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1.
Nat Commun ; 11(1): 4484, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901027

RESUMO

Chronic stress is a key risk factor for mood disorders like depression, but the stress-induced changes in brain circuit function and gene expression underlying depression symptoms are not completely understood, hindering development of novel treatments. Because of its projections to brain regions regulating reward and anxiety, the ventral hippocampus is uniquely poised to translate the experience of stress into altered brain function and pathological mood, though the cellular and molecular mechanisms of this process are not fully understood. Here, we use a novel method of circuit-specific gene editing to show that the transcription factor ΔFosB drives projection-specific activity of ventral hippocampus glutamatergic neurons causing behaviorally diverse responses to stress. We establish molecular, cellular, and circuit-level mechanisms for depression- and anxiety-like behavior in response to stress and use circuit-specific gene expression profiling to uncover novel downstream targets as potential sites of therapeutic intervention in depression.


Assuntos
Aprendizagem da Esquiva/fisiologia , Hipocampo/fisiologia , Proteínas Proto-Oncogênicas c-fos/fisiologia , Animais , Ansiedade/metabolismo , Comportamento Animal/fisiologia , Técnicas de Inativação de Genes , Inativação Gênica , Hipocampo/anatomia & histologia , Hipocampo/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-fos/deficiência , Proteínas Proto-Oncogênicas c-fos/genética , Comportamento Social , Estresse Psicológico
2.
Nucleic Acids Res ; 48(17): 9550-9570, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32810208

RESUMO

Genomic enhancer elements regulate gene expression programs important for neuronal fate and function and are implicated in brain disease states. Enhancers undergo bidirectional transcription to generate non-coding enhancer RNAs (eRNAs). However, eRNA function remains controversial. Here, we combined Assay for Transposase-Accessible Chromatin using Sequencing (ATAC-Seq) and RNA-Seq datasets from three distinct neuronal culture systems in two activity states, enabling genome-wide enhancer identification and prediction of putative enhancer-gene pairs based on correlation of transcriptional output. Notably, stimulus-dependent enhancer transcription preceded mRNA induction, and CRISPR-based activation of eRNA synthesis increased mRNA at paired genes, functionally validating enhancer-gene predictions. Focusing on enhancers surrounding the Fos gene, we report that targeted eRNA manipulation bidirectionally modulates Fos mRNA, and that Fos eRNAs directly interact with the histone acetyltransferase domain of the enhancer-linked transcriptional co-activator CREB-binding protein (CBP). Together, these results highlight the unique role of eRNAs in neuronal gene regulation and demonstrate that eRNAs can be used to identify putative target genes.


Assuntos
Elementos Facilitadores Genéticos , Regulação da Expressão Gênica , Neurônios/fisiologia , RNA/fisiologia , Animais , Proteína de Ligação a CREB/genética , Proteína de Ligação a CREB/metabolismo , Sistemas CRISPR-Cas , Células Cultivadas , Cromatina/metabolismo , Células HEK293 , Humanos , Neurônios/citologia , Proteínas Proto-Oncogênicas c-fos/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno , Ratos , Reprodutibilidade dos Testes , Análise de Sequência de RNA , Imagem Individual de Molécula
3.
Toxicol Lett ; 333: 140-149, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32755622

RESUMO

Chrysotile is the only type of asbestos still widely exploited, and all kinds of asbestos including chrysotile was classified as a group I carcinogen by the IARC. There is a wealth of evidence that chrysotile can cause a range of cancers, including cancer of the lung, larynx, ovary, and mesothelioma. As the second largest chrysotile producer, China is at great risk of occupational exposure. Moreover, our previous experiment and some other studies have shown that the toxicity of mineral fibre from various mining areas may be different. To explore the oncogenic potential of chrysotile from different mining areas of China, Wistar rats were administered 0.5 mL chrysotile asbestos suspension of 2.0 mg/mL (from Akesai, Gansu; Mangnai, Qinghai; XinKang, Sichuan; and Shannan, Shaanxi) dissolved in saline by intratracheal instillation once-monthly and were sacrificed at 1 mo, 6 mo, and 12 mo. Our results found that chrysotile caused lung inflammation and lung tissue damage. Moreover, prolonged exposure of chrysotile can induce inactivation of the tumor suppressor gene P53 and P16 and activation of the protooncogene C-JUN and C-FOS both in the messenger RNA and protein level. In addition, chrysotile from Shannan and XinKang has a stronger effect which may link to cancer than that from Akesai and Mangnai.


