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1.
Mol Ther Nucleic Acids ; 18: 518-532, 2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31671345

RESUMO

Long non-coding RNAs (lncRNAs) have been shown to be crucial regulators in numerous human diseases. However, little is known about their effects on early recurrent miscarriage (RM). Here we aimed to investigate the role of lncRNA EPB41L4A-AS1 on placental trophoblast cell metabolic reprogramming, which might be involved in the pathogenesis of RM. After microarray and GEO database analyses, we found that EPB41L4A-AS1 was significantly increased in early RM placental tissue, and this increase may relate to estradiol-mediated upregulation of PGC-1α. EPB41L4A-AS1 overexpression inhibits glycolysis but increases the dependence on fatty acid oxidation in mitochondrion metabolism and suppresses the Warburg effect, which is necessary for rapid growth of the placental villus, leading to miscarriage. Mechanistic analyses demonstrated that EPB41L4A-AS1 functions as a lncRNA in the regulation of VDAC1 and HIF-1α expression through enhancement of H3K4me3 levels in the promoters of VDAC1 and HIF1A-AS1, a natural antisense transcript (NAT) lncRNA of HIF-1α. Taken together, these findings demonstrate that aberrant expression of EPB41L4A-AS1 is involved in the etiology of early RM, and it may be a candidate diagnostic hallmark and a potential therapeutic target for early RM treatment.

2.
Cell Mol Life Sci ; 76(15): 3005-3018, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31006037

RESUMO

The accumulation of intracellular ß-amyloid peptide (Aß) is important pathological characteristic of Alzheimer's disease (AD). However, the exact underlying molecular mechanism remains to be elucidated. Here, we reported that Nuclear Paraspeckle Assembly Transcript 1 (NEAT1), a long n on-coding RNA, exhibits repressed expression in the early stage of AD and its down-regulation declines neuroglial cell mediating Aß clearance via inhibiting expression of endocytosis-related genes. We find that NEAT1 is associated with P300/CBP complex and its inhibition affects H3K27 acetylation (H3K27Ac) and H3K27 crotonylation (H3K27Cro) located nearby to the transcription start site of many genes, including endocytosis-related genes. Interestingly, NEAT1 inhibition down-regulates H3K27Ac but up-regulates H3K27Cro through repression of acetyl-CoA generation. NEAT1 also mediates the binding between STAT3 and H3K27Ac but not H3K27Cro. Therefore, the decrease of H3K27Ac and/or the increase of H3K27Cro declines expression of multiple related genes. Collectively, this study first reveals the different roles of H3K27Ac and H3K27Cro in regulation of gene expression and provides the insight of the epigenetic regulatory mechanism of NEAT1 in gene expression and AD pathology.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Fragmentos de Peptídeos/metabolismo , RNA Longo não Codificante/metabolismo , Acetilcoenzima A/metabolismo , Acetilação/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/farmacologia , Animais , Caveolina 2/antagonistas & inibidores , Caveolina 2/genética , Caveolina 2/metabolismo , Modelos Animais de Doenças , Epigênese Genética , Expressão Gênica/efeitos dos fármacos , Histonas/metabolismo , Camundongos , Camundongos Transgênicos , Neuroglia/citologia , Neuroglia/metabolismo , Fragmentos de Peptídeos/farmacologia , Interferência de RNA , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Fator de Transcrição STAT3/metabolismo , Fator de Crescimento Transformador beta2/antagonistas & inibidores , Fator de Crescimento Transformador beta2/genética , Fator de Crescimento Transformador beta2/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo
3.
EBioMedicine ; 41: 200-213, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30796006

RESUMO

BACKGROUND: LncRNAs have been found to be involved in various aspects of biological processes. In this study, we aimed to uncover the molecular mechanisms of lncRNA EPB41L4A-AS1 in regulating glycolysis and glutaminolysis in cancer cells. METHODS: The expression of EPB41L4A-AS1 in cancer patients was analyzed in TCGA and GEO datasets. The level of cellular metabolism was determined by extracellular flux analyzer. The relationship between p53 and EPB41L4A-AS1 was explored by qRT-PCR, luciferase assay and ChIP assay. The interactions between EPB41L4A-AS1 and HDAC2 or NPM1 were determined by RNA immunoprecipitation, RNA pull-down assay and RNA-FISH- immunofluorescence. FINDINGS: EPB41L4A-AS1 was a p53-regulated gene. Low expression and deletion of lncRNA EPB41L4A-AS1 were found in a variety of human cancers and associated with poor prognosis of cancer patients. Knock down EPB41L4A-AS1 expression triggered Warburg effect, demonstrated as increased aerobic glycolysis and glutaminolysis. EPB41L4A-AS1 interacted and colocalized with HDAC2 and NPM1 in nucleolus. Silencing EPB41L4A-AS1 reduced the interaction between HDAC2 and NPM1, released HDAC2 from nucleolus and increased its distribution in nucleoplasm, enhanced HDAC2 occupation on VHL and VDAC1 promoter regions, and finally accelerated glycolysis and glutaminolysis. Depletion of EPB41L4A-AS1 increased the sensitivity of tumor to glutaminase inhibitor in tumor therapy. INTERPRETATION: EPB41L4A-AS1 functions as a repressor of the Warburg effect and plays important roles in metabolic reprogramming of cancer.


