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1.
Cells ; 9(8)2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32717825

RESUMO

The critical role of the Hippo pathway has been recently investigated in various cancers, but little is known about its role in glioblastoma (GBM). In order to evaluate the clinical relevance of the Hippo pathway in GBM, we generated a core gene expression signature from four different previously-established silence of Hippo pathway (SOH) signatures. Based on a newly generated core SOH signature, a SOH and active Hippo pathway (AH) was predicted in GBM samples from The Cancer Genome Atlas (TCGA) and validated in a separate cohort. A comparative analysis was performed on multi-panel genomic datasets from TCGA and the possible association of SOH with immune activity and epithelial mesenchymal transition was also evaluated. The SOH signature was associated with poor prognosis in GBM in both cohorts. Expression levels of CTGF and CYR61, the most reliable and well-known downstream targets of YAP1, were markedly increased in the SOH subgroup of GBM patients. SOH signature was strongly associated with a high immune signature score and mesenchymal features. Genes differentially expressed between SOH and AH groups revealed many markers for inhibitory immune checkpoints and M2-polarized macrophages were upregulated in the SOH subgroup, suggesting that SOH may induce the resistance of cancer cells to host immune response in GBM. In summary, SOH is significantly associated with the poor prognosis of GBM patients and is possibly mediated by pro-tumoral immunosuppression.


Assuntos
Neoplasias Encefálicas/genética , Glioblastoma/genética , Terapia de Imunossupressão/métodos , Proteínas Serina-Treonina Quinases/genética , Neoplasias Encefálicas/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/metabolismo , Via de Sinalização Hippo , Humanos , Masculino
2.
Cell Rep ; 17(6): 1621-1631, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27806300

RESUMO

Even though hyperthermia is a promising treatment for cancer, the relationship between specific temperatures and clinical benefits and predictors of sensitivity of cancer to hyperthermia is poorly understood. Ovarian and uterine tumors have diverse hyperthermia sensitivities. Integrative analyses of the specific gene signatures and the differences in response to hyperthermia between hyperthermia-sensitive and -resistant cancer cells identified CTGF as a key regulator of sensitivity. CTGF silencing sensitized resistant cells to hyperthermia. CTGF small interfering RNA (siRNA) treatment also sensitized resistant cancers to localized hyperthermia induced by copper sulfide nanoparticles and near-infrared laser in orthotopic ovarian cancer models. CTGF silencing aggravated energy stress induced by hyperthermia and enhanced apoptosis of hyperthermia-resistant cancers.


Assuntos
Fator de Crescimento do Tecido Conjuntivo/metabolismo , Hipertermia Induzida , Neoplasias Ovarianas/metabolismo , Neoplasias Uterinas/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Genes Neoplásicos , Humanos , Camundongos , Modelos Biológicos , Neoplasias Ovarianas/genética , Proteômica , Neoplasias Uterinas/genética
3.
Sci Rep ; 6: 30217, 2016 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-27456065

RESUMO

Disruption of the TGF-ß pathway is associated with liver fibrosis and suppression of liver tumorigenesis, conditions associated with low Vitamin D (VD) levels. However, potential contributions of VD to liver tumor progression in the context of TGF-ß signaling remain unexplored. Our analyses of VD deprivation (VDD) in in vivo models of liver tumor formation revealed striking three-fold increases in tumor burden in Smad3(+/-) mice, with a three-fold increase in TLR7 expression compared to controls. ChIP and transcriptional assays confirm Smad3 binding at two TLR7 promoter SBE sites. Molecular interactions between TGF-ß pathway and VDD were validated clinically, where an absence of VD supplementation was associated with low TGF-ß pathway member expression levels and ß-catenin activation in fibrotic/cirrhotic human liver tissues. Subsequent supplementing VD led to restoration of TGF-ß member expression with lower ß-catenin levels. Bioinformatics analysis provides positive supportive correlation between somatic mutations for VD-related genes and the TGF-ß pathway. We conclude that VDD promotes tumor growth in the context of Smad3 disruption, potentially through regulation of TLR7 expression and ß-catenin activation. VD could therefore be a strong candidate for liver cancer prevention in the context of aberrant Smad3 signaling.