Assuntos
Asbestos Serpentinas/toxicidade , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Poluentes Ambientais/toxicidade , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Pulmão/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Asbestos Serpentinas/química , Líquido da Lavagem Broncoalveolar/citologia , China , Inibidor p16 de Quinase Dependente de Ciclina/genética , Citocinas/metabolismo , Poluentes Ambientais/química , Expressão Gênica/efeitos dos fármacos , Exposição por Inalação/efeitos adversos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Contagem de Leucócitos , Leucócitos/citologia , Leucócitos/efeitos dos fármacos , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Fibras Minerais/toxicidade , Proteínas Proto-Oncogênicas c-fos/genética , Ratos Wistar , Proteína Supressora de Tumor p53/genética
4.
Proc Natl Acad Sci U S A ; 117(32): 19556-19565, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32694207

RESUMO

Opioid addiction is a chronic, relapsing disorder associated with persistent changes in brain plasticity. Reconfiguration of neuronal connectivity may explain heightened abuse liability in individuals with a history of chronic drug exposure. To characterize network-level changes in neuronal activity induced by chronic opiate exposure, we compared FOS expression in mice that are morphine-naïve, morphine-dependent, or have undergone 4 wk of withdrawal from chronic morphine exposure, relative to saline-exposed controls. Pairwise interregional correlations in FOS expression data were used to construct network models that reveal a persistent reduction in connectivity strength following opiate dependence. Further, we demonstrate that basal gene expression patterns are predictive of changes in FOS correlation networks in the morphine-dependent state. Finally, we determine that regions of the hippocampus, striatum, and midbrain are most influential in driving transitions between opiate-naïve and opiate-dependent brain states using a control theoretic approach. This study provides a framework for predicting the influence of specific therapeutic interventions on the state of the opiate-dependent brain.


Assuntos
Encéfalo/fisiopatologia , Dependência de Morfina/fisiopatologia , Rede Nervosa/fisiopatologia , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Conectoma , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Neurológicos , Morfina/administração & dosagem , Morfina/efeitos adversos , Dependência de Morfina/metabolismo , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/metabolismo , Plasticidade Neuronal/genética , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Síndrome de Abstinência a Substâncias/genética , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/fisiopatologia
5.
Am J Physiol Cell Physiol ; 319(2): C345-C358, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32520608

RESUMO

The maturity of osteoblasts by proliferation and differentiation in preosteoblasts is essential for maintaining bone homeostasis. The beneficial effects of vitamin D on bone homeostasis in mammals have been demonstrated experimentally and clinically. However, the direct actions of vitamin D on preosteoblasts remain to be fully elucidated. In this study, we found that the functional activity of intermediate-conductance Ca2+-activated K+ channels (KCa3.1) positively regulated cell proliferation in MC3T3-E1 cells derived from mouse preosteoblasts by enhancing intracellular Ca2+ signaling. We examined the effects of treatment with vitamin D receptor (VDR) agonist on the expression and activity of KCa3.1 by real-time PCR examination, Western blotting, Ca2+ imaging, and patch clamp analyses in mouse MC3T3-E1 cells. Following the downregulation of KCa3.1 transcriptional modulators such as Fra-1 and HDAC2, KCa3.1 activity was suppressed in MC3T3-E1 cells treated with VDR agonists. Furthermore, application of the KCa3.1 activator DCEBIO attenuated the VDR agonist-evoked suppression of cell proliferation rate. These findings suggest that a decrease in KCa3.1 activity is involved in the suppression of cell proliferation rate in VDR agonist-treated preosteoblasts. Therefore, KCa3.1 plays an important role in bone formation by promoting osteoblastic proliferation under physiological conditions.


