, no prospective trial has confirmed this hypothesis and contradictory data have been published in the melanoma field. OBJECTIVE: We aimed to investigate the outcomes of patients with metastatic melanoma depending on the first-line treatment. PATIENTS AND METHODS: In this ambidirectional cohort, single-center study, we included 253 consecutive melanoma patients treated in our institution with an anti-PD1 antibody or BRAF/MEK inhibitors, who started first-line treatment between December 2015 and March 2018. Kaplan-Meier estimator, log-rank test, and Cox proportional hazard model were used in this analysis. RESULTS: First-line median progression-free survival (PFS) for all patients was 5.7 months (m), 6.9 m on anti-PD-1 therapy and 5.6 m for combination targeted therapy. Patients with BRAF mutated melanoma had 6.0 m median PFS on immunotherapy. At a median follow-up of 23.2 m with 149 events, in BRAF wild-type patients treated with anti-PD1, median overall survival (OS) was 18.1 m. BRAF mutated patients treated with first-line BRAF/MEK inhibitors had 11.7 m median OS. High neutrophil to lymphocyte ratio, high LDH level, ECOG > 0, and the presence of brain metastases negatively impacted PFS and OS. CONCLUSIONS: In BRAF mutated patients with normal LDH, first-line immunotherapy seems a more effective approach. We have demonstrated that although BRAF mutation is a negative prognostic factor in stage IV melanoma, the use of two different systemic treatment modalities allows achievement of comparable survival in BRAF mutated and BRAF wild-type patients.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/enzimologia , Mutação , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/enzimologia , Intervalo Livre de Doença , Feminino , Humanos , MAP Quinase Quinase Quinases/antagonistas & inibidores , Masculino , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Padrões de Prática Médica , Receptor de Morte Celular Programada 1/imunologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Estudos Retrospectivos , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/secundário , Taxa de Sobrevida
14.
Eur J Dermatol ; 29(5): 477-483, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31647461

RESUMO

Transglutaminase 3 (TG3) belongs to a family of Ca2+-dependent enzymes which catalyse protein crosslinking. TG3 is important for proper development of the skin and hair shaft, and knock-out mice for the Tgm3 gene are sensitive to UVB-induced photodamage due to aberrations in cornified envelope formation. Loss of TG3 is reported in head and neck and oesophageal squamous cell carcinoma, yet, its expression in skin cancer has not been studied. The aim of the present study was to analyse the expression pattern of TG3 in skin cancer. TG3 expression was investigated based on immunohistochemical staining of a tissue micro-array of different types of skin cancer, as well as meta-analysis of public gene array data. Our findings demonstrated that TG3 is normally expressed in spinous/granular layers of the epidermis, but is absent in melanocytes as well as melanoma samples. As expected, its expression was absent in poorly differentiated squamous cell carcinoma of the skin. Surprisingly, we show that samples of basal cell carcinoma demonstrated strong staining for TG3 both in the cytoplasm and nucleus. Furthermore, at the mRNA level, the expression pattern of TGM3 was crucially altered in BCC, but not other types of skin cancer. These findings lead to new questions regarding TG3 involvement in basal cell carcinoma tumourigenesis. Moreover, the expression pattern of TG3 renders it a potential specific marker for basal cell carcinoma diagnosis.


Assuntos
Carcinoma Basocelular/enzimologia , Neoplasias Cutâneas/enzimologia , Transglutaminases/biossíntese , Biomarcadores Tumorais/biossíntese , Imunofluorescência , Humanos , Microscopia Confocal , Análise Serial de Proteínas , RNA Mensageiro/biossíntese
15.
J Biochem Mol Toxicol ; 33(12): e22409, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31617652