Assuntos
Núcleo Celular/metabolismo , Glicólise , Histona Desacetilase 2/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/genética , Neoplasias/metabolismo , RNA Longo não Codificante/genética , Transporte Ativo do Núcleo Celular , Animais , Glutaminase/metabolismo , Células HeLa , Células Hep G2 , Humanos , Camundongos , Camundongos Nus , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , RNA Longo não Codificante/metabolismo
4.
Apoptosis ; 22(11): 1321-1335, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28936716

RESUMO

Reactive oxygen species (ROS), a group of ions and molecules, include hydroxyl radicals (·OH), alkoxyl radicals, superoxide anion (O2·-), singlet oxygen (1O2) and hydrogen peroxide (H2O2). Hydroxyl radicals and alkoxyl radicals are extremely and highly reactive species respectively. Endogenous ROS are mainly formed in mitochondrial respiratory chain. Low levels of ROS play important roles in regulating biological functions in mammalian cells. However, excess production of ROS can induce cell death by oxidative damaging effects to intracellular biomacromolecules. Cancer cell death types induced by ROS include apoptotic, autophagic, ferroptotic and necrotic cell death. Since abnormal metabolism in cancer cells, they have higher ROS content compared to normal cells. The higher endogenous ROS levels in cancer cells endow them more susceptible to the ROS-induction treatment. Indeed, some anticancer drugs currently used in clinic, such as molecular targeted drugs and chemotherapeutic agents, effectively kill cancer cells by inducing ROS generation. In addition, photodynamic therapy (PDT) is mainly based on induction of ROS burst to kill cancer cells. The mechanism of cell death induced by radiotherapy using ionizing radiation also refers to ROS production. Moreover, ROS play an important role in tumor immune therapy. Altogether, combining above traditional treatments with ROS-induced agents will be considered as a promising strategy in cancer therapy. In this review, we focus on our current understanding of the anticancer effects of ROS.


Assuntos
Complexo de Proteínas da Cadeia de Transporte de Elétrons/genética , Regulação Neoplásica da Expressão Gênica , Terapia de Alvo Molecular/métodos , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Espécies Reativas de Oxigênio/agonistas , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos da radiação , Necrose/induzido quimicamente , Necrose/genética , Necrose/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Radiação Ionizante , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
5.
Biomater Sci ; 5(10): 2048-2055, 2017 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-28736778

RESUMO

Black phosphorus (BP), a new type of two-dimensional nanomaterial, has attracted crucial attention in recent years owing to its excellent properties and great potential in various chemical, physical, and biological fields. In this study, BP nanosheets loaded with Au nanoparticles (BP-Au NSs) are obtained by a one-step facile synthetic method. The Au nanostructures can not only enhance the photothermal efficiency of the nanocomposites, but also endow BP-Au NSs with the potential to act as effective surface-enhanced Raman scattering (SERS) substrates for Raman biodetection. Cancer photothermal therapy (PTT) has been carried out in vitro and in vivo using BP-Au NSs as nanoagents. Under irradiation by an 808 nm laser, BP-Au NSs are capable of producing sufficient hyperthermia to destroy cancer cells, and the transplanted tumors in most of the tumor-bearing mice disappeared; BP-Au NSs are more effective than bare BP nanosheets. The PTT effect can also be monitored by a Raman technique that benefits from the high SERS activity of the BP-Au NSs. The molecular fingerprint features of breast tumors before and after PTT treatment were clearly identified using SERS analysis. The theranostic applications of BP-Au NSs exhibit promising potential in biomedicine.