Assuntos
Neoplasias Hepáticas Experimentais/patologia , Glicoproteínas de Membrana/metabolismo , Proteína Smad3/genética , Receptor 7 Toll-Like/metabolismo , Fator de Crescimento Transformador beta/genética , Deficiência de Vitamina D/complicações , Proteínas Wnt/metabolismo , Animais , Humanos , Neoplasias Hepáticas Experimentais/complicações , Masculino , Camundongos , Camundongos Transgênicos , Transdução de Sinais , Vitamina D/administração & dosagem
4.
Anticancer Res ; 34(2): 811-817, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24511017

RESUMO

AIM: We aimed to investigate the clinical significance of the activation of Yes-Associated Protein 1 (YAP1), a key downstream effector of Hippo tumor-suppressor pathway, in ovarian cancer. MATERIALS AND METHODS: A gene expression signature reflecting activation of YAP1 was developed from gene expression data of 267 samples from patients with ovarian cancer. A refined ovarian cancer YAP1 signature was validated in an independent ovarian cancer cohort (n=185). Associations between the YAP1 signature and prognosis were assessed using Kaplan-Meier plots, the log-rank test, and a Cox proportional hazards model. RESULTS: We identified a 612-gene expression signature reflecting YAP1 activation in ovarian cancer. In multivariate analysis, the signature was an independent predictor of overall survival (hazard ratio=1.66; 95% confidence interval=1.1 to 2.53; p=0.01). In subset analysis, the signature identified patients likely to benefit from taxane-based adjuvant chemotherapy. CONCLUSION: Activation of YAP1 is significantly associated with prognosis and the YAP1 signature can predict response to taxane-based adjuvant chemotherapy in patients with ovarian cancer.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Fosfoproteínas/genética , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise por Conglomerados , Estudos de Coortes , Resistencia a Medicamentos Antineoplásicos , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Via de Sinalização Hippo , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias Ovarianas/metabolismo , Fosfoproteínas/biossíntese , Fosfoproteínas/metabolismo , Prognóstico , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Taxoides/administração & dosagem , Fatores de Transcrição , Proteínas de Sinalização YAP , Adulto Jovem
5.
EMBO Mol Med ; 4(2): 125-41, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22253197

RESUMO

Cancer cells are metabolically stressed during tumour progression due to limited tumour vascularity and resultant nutrient, growth factor and oxygen deficiency that can induce cell death and inhibit tumour growth. We demonstrate that Rab25, a small GTPase involved in endosomal recycling, that is genomically amplified in multiple tumour lineages, is a key regulator of cellular bioenergetics and autophagy. RAB25 enhanced survival during nutrient stress by preventing apoptosis and autophagy via binding and activating AKT leading to increased glucose uptake and improved cellular bioenergetics. Unexpectedly, Rab25 induced the accumulation of glycogen in epithelial cancer cells, a process not previously identified. Strikingly, an increase in basal ATP levels combined with AKT-dependent increases in glucose uptake and glycogen storage allowed maintenance of ATP levels during bioenergetic stress. The clinical relevance of these findings was validated by the ability of a Rab25-dependent expression profile enriched for bioenergetics targets to identify patients with a poor prognosis. Thus, Rab25 is an unexpected regulator of cellular bioenergetics implicated as a useful biomarker and potential therapeutic target.