RESUMO

Melanoma is the most aggressive type of cutaneous tumor and the occurrence of metastasis makes it resistant to almost all available treatment and becomes incorrigible. Hence, identifying metastasis-related biomarkers and effective therapeutic targets will assist in preventing metastasis and ameliorating cutaneous melanoma. In our present study, we reported kinesin family member 18B (KIF18B) as a novel contributor in cutaneous melanoma proliferation and metastasis, and it was found to be of great significance in predicting the prognosis of cutaneous melanoma patients. Bioinformatics analysis based on ONCOMINE, The Cancer Genome Atlas, and Genotype-Tissue Expression database revealed that KIF18B was highly expressed in cutaneous melanoma and remarkably correlated with unfavorable clinical outcomes. Consistently, the results of the quantitative real-time polymerase chain reaction exhibited that the expression of KIF18B was significantly higher in cutaneous melanoma cell lines than that in normal cells. In vitro, biological assays found that knockdown of KIF18B in cutaneous melanoma cells noticeably repressed cell proliferation, migration, and invasion, while inducing cell apoptosis. Moreover, the protein expression of E-cadherin was enhanced while the expression of N-cadherin, vimentin, and Snail was decreased in M14 cells after knocking down KIF18B. In addition, the phosphorylation of phosphoinositide 3-kinase (PI3K) and extracellular-signal-regulated kinase (ERK) was significantly suppressed in M14 cells with silenced KIF18B. Above all, our results indicated that the repression of cutaneous melanoma cell migration and proliferation caused by KIF18B depletion suggested an oncogenic role of KIF18B in cutaneous melanoma, which acts through modulating epithelial-mesenchymal transition and ERK/PI3K pathway.


Assuntos
Proliferação de Células , Cinesina/metabolismo , Melanoma/enzimologia , Melanoma/secundário , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/secundário , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Transição Epitelial-Mesenquimal , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Estimativa de Kaplan-Meier , Cinesina/genética , Invasividade Neoplásica , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Prognóstico , Fatores de Transcrição da Família Snail/metabolismo , Vimentina/metabolismo
16.
Eur J Clin Invest ; 49(12): e13175, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31571214

RESUMO

BACKGROUND: Squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) represent the most common forms of nonmelanoma skin cancers (NMSCs). Although successful treatment of these neoplasms is based on surgical excision, an increasing number of BCCs relapses and many SCCs display high rates of recurrence and metastasis. Nicotinamide N-methyltransferase (NNMT) is a cytosolic enzyme, which was found to be upregulated in different solid tumours. However, there are no data regarding enzyme expression in NMSCs. The aim of this study was therefore to evaluate the potential involvement of NNMT in BCCs and SCCs. MATERIALS AND METHODS: Immunohistochemical analyses were carried out on 40 BCC cases and 39 SCC cases, to evaluate enzyme expression in tumour and surrounding healthy margins. Moreover, the relationship between NNMT intratumour levels and clinico-pathological parameters were explored. RESULTS: Nicotinamide N-methyltransferase was found to be overexpressed in BCCs compared with control tissues, while a significant enzyme downregulation was detected in SCCs with respect to corresponding healthy margins. In addition, NNMT levels were negatively related to aggressiveness of both BCCs (distinguishing between infiltrative and nodular tumours) and SCCs (considering head and neck forms and tumours of the extremities and trunk). CONCLUSIONS: These evidences seem to demonstrate that the different NNMT dysregulation detected in BCC and SCC may be the result of important biological traits distinctively characterizing these two forms within NMSCs. In addition, enzyme levels seem to be inversely correlated with tumour aggressiveness, thus suggesting the potential suitability of the enzyme as a prognostic biomarker for both neoplasms.


Assuntos
Carcinoma Basocelular/enzimologia , Carcinoma de Células Escamosas/enzimologia , Neoplasias de Cabeça e Pescoço/enzimologia , Nicotinamida N-Metiltransferase/metabolismo , Neoplasias Cutâneas/enzimologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/enzimologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Basocelular/patologia , Carcinoma de Células Escamosas/patologia , Regulação para Baixo , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estudos Retrospectivos , Neoplasias Cutâneas/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carga Tumoral
17.
Int J Nanomedicine ; 14: 7561-7581, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571864