Assuntos
Ouro/química , Neoplasias Mamárias Experimentais/terapia , Nanocompostos/uso terapêutico , Fósforo/química , Fototerapia/métodos , Animais , Linhagem Celular Tumoral , Técnicas de Química Sintética , Feminino , Neoplasias Mamárias Experimentais/patologia , Nanopartículas Metálicas/química , Camundongos , Nanotecnologia , Análise Espectral Raman , Resultado do Tratamento
6.
Cell Death Dis ; 7(11): e2454, 2016 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-27809310

RESUMO

Estrogen-dependent breast cancer is often treated with the aromatase inhibitors or estrogen receptor (ER) antagonists. Tamoxifen as a major ER antagonist is usually used to treat those patients with ERα-positive breast cancer. However, a majority of patients with ERα positive fail to respond to tamoxifen due to the presence of intrinsic or acquired resistance to the drug. Altered expression and functions of microRNAs (miRNAs) have been reportedly associated with tamoxifen resistance. In this study, we investigated the role of miR-27b-3p in resistance of breast cancer to tamoxifen. MiR-27b-3p levels were remarkably reduced in the tamoxifen-resistant breast cancer cells compared with their parental cells. In addition, miR-27b-3p was also significantly downregulated in breast tumor tissues relative to adjacent non-tumor tissues. Moreover, the expression levels of miR-27b-3p were lower in the breast cancer tissues from tamoxifen-resistant patients compared with that from untreated-tamoxifen patients. Notably, tamoxifen repressed miR-27b-3p expression, whereas estrogen induced miR-27b-3p expression in breast cancer cells. Besides, we provided experimental evidences that miR-27b-3p enhances the sensitivity of breast cancer cells to tamoxifen in vitro and in vivo models. More importantly, we validated that miR-27b-3p directly targeted and inhibited the expression of nuclear receptor subfamily 5 group A member 2 (NR5A2) and cAMP-response element binding protein 1 (CREB1) and therefore augmented tamoxifen-induced cytotoxicity in breast cancer. Lastly, miR-27b-3p levels were found to be significantly negatively correlated with both NR5A2 and CREB1 levels in breast cancer tissues. Our findings provided further evidence that miR-27b-3p might be considered as a novel and potential target for the diagnosis and treatment of tamoxifen-resistant breast cancer.


Assuntos
Neoplasias da Mama/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , MicroRNAs/genética , Receptores Citoplasmáticos e Nucleares/genética , Tamoxifeno/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Neoplasias da Mama/patologia , Sobrevivência Celular/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Regulação para Baixo/genética , Resistencia a Medicamentos Antineoplásicos/genética , Estrogênios/farmacologia , Feminino , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/metabolismo , Modelos Biológicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Cell Death Dis ; 7(11): e2463, 2016 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-27831559

RESUMO

Chemoresistance is a major obstacle to effective breast cancer chemotherapy. However, the underlying molecular mechanisms remain unclear. In this study, nuclear receptor coactivator 3 (NCOA3) was found to be significantly increased in taxol-resistant breast cancer tissues and cells. Moreover, overexpression of NCOA3 enhanced breast cancer cell resistance to taxol, whereas depletion of NCOA3 decreased taxol resistance. Subsequently, we investigated whether NCOA3 expression was regulated by miRNAs in breast cancer. By bioinformatics prediction in combination with the data of previous report, miR-17 and miR-20b were selected as the potential miRNAs targeting NCOA3. By real-time PCR analysis, we found that miR-17 and miR-20b were significantly reduced in taxol-resistant breast cancer tissues and cells. In addition, we provided some experimental evidences that miR-17 and miR-20b attenuated breast cancer resistance to taxol in vitro and in vivo models. Furthermore, by luciferase reporter assays, we further validated that both miR-17 and miR-20b directly binded the 3'-untranslated region of NCOA3 mRNA and inhibited its expression in breast cancer cells. Finally, both miR-17 and miR-20b levels were found to be significantly negatively correlated with NCOA3 mRNA levels in breast cancer tissues. Together, our results indicated that loss of miR-17 and miR-20b enhanced breast cancer resistance to taxol by upregulating NCOA3 levels. Our study suggested miR-17, miR-20b and NCOA3 may serve as some predictive biomarkers and potential therapeutic targets in taxol-resistant breast cancer treatment.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , MicroRNAs/genética , Coativador 3 de Receptor Nuclear/genética , Paclitaxel/uso terapêutico , Regulação para Cima/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Sequência de Bases , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos Nus , MicroRNAs/metabolismo , Coativador 3 de Receptor Nuclear/metabolismo , Paclitaxel/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tamoxifeno/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
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