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1.
Cancer Lett ; 500: 51-63, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33296708

RESUMO

Lung cancer is the leading cause of cancer-related deaths, worldwide. Non-small cell lung cancer (NSCLC) is the most prevalent lung cancer subtype. YAP and TAZ have been implicated in lung cancer by acting as transcriptional co-activators of oncogenes or as transcriptional co-repressors of tumor suppressor genes. Previously we reported that YAP and TAZ regulate microRNAs expression in NSCLC. Among the set of regulated miRNAs, the oncogenic miR-25, 93, and 106b, clustering within the MCM7 gene were selected for further studies. We firstly identified Transforming Growth Factor-ß (TGF-ß) Receptor 2 (TGFBR2), a member of the TGF-ß signaling, as a target of the miRNA cluster, which exhibited prognostic value because of its tumor suppressor activity. We found that YAP/TAZ-mediated repression of TGFBR2 occurs both: post-transcriptionally through the miR-106b-25 cluster and transcriptionally by engaging the EZH2 epigenetic repressor that we reported here as a novel target gene of YAP/TAZ. Furthermore, we document that YAP/TAZ and EZH2 cooperate in lung tumorigenesis by transcriptionally repressing a specific subset of tumor suppressor genes, including TGFBR2. Our findings point to YAP/TAZ and EZH2 as potential therapeutic targets for NSCLC treatment.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Fatores de Transcrição/genética , Células A549 , Carcinogênese/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Proteínas de Ligação a DNA/genética , Epigênese Genética/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , MicroRNAs/genética , Componente 7 do Complexo de Manutenção de Minicromossomo/genética , Proteínas Nucleares/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Fatores de Transcrição de Domínio TEA , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Fator de Crescimento Transformador beta1/genética , Proteínas Supressoras de Tumor/genética , Proteínas de Sinalização YAP
2.
J Exp Clin Cancer Res ; 38(1): 349, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399037

RESUMO

BACKGROUND: Over the past decade, newly designed cancer therapies have not significantly improved the survival of patients diagnosed with Malignant Pleural Mesothelioma (MPM). Among a limited number of genes that are frequently mutated in MPM several of them encode proteins that belong to the HIPPO tumor suppressor pathway. METHODS: The anticancer effects of the top flower standardized extract of Filipendula vulgaris (Dropwort) were characterized in "in vitro" and "in vivo" models of MPM. At the molecular level, two "omic" approaches were used to investigate Dropwort anticancer mechanism of action: a metabolomic profiling and a phosphoarray analysis. RESULTS: We found that Dropwort significantly reduced cell proliferation, viability, migration and in vivo tumor growth of MPM cell lines. Notably, Dropwort affected viability of tumor-initiating MPM cells and synergized with Cisplatin and Pemetrexed in vitro. Metabolomic profiling revealed that Dropwort treatment affected both glycolysis/tricarboxylic acid cycle as for the decreased consumption of glucose, pyruvate, succinate and acetate, and the lipid metabolism. We also document that Dropwort exerted its anticancer effects, at least partially, promoting YAP and TAZ protein ubiquitination. CONCLUSIONS: Our findings reveal that Dropwort is a promising source of natural compound(s) for targeting the HIPPO pathway with chemo-preventive and anticancer implications for MPM management.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Metabolismo Energético/efeitos dos fármacos , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/metabolismo , Mesotelioma/etiologia , Mesotelioma/metabolismo , Extratos Vegetais/farmacologia , Fatores de Transcrição/metabolismo , Aciltransferases , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Filipendula/química , Humanos , Neoplasias Pulmonares/patologia , Mesotelioma/patologia , Mesotelioma Maligno , Camundongos , Extratos Vegetais/química , Ligação Proteica
3.
Haematologica ; 104(1): 82-92, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30076175

