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1.
Cell Oncol (Dordr) ; 40(3): 219-233, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28390038

RESUMO

PURPOSE: Hepatocellular carcinoma (HCC) is one of the most common human malignancies. It has frequently been associated with metabolic perturbations and liver damages. Various members of the family of acyl-CoA synthetases are known to be involved in the production of bioactive fatty acids, and altered expression of its encoding genes has been found to be involved in metabolic perturbations. For the development of novel diagnostic and therapeutic HCC options, a fundamental understanding of the mechanisms associated with the deregulation of candidate genes involved in metabolic perturbation is required. METHODS: A meta-analysis of multiple HCC mRNA profiles was performed to identify consistently deregulated genes. Expression of the acyl-CoA synthetase medium chain family member 3 (ACSM3) gene was subsequently assessed in different HCC tumor stages and correlated with various clinicopathological features. Transcription regulation, survival and pathway-associated features of the ACSM3 gene were investigated using integrative functional genomic and molecular cell biological methods. RESULTS: We found that expression of the ACSM3 gene was significantly reduced in HCC tissues and was frequently downregulated in patients exhibiting high alpha-fetoprotein (AFP) levels, high alanine aminotransferase (ALT) levels, multiple nodules and large tumors. Loss of ACSM3 expression was found to correlate with advanced HCC stages and a poor survival. In addition, HNF4α was found to positively regulate the expression of the ACSM3 gene, while PPARγ was found to transcriptionally repress it. Downregulation of ACSM3 expression was perceived upon activation of the TGFß, WNT, AKT and MYC signalling pathways. In addition, we found that ACSM3 expression correlates with fatty acid oxidation in HCC. CONCLUSION: Our data provide evidence for a differential expression and regulation of the ACSM3 gene in HCC, and may lay a foundation for therapeutically targeting fatty acid metabolism in these tumors.


Assuntos
Carcinoma Hepatocelular/patologia , Coenzima A Ligases/biossíntese , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Hepáticas/patologia , Adulto , Idoso , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Coenzima A Ligases/genética , Ácidos Graxos/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Masculino , Pessoa de Meia-Idade , Oxirredução , Transcriptoma
2.
Clin Lymphoma Myeloma Leuk ; 16(5): 253-263.e6, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27061493

RESUMO

PURPOSE: The biological response of electron beam radiation (EBR) in tumors remains underexplored. This study describes the molecular biological and genomic impact of EBR on tumor cells. METHODS: A mouse model bearing Dalton's lymphoma ascites cells was exposed to an 8-MeV pulsed electron beam, at a dose rate of 2 Gy/min using a microtron, a linear accelerator. The radiation-induced changes were assessed by histopathology, fluorescence-activated cell sorting, signaling pathway-focused reporter assays, and gene expression by microarray analysis. RESULTS: EBR was found to increase apoptosis and G2-M cell cycle arrest with concomitant tumor regression in vivo. The microarray data revealed that EBR induced tumor regression, apoptosis, and cell cycle arrest mediated by p53, PPAR, and SMAD2/3/4 signaling pathways. Activation of interferon regulatory factor and NFkB signaling were also found upon EBR. Chemo-genomics exploration revealed the possibility of drugs that can be effectively used in combination with EBR. CONCLUSION: For the first time, an 8-MeV pulse EBR induced genomic changes, and their consequence in molecular and biological processes were identified in lymphoma cells. The comprehensive investigation of radiation-mediated responses in cancer cells also revealed the potential therapeutic features of EBR.


Assuntos
Elétrons , Genômica , Linfoma/genética , Radiação Ionizante , Animais , Pontos de Checagem do Ciclo Celular/efeitos da radiação , Linhagem Celular Tumoral , Análise por Conglomerados , Biologia Computacional/métodos , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Elétrons/uso terapêutico , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genômica/métodos , Humanos , Linfoma/patologia , Linfoma/radioterapia , Masculino , Camundongos , Transdução de Sinais/efeitos da radiação , Transcriptoma , Carga Tumoral/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto
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