Assuntos
Trifosfato de Adenosina/metabolismo , Glicogênio/metabolismo , Neoplasias/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo , Apoptose , Autofagia , Morte Celular/fisiologia , Metabolismo Energético , Humanos , Células Tumorais Cultivadas , Proteínas rab de Ligação ao GTP/genética
6.
Mol Cancer Ther ; 10(12): 2350-62, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21992792

RESUMO

Tumor cell proliferation requires both growth signals and sufficient cellular bioenergetics. The AMP-activated protein kinase (AMPK) pathway seems dominant over the oncogenic signaling pathway suppressing cell proliferation. This study investigated the preclinical efficacy of targeting the tumor bioenergetic pathway using a glycolysis inhibitor 2-deoxyglucose (2DG) and AMPK agonists, AICAR and metformin. We evaluated the in vitro antitumor activity of 2DG, metformin or AICAR alone, and 2DG in combination either with metformin or AICAR. We examined in vivo efficacy using xenograft mouse models. 2DG alone was not sufficient to promote tumor cell death, reflecting the limited efficacy showed in clinical trials. A combined use of 2DG and AICAR also failed to induce cell death. However, 2DG and metformin led to significant cell death associated with decrease in cellular ATP, prolonged activation of AMPK, and sustained autophagy. Gene expression analysis and functional assays revealed that the selective AMPK agonist AICAR augments mitochondrial energy transduction (OXPHOS) whereas metformin compromises OXPHOS. Importantly, forced energy restoration with methyl pyruvate reversed the cell death induced by 2DG and metformin, suggesting a critical role of energetic deprivation in the underlying mechanism of cell death. The combination of 2DG and metformin inhibited tumor growth in mouse xenograft models. Deprivation of tumor bioenergetics by dual inhibition of energy pathways might be an effective novel therapeutic approach for a broad spectrum of human tumors.


Assuntos
Desoxiglucose/uso terapêutico , Metabolismo Energético/efeitos dos fármacos , Metformina/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Desoxiglucose/administração & dosagem , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Metformina/administração & dosagem , Camundongos , Camundongos Nus , Neoplasias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Gastroenterology ; 141(2): 476-85, 485.e1-11, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21684283

RESUMO

BACKGROUND & AIMS: Gastric cancer (GC) is a heterogeneous disease comprising multiple subtypes that have distinct biological properties and effects in patients. We sought to identify new, intrinsic subtypes of GC by gene expression analysis of a large panel of GC cell lines. We tested if these subtypes might be associated with differences in patient survival times and responses to various standard-of-care cytotoxic drugs. METHODS: We analyzed gene expression profiles for 37 GC cell lines to identify intrinsic GC subtypes. These subtypes were validated in primary tumors from 521 patients in 4 independent cohorts, where the subtypes were determined by either expression profiling or subtype-specific immunohistochemical markers (LGALS4, CDH17). In vitro sensitivity to 3 chemotherapy drugs (5-fluorouracil, cisplatin, oxaliplatin) was also assessed. RESULTS: Unsupervised cell line analysis identified 2 major intrinsic genomic subtypes (G-INT and G-DIF) that had distinct patterns of gene expression. The intrinsic subtypes, but not subtypes based on Lauren's histopathologic classification, were prognostic of survival, based on univariate and multivariate analysis in multiple patient cohorts. The G-INT cell lines were significantly more sensitive to 5-fluorouracil and oxaliplatin, but more resistant to cisplatin, than the G-DIF cell lines. In patients, intrinsic subtypes were associated with survival time following adjuvant, 5-fluorouracil-based therapy. CONCLUSIONS: Intrinsic subtypes of GC, based on distinct patterns of expression, are associated with patient survival and response to chemotherapy. Classification of GC based on intrinsic subtypes might be used to determine prognosis and customize therapy.


Assuntos
Biomarcadores Tumorais/metabolismo , Caderinas/metabolismo , Galectina 4/metabolismo , Perfilação da Expressão Gênica , Neoplasias Gástricas/classificação , Neoplasias Gástricas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Cisplatino/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Humanos , Estimativa de Kaplan-Meier , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Adulto Jovem
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