RESUMO

MicroRNAs, non-coding regulators of gene expression, are likely to function as important downstream effectors of many transcription factors including MYB. Optimal levels of MYB are required for transformation/maintenance of BCR-ABL-expressing cells. We investigated whether MYB silencing modulates microRNA expression in Philadelphia-positive (Ph+) leukemia cells and if MYB-regulated microRNAs are important for the "MYB addiction" of these cells. Thirty-five microRNAs were modulated by MYB silencing in lymphoid and erythromyeloid chronic myeloid leukemia-blast crisis BV173 and K562 cells; 15 of these were concordantly modulated in both lines. We focused on the miR-17-92 cluster because of its oncogenic role in tumors and found that: i) it is a direct MYB target; ii) it partially rescued the impaired proliferation and enhanced apoptosis of MYB-silenced BV173 cells. Moreover, we identified FRZB, a Wnt/ß-catenin pathway inhibitor, as a novel target of the miR-17-92 cluster. High expression of MYB in blast cells from 2 Ph+leukemia patients correlated positively with the miR-17-92 cluster and inversely with FRZB. This expression pattern was also observed in a microarray dataset of 122 Ph+acute lymphoblastic leukemias. In vivo experiments in NOD scid gamma mice injected with BV173 cells confirmed that FRZB functions as a Wnt/ß-catenin inhibitor even as they failed to demonstrate that this pathway is important for BV173-dependent leukemogenesis. These studies illustrate the global effects of MYB expression on the microRNAs profile of Ph+cells and supports the concept that the "MYB addiction" of these cells is, in part, caused by modulation of microRNA-regulated pathways affecting cell proliferation and survival.


Assuntos
Crise Blástica/metabolismo , Regulação Leucêmica da Expressão Gênica , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , MicroRNAs/biossíntese , Família Multigênica , Proteínas Proto-Oncogênicas c-myb/biossíntese , RNA Neoplásico/biossíntese , Ativação Transcricional , Animais , Crise Blástica/tratamento farmacológico , Crise Blástica/genética , Crise Blástica/patologia , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-myb/genética , RNA Neoplásico/genética , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Cancer Lett ; 433: 18-32, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29933048

RESUMO

Osteosarcoma (OS) is the most aggressive type of primary solid tumor that develops in bone. Whilst conventional chemotherapy can improve survival rates, the outcome for patients with metastatic or recurrent OS remains poor, so novel treatment agents and strategies are required. Research into new anticancer therapies has paved the way for the utilisation of natural compounds as they are typically less expensive and less toxic compared to conventional chemotherapeutics. Previously published works indicate that Agave exhibits anticancer properties, however potential molecular mechanisms remain poorly understood. In the present study, we investigate the anticancer effects of Agave leaf extract in OS cells suggesting that Agave inhibits cell viability, colony formation, and cell migration, and can induce apoptosis in OS cell lines. Moreover, Agave sensitizes OS cells to cisplatin (CDDP) and radiation, to overcome chemo- and radio-resistance. We demonstrate that Agave extract induces a marked decrease of Yes Associated Protein (YAP) and Tafazzin (TAZ) mRNA and protein expression upon treatment. We propose an initial mechanism of action in which Agave induces YAP/TAZ protein degradation, followed by a secondary event whereby Agave inhibits YAP/TAZ transcription, effectively deregulating the Nuclear Factor kappa B (NF-κB) p65:p50 heterodimers responsible for transcriptional induction of YAP and TAZ.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Agave/química , Neoplasias Ósseas/metabolismo , Osteossarcoma/metabolismo , Fosfoproteínas/metabolismo , Extratos Vegetais/farmacologia , Fatores de Transcrição/metabolismo , Aciltransferases , Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Fosfoproteínas/genética , Extratos Vegetais/química , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteólise , Tolerância a Radiação/efeitos dos fármacos , Fatores de Transcrição/genética , Proteínas de Sinalização YAP
5.
Oncotarget ; 7(15): 20532-48, 2016 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-26967561

RESUMO

We have previously shown that melatonin exerts tumor suppressor activities by inducing the p38-p53 axis. This occurred within a few hours while no data are available on how melatonin pathway can be sustained on the long term. Here we show that miR-24, which has been demonstrated to target genes involved in the DNA repair process, targets p38, p53, PML and H2AX simultaneously. We show that long-term treatment with melatonin can decrease miR-24 levels post-transcriptionally, which pairs with a long-wave regulation of genes involved in cell proliferation, DNA damage, RNA metabolism and cell shape and transformation. Moreover, we show that melatonin can inhibit cell proliferation and migration, at least in part, by downregulating miR-24. Furthermore, we propose the involvement of hnRNP A1, which is downregulated by melatonin and involved in miRNA processing, in the regulation of miR-24 levels by melatonin. We conclude showing that miR-24 is upregulated in colon, breast and head and neck datasets and its levels negatively correlate with overall survival.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Neoplasias do Colo/patologia , Melatonina/farmacologia , MicroRNAs/genética , Apoptose , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Proliferação de Células , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Feminino , Ribonucleoproteína Nuclear Heterogênea A1/genética , Ribonucleoproteína Nuclear Heterogênea A1/metabolismo , Humanos , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas
6.
Methods Mol Biol ; 1379: 189-99, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26608301

RESUMO

The efficacy of a given drug resides mainly on its ability to specifically target disease mechanisms. Natural products represent the leading source of bioactive molecules with a broad range of activities. It is becoming increasingly clear that natural compounds exert their chemopreventive or antitumoral activities targeting simultaneously diverse cellular pathways. Here we describe the use of antibody array to assess the effects of natural compounds on the expression of multiple proteins and of their posttranslational modifications in cellular systems. This might turn to be a very flexible application for cancer chemoprevention studies.