RESUMO

Introduction: This study was conducted to elucidate the chemopreventive potential, cytotoxic, and suppression of cellular metastatic activity of etodolac (ETD)-loaded nanocarriers. Methods: To esteem the effect of charge and composition of the nanovectors on their performance, four types of vectors namely, negative lipid nanovesicles; phosalosomes (N-Phsoms), positive phosalosomes (P-Phsoms), nanostructured lipid carriers (NLCs) and polymeric alginate polymer (AlgNPs) were prepared and compared. ETD was used as a model cyclo-oxygenase-2 (COX-2) inhibitor to evaluate the potency of these nanovectors to increase ETD permeation and retention through human skin and cytotoxicity against squamous cell carcinoma cell line (SCC). Moreover, the chemopreventive activity of ETD nanovector on mice skin cancer model was evaluated. Results: Among the utilized nanovectors, ETD-loaded N-Phsoms depicted spherical vesicles with the smallest particle size (202.96±2.37 nm) and a high zeta potential of -24.8±4.16 mV. N-Phsoms exhibited 1.5, and 3.6 folds increase in the ETD amount deposited in stratum corneum, epidermis and dermis. Moreover, cytotoxicity studies revealed a significant cytotoxic potential of such nanovector with IC50=181.76 compared to free ETD (IC50=982.75), correlated to enhanced cellular internalization. Its efficacy extended to a reduction in the relative tumor weight with 1.70 and 1.51-fold compared to positive control and free ETD, that manifested by a 1.72-fold reduction in both COX-2 and proliferating cell nuclear antigen mRNA (PCNA-mRNA) levels and 2.63-fold elevation in caspase-3 level in skin tumors relative to the positive control group with no hepato-and nephrotoxicity. Conclusion: Encapsulation of ETD in nanovector enhances its in-vitro and in-vivo anti-tumor activity and opens the door for encapsulation of more relevant drugs.


Assuntos
Quimioprevenção , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Ciclo-Oxigenase 2/metabolismo , Nanoestruturas/química , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/enzimologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/toxicidade , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Etodolac/farmacologia , Etodolac/uso terapêutico , Feminino , Humanos , Concentração Inibidora 50 , Lipídeos/química , Camundongos , Nanoestruturas/ultraestrutura , Tamanho da Partícula , Estudos Prospectivos , Absorção Cutânea/efeitos dos fármacos , Neoplasias Cutâneas/patologia , Eletricidade Estática , Resultado do Tratamento
18.
J Clin Oncol ; 37(33): 3142-3151, 2019 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-31580757

RESUMO

PURPOSE: BRAF/MEK inhibition is a standard of care for patients with BRAF V600E/K-mutated metastatic melanoma. For patients with less frequent BRAF mutations, however, efficacy data are limited. METHODS: In the current study, 103 patients with metastatic melanoma with rare, activating non-V600E/K BRAF mutations that were treated with either a BRAF inhibitor (BRAFi), MEK inhibitor (MEKi), or the combination were included. BRAF mutation, patient and disease characteristics, response, and survival data were analyzed. RESULTS: Fifty-eight patient tumors (56%) harbored a non-E/K V600 mutation, 38 (37%) a non-V600 mutation, and seven had both V600E and a rare BRAF mutation (7%). The most frequent mutations were V600R (43%; 44 of 103), L597P/Q/R/S (15%; 15 of 103), and K601E (11%; 11 of 103). Most patients had stage IV disease and 42% had elevated lactate dehydrogenase at BRAFi/MEKi initiation. Most patients received combined BRAFi/MEKi (58%) or BRAFi monotherapy (37%). Of the 58 patients with V600 mutations, overall response rate to BRAFi monotherapy and combination BRAFi/MEKi was 27% (six of 22) and 56% (20 of 36), respectively, whereas median progression-free survival (PFS) was 3.7 months and 8.0 months, respectively (P = .002). Of the 38 patients with non-V600 mutations, overall response rate was 0% (zero of 15) to BRAFi, 40% (two of five) to MEKi, and 28% (five of 18) to combination treatment, with a median PFS of 1.8 months versus 3.7 months versus 3.3 months, respectively. Multivariable analyses revealed superior survival (PFS and overall survival) with combination over monotherapy in rare V600 and non-V600 mutated melanoma. CONCLUSION: Patients with rare BRAF mutations can respond to targeted therapy, however, efficacy seems to be lower compared with V600E mutated melanoma. Combination BRAFi/MEKi seems to be the best regimen for both V600 and non-V600 mutations. Yet interpretation should be done with care because of the heterogeneity of patients with small sample sizes for some of the reported mutations.