Assuntos
Canais de Potássio Ativados por Cálcio de Condutância Intermediária/genética , Osteoblastos/metabolismo , Receptores de Calcitriol/genética , Vitamina D/genética , Células 3T3 , Animais , Benzimidazóis/farmacologia , Cálcio/metabolismo , Sinalização do Cálcio/genética , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Histona Desacetilase 2/genética , Humanos , Camundongos , Osteoblastos/citologia , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Técnicas de Patch-Clamp , Proteínas Proto-Oncogênicas c-fos/genética , Receptores de Calcitriol/agonistas , Transdução de Sinais/efeitos dos fármacos
6.
Nat Neurosci ; 23(8): 952-958, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32514139

RESUMO

In Alzheimer's disease (AD), hippocampus-dependent memories underlie an extensive decline. The neuronal ensemble encoding a memory, termed engram, is partially recapitulated during memory recall. Artificial activation of an engram can restore memory in a mouse model of early AD, but its fate and the factors that render the engram nonfunctional are yet to be revealed. Here, we used repeated two-photon in vivo imaging to analyze fosGFP transgenic mice (which express enhanced GFP under the Fos promoter) performing a hippocampus-dependent memory task. We found that partial reactivation of the CA1 engram during recall is preserved under AD-like conditions. However, we identified a novelty-like ensemble that interfered with the engram and thus compromised recall. Mimicking a novelty-like ensemble in healthy mice was sufficient to affect memory recall. In turn, reducing the novelty-like signal rescued the recall impairment under AD-like conditions. These findings suggest a novel mechanistic process that contributes to the deterioration of memories in AD.


Assuntos
Doença de Alzheimer/fisiopatologia , Hipocampo/fisiologia , Rememoração Mental/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Neurônios/fisiologia , Optogenética , Proteínas Proto-Oncogênicas c-fos/genética
8.
J Neuroimmunol ; 344: 577244, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32330748

RESUMO

Toll-like receptor 2 (TLR2) recognizes a wide range of microbial molecules and plays critical roles in the initiation of innate immune responses. In the present study, we aimed to investigate whether the depletion of microglia and macrophages with clodronate liposomes (Clod-Lips) attenuates the activation of mouse brain circuits for TLR2-mediated inflammation and hypothermia. The peripheral administration of the TLR2 agonist zymosan induced nuclear factor-κB activation in microglia and macrophages and Fos expression in astrocytes/tanycytes and neurons in the circumventricular organs (CVOs). The depletion of microglia and macrophages with Clod-Lips markedly decreased zymosan-induced Fos expression in astrocytes/tanycytes and neurons in the CVOs. The treatment with Clod-Lips significantly attenuated zymosan-induced hypothermia. These results indicate that microglia and macrophages in the CVOs participate in the initiation and transmission of inflammatory responses after the peripheral administration of zymosan.


Assuntos
Ácido Clodrônico/administração & dosagem , Hipotermia/metabolismo , Macrófagos/metabolismo , Microglia/metabolismo , Proteínas Proto-Oncogênicas c-fos/biossíntese , Zimosan/toxicidade , Fatores Etários , Animais , Conservadores da Densidade Óssea/administração & dosagem , Portadores de Fármacos/administração & dosagem , Expressão Gênica , Hipotermia/induzido quimicamente , Hipotermia/prevenção & controle , Lipossomos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/genética , Receptor 2 Toll-Like/agonistas , Receptor 2 Toll-Like/metabolismo
9.
J Biol Regul Homeost Agents ; 34(1 Suppl. 2): 1-5, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32270661