Assuntos
Anticorpos/imunologia , Produtos Biológicos/uso terapêutico , Avaliação Pré-Clínica de Medicamentos/métodos , Neoplasias/prevenção & controle , Análise Serial de Proteínas/métodos , Quimioprevenção , Coloração e Rotulagem
7.
PLoS One ; 10(4): e0124894, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25849303

RESUMO

Vitamin D plays a role in cancer development and acts through the vitamin D receptor (VDR). It regulates the action of hormone responsive genes and is involved in cell cycle regulation, differentiation and apoptosis. VDR is a critical component of the vitamin D pathway and different common single nucleotide polymorphisms have been identified. Cdx2 VDR polymorphism can play an important role in breast cancer, modulating the activity of VDR. The objective of this study is to assess the relationship between the Cdx2 VDR polymorphism and the activities of VDR in human breast cancer cell lines and carcinomas breast patients. Cdx2 VDR polymorphism and antiproliferative effects of vitamin D treatment were investigated in a panel of estrogen receptor-positive (MCF7 and T-47D) and estrogen receptor-negative (MDA-MB-231, SUM 159PT, SK-BR-3, BT549, MDA-MB-468, HCC1143, BT20 and HCC1954) human breast cancer cell lines. Furthermore, the potential relationship among Cdx2 VDR polymorphism and a number of biomarkers used in clinical management of breast cancer was assessed in an ad hoc set of breast cancer cases. Vitamin D treatment efficacy was found to be strongly dependent on the Cdx2 VDR status in ER-negative breast cancer cell lines tested. In our series of breast cancer cases, the results indicated that patients with variant homozygote AA were associated with bio-pathological characteristics typical of more aggressive tumours, such as ER negative, HER2 positive and G3. Our results may suggest a potential effect of Cdx2 VDR polymorphism on the efficacy of vitamin D treatment in aggressive breast cancer cells (estrogen receptor negative). These results suggest that Cdx2 polymorphism may be a potential biomarker for vitamin D treatment in breast cancer, independently of the VDR receptor expression.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proteínas de Homeodomínio/genética , Polimorfismo Genético , Receptores de Calcitriol/genética , Neoplasias da Mama/metabolismo , Fator de Transcrição CDX2 , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Homeodomínio/metabolismo , Humanos , Células MCF-7 , Estudos Retrospectivos , Vitamina D/farmacologia
8.
Lung Cancer ; 85(2): 197-204, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24863004

RESUMO

BACKGROUND: Thymic epithelial tumors (TET) are the most frequent human primary mediastinal tumors in adults. A deep biological characterization of the processes at the basis of the transformed phenotype could strongly improve our understanding of the morphological and clinical heterogeneity of these diseases. MicroRNAs (miRNAs) are non-coding RNAs involved in post-transcriptional regulation and their altered expression accounts for the pathogenesis of several tumors. OBJECTIVES: The aim of this study was to identify the miRNAs that are differentially expressed in tumor vs normal thymic tissues or among the different tumor histotypes and that could impact on the biology of TET. MATERIALS AND METHODS: microRNAs expression profiling was performed by microarray analysis of formalin-fixed paraffin embedded (FFPE) tissue from 54 thymic tumor samples and 12 normal counterparts, derived from two patient cohorts. RESULTS AND CONCLUSION: We identified groups of miRNAs differentially expressed between: (i) TET and normal thymic tissues, (ii) thymomas and thymic carcinomas, (iii) histotype groups. Moreover, we identified putative molecular pathways targeted by these differentially expressed miRNAs that could be involved in thymic carcinogenesis and in the maintenance and spreading of this tumor.


Assuntos
Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias Epiteliais e Glandulares/genética , Neoplasias do Timo/genética , Análise por Conglomerados , Receptores ErbB/genética , Humanos , Neoplasias Epiteliais e Glandulares/patologia , Timo/metabolismo , Neoplasias do Timo/patologia
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