Assuntos
Melanoma/tratamento farmacológico , Melanoma/genética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Melanoma/enzimologia , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Mutação , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Estudos Retrospectivos , Neoplasias Cutâneas/enzimologia , Taxa de Sobrevida , Translocação Genética , Adulto Jovem
19.
Oncol Rep ; 42(5): 1805-1814, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31545452

RESUMO

Cutaneous squamous cell carcinoma (cSCC) is a common malignancy initiated by keratinocytes of the epidermis, which are able to invade the dermis and its periphery. Although most patients with cSCC present with curable localized tumors, recurrence, metastasis and mortality occasionally occur. In the present study, nicotinamide N­methyltransferase (NNMT) was identified as an upregulated protein in the SCC12 cell line, which has high invasive potential compared with the SCC13 cell line. The effects of NNMT knockdown on proliferation, migration and invasion were investigated using SCC cells. shRNA­mediated downregulation of NNMT expression levels inhibited the proliferation and density­dependent growth of SCC12 cells. In addition, the results of a cell motility assay showed that the migration and invasion of SCC cells were markedly decreased in NNMT­knockdown cells. The assessment of epithelial­mesenchymal transition (EMT)­associated gene expression using PCR array analysis revealed that high NNMT expression levels were accompanied by high expression levels of EMT­associated genes, and that NNMT knockdown effectively suppressed the expression of matrix metalloproteinase 9, osteopontin, versican core protein and zinc finger protein SNAI2 in SCC12 cells. These results revealed that the upregulation of NNMT induced cellular invasion via EMT­related gene expression in SCC cells.


Assuntos
Carcinoma de Células Escamosas/enzimologia , Nicotinamida N-Metiltransferase/metabolismo , Neoplasias Cutâneas/enzimologia , Regulação para Cima , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Nicotinamida N-Metiltransferase/genética
20.
Biomed Pharmacother ; 120: 109438, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31541886

RESUMO

PURPOSE: The aim was to study the mechanism of LncRNA FOXD3-AS1 in cutaneous melanoma. METHODS: FOXD3-AS1 levels in 47 pairs of melanoma samples were detected. We used qRT-PCR to detect FOXD3-AS1, miR-325 and MAP3K2 expression in different staging samples and cutaneous melanoma cell lines. We used Kaplan-Meier curve to analyze survival rate in patients with FOXD3-AS1 high and low expression. Sh-FOXD3-AS1, miR-325, miR-325 inhibitor and oeMAP3K2 were transfected. The proliferation of A375 and SK-MEL-1 was detected by CCK8 and EdU labeling assay and cell clone formation assay. Dual luciferase reporter assay and pull down assay was used to confirm the binding site of FOXD3-AS1, miR-325 and MAP3K2. Flow cytometry was applied to detect the effect of lncRNA on cell cycle. The migration and invasion ability were detected by transwell assay. RESULTS: LncRNA FOXD3-AS1 highly expressed in cutaneous melanoma cells and tissues. Patients with highly expressed LncRNA FOXD3-AS1 were always with shorter overall survival time. When LncRNA FOXD3-AS1 was knockdown, proliferation, invasion and migration of cutaneous malignant melanoma, and tumor weight was inhibited, and cell cycle was arrested. LncRNA FOXD3-AS1 negatively regulated the expression of miR-325, and then improved the level of MAP3K2. MiR-325 was with similarly effects on above biological process, and MAP3K2 overexpression could rescue the influence of sh-FOXD3-AS1. Tumor volume and weight were measured to confirm the effect of sh-FOXD3-AS1 in vivo. CONCLUSION: LncRNA FOXD3-AS1 could promote proliferation, invasion and migration of cutaneous malignant melanoma via regulating miR-325/MAP3K2 axis.


Assuntos
Movimento Celular , Proliferação de Células , MAP Quinase Quinase Quinase 2/metabolismo , Melanoma/enzimologia , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Neoplasias Cutâneas/enzimologia , Animais , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , MAP Quinase Quinase Quinase 2/genética , Masculino , Melanoma/genética , Melanoma/patologia , Camundongos , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , RNA Longo não Codificante/genética , Transdução de Sinais , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Carga Tumoral
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