RESUMO

Collagenated heretologous cortico-cancelleus bone mix (CHCCBM) is largely employed in maxillary and dental surgery for regeneration procedures, and is similar to human bone from chemical and physical point of view and promotes osteogenesis. In order to get more inside how this biomaterial induces osteoblast gene expression to promote bone formation, the mRNA levels of bone related genes were compared in human osteoblasts and dental pulp stem cells, using real time RT-PCR. The obtained results demonstrated that CHCCBM enhance stem cells differentiation and deposition of matrix by the activation of osteoblast related genes SP7, FOSL1 and SPP1.


Assuntos
Polpa Dentária/citologia , Osteoblastos/citologia , Osteogênese , Células-Tronco/citologia , Diferenciação Celular , Células Cultivadas , Humanos , Osteopontina/genética , Proteínas Proto-Oncogênicas c-fos/genética , RNA Mensageiro/genética , Fator de Transcrição Sp7/genética
10.
PLoS Genet ; 16(3): e1008470, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32203506

RESUMO

Cell invasion allows cells to migrate across compartment boundaries formed by basement membranes. Aberrant cell invasion is a first step during the formation of metastases by malignant cancer cells. Anchor cell (AC) invasion in C. elegans is an excellent in vivo model to study the regulation of cell invasion during development. Here, we have examined the function of egl-43, the homolog of the human Evi1 proto-oncogene (also called MECOM), in the invading AC. egl-43 plays a dual role in this process, firstly by imposing a G1 cell cycle arrest to prevent AC proliferation, and secondly, by activating pro-invasive gene expression. We have identified the AP-1 transcription factor fos-1 and the Notch homolog lin-12 as critical egl-43 targets. A positive feedback loop between fos-1 and egl-43 induces pro-invasive gene expression in the AC, while repression of lin-12 Notch expression by egl-43 ensures the G1 cell cycle arrest necessary for invasion. Reducing lin-12 levels in egl-43 depleted animals restored the G1 arrest, while hyperactivation of lin-12 signaling in the differentiated AC was sufficient to induce proliferation. Taken together, our data have identified egl-43 Evi1 as an important factor coordinating cell invasion with cell cycle arrest.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , Pontos de Checagem do Ciclo Celular/genética , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Expressão Gênica/genética , Proteína do Locus do Complexo MDS1 e EVI1/genética , Proto-Oncogenes/genética , Animais , Membrana Basal/metabolismo , Diferenciação Celular/genética , Proliferação de Células/genética , Proteínas Proto-Oncogênicas c-fos/genética , Receptores Notch/genética , Transdução de Sinais/genética , Fatores de Transcrição/genética
11.
Medicine (Baltimore) ; 99(9): e19394, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32118792

RESUMO

This study aimed to investigate the expression of c-Fos and matrix metallopeptidase 9 (MMP-9) in dental pulp of patients receiving orthodontic treatment via wire appliance.Fifteen patients (30 teeth in total) were randomly assigned to five groups: t = 0, t = 1, t = 4, t = 8 and t = 12 (n = 6). The first maxillary premolars of patients in the t = 0 group were extracted without any orthodontic treatment. An intrusive force of 300 g was applied on first maxillary premolars in the other four groups via wire appliances. This force was maintained for 1 week for t = 1 group, 4 weeks for t = 4 group, 8 weeks for t = 8 group, or 12 weeks for t = 12 group, before the teeth were extracted.The expression of c-Fos and MMP-9 in the pulps of each group was analyzed by immunohistochemical staining and real-time PCR. The relationship in the protein expression between c-Fos and MMP-9 in the dental pulp was analyzed by Pearson correlation analysis.Intrusive force of 300 g increased the expression of both c-Fos and MMP-9 in the dental pulp. The protein expression of MMP-9 in the dental pulp was significantly correlated with the expression of c-Fos (P < .001).Extreme intrusive force upregulates c-Fos and MMP-9 expression in the dental pulp. Moreover, protein expression of c-Fos and MMP-9 is significantly correlated under intrusive force.


Assuntos
Polpa Dentária/lesões , Metaloproteinase 9 da Matriz/análise , Proteínas Proto-Oncogênicas c-fos/análise , Estresse Mecânico , Adulto , Análise de Variância , China , Polpa Dentária/patologia , Feminino , Humanos , Masculino , Metaloproteinase 9 da Matriz/genética , Proteínas Proto-Oncogênicas c-fos/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos
12.
J Pharmacol Sci ; 143(2): 97-105, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32173264

RESUMO

Folate deficiency has been suggested as a risk factor for depression in preclinical and clinical studies. Several hypotheses of mechanisms underlying folate deficiency-induced depressive symptoms have been proposed, but the detailed mechanisms are still unclear. In this study, we assessed whether post-weaning folate deficiency affect neurological and psychological function. The low folate diet-fed mice showed depression-like behavior in the forced swim test. In contrast, spontaneous locomotor activity, social behavior, coordinated motor skills, anxiety-like behavior and spatial memory did not differ between control and low folate diet-fed mice. In the dentate gyrus (DG) of the hippocampus, decreased number of newborn mature neurons and increased number of immature neurons were observed in low folate diet-fed mice. Staining with Golgi-Cox method revealed that dendritic complexity, spine density and the number of mature spines of neurons were markedly reduced in the DG of low folate diet-fed mice. Stress response of neurons indicated as c-Fos expression was also reduced in the DG of low folate diet-fed mice. These results suggest that reduction in the degree of maturation of newborn hippocampal neurons underlies folate deficiency-induced depressive symptoms.


Assuntos
Giro Denteado/citologia , Giro Denteado/patologia , Depressão/etiologia , Depressão/patologia , Deficiência de Ácido Fólico/complicações , Neurônios/patologia , Desmame , Animais , Expressão Gênica , Masculino , Camundongos Endogâmicos , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo
13.
Life Sci ; 248: 117461, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32097665

RESUMO

AIMS: To compare how OCT4A proteins interact with and regulate multiple OCT4A-octamer motifs (OMs) in different regions of the FOS gene expressed in somatic cancer cells versus pluripotent stem cells. MATERIALS AND METHODS: Two FOS reporter gene systems harboring predicted OMs or their mutational counterparts were introduced into HeLa and NCCIT cells with varying OCT4A protein levels. The transcription of dsGFP reflecting FOS expression was quantitated by RT-qPCR, the OCT4A-OMs binding and the correlation between OCT4A and FOS transcription was determined by ChIP-PCR and RNA-Seq, respectively. KEY FINDINGS: In NCCIT cells, abundant OCT4A proteins bound to and inhibited OM1 and OM2 at the promoter of the FOS gene. RA-induced OCT4A down-regulation transiently increased FOS transcription. In contrast, in HeLa cells that contain much lower levels of endogenous OCT4A proteins, OCT4A primarily bound to and activate OM1 thereby promoting FOS transcription. OCT4A KO significantly reduced FOS expression. Ectopically introduced OCT4A, at its leaked or induced expression level, promoted FOS transcription by binding to OM2/OM3 or OM1/OM3, respectively. Thus, the interaction of OCT4A proteins with different OMs is cellular context- and protein level-dependent, and such complicated OCT4A binding mode can only be reflected by a dsGFP-based reporter harboring the full-length FOS gene but not by that merely having the FOS promoter. SIGNIFICANCE: Our findings unravel an additional layer of regulatory mechanisms that account for the cellular context- and dose-related versatile functions of OCT4A protein, and further underscore the importance of precise modulation of OCT4A in the regenerative medicine and anticancer therapies.


Assuntos
Regulação da Expressão Gênica , Fator 3 de Transcrição de Octâmero/genética , Células-Tronco Pluripotentes/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Motivos de Aminoácidos , Linhagem Celular Tumoral , Genes Reporter , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HeLa , Humanos , Fator 3 de Transcrição de Octâmero/metabolismo , Especificidade de Órgãos , Células-Tronco Pluripotentes/citologia , Regiões Promotoras Genéticas , Ligação Proteica , Proteínas Proto-Oncogênicas c-fos/metabolismo , Transdução de Sinais , Transcrição Genética
14.
Neurobiol Aging ; 87: 98-107, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31889558

RESUMO

Homing pigeons experience age-related spatial-cognitive decline similar to that seen in mammals. In contrast to mammals, however, previous studies have shown the hippocampal formation (HF) of old, cognitively impaired pigeons to be greater in volume and neuron number compared with young pigeons. As a partial explanation of the cognitive decline in older birds, it was hypothesized that older pigeons have reduced HF activation during spatial learning. The present study compared HF activation (via the activity-dependent expression of the immediate early gene c-Fos) between younger and older pigeons during learning of a spatial, delayed nonmatch-to-sample task. On the last day of training, c-Fos activation significantly correlated with behavioral performance in the young, but not old, pigeons suggesting more HF engagement by the young pigeons in solving the task. The behavioral correlation was additionally associated with consistently higher, but insignificant c-Fos activation across practically every HF subdivision in the young compared with the old pigeons. In sum, the results of the present study are consistent with the hypothesis that age-related decline in the spatial cognitive ability of homing pigeons is in part a result of an older HF being less responsive to the processing of spatial information. However, alternative interpretations of the data are discussed.


Assuntos
Envelhecimento/genética , Envelhecimento/fisiologia , Comportamento Animal , Envelhecimento Cognitivo/psicologia , Columbidae/genética , Columbidae/fisiologia , Hipocampo/patologia , Hipocampo/fisiopatologia , Comportamento de Retorno ao Território Vital , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Memória Espacial/fisiologia , Animais , Expressão Gênica , Neurônios/patologia , Tamanho do Órgão , Proteínas Proto-Oncogênicas c-fos/fisiologia
15.
Oncol Rep ; 43(2): 655-661, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31894310

RESUMO

Alterations in DNA methylation have a central role in the development and outcome of most human malignancies. Non­small cell lung cancer (NSCLC), the most common lung cancer, leads to the largest number of cancer­related deaths worldwide. FBJ murine osteosarcoma viral oncogene homolog B (FOSB) is a key component of the activator protein­1 transcription factor and regulates gene networks associated within oncogenic transformation. The role of FOSB in the development of NSCLC is still elusive. Therefore, the methylation status of the FOSB gene was investigated in NSCLC and its clinical significance in NSCLC progression was evaluated. The methylation status of the promoter and exon 4 regions of the FOSB gene were analyzed in 176 NSCLC specimens by bisulfite pyrosequencing and the association between FOSB methylation status and patient survival was investigated. Compared to adjacent non­malignant tissues, FOSB promoter exhibited exclusive unmethylation in all malignant tissues and the exon 4 region was found unmethylated in 18 (10.2% of the total) tumor samples. Exon 4 unmethylation was associated with downregulation of its mRNA and tended to occur in patients with lymph node metastasis. Univariate and multivariate analyses revealed that exon 4 unmethylation was significantly associated with unfavorable overall survival in patients with stage II­IIIA NSCLC (log­rank P=0.05, adjusted hazard ratio=2.43, 95% confidence interval=1.04­5.68, P=0.04). FOSB was identified as a novel gene with tumor­specific gene body unmethylation in NSCLC and a novel predictive biomarker for NSCLC prognosis. Moreover, the present results indicated that FOSB may have a tumor suppressor function in the progression of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Metilação de DNA , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas c-fos/genética , Análise de Sequência de DNA/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Linhagem Celular Tumoral , Éxons , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Regiões Promotoras Genéticas , Análise de Sobrevida
16.
Neuron ; 105(1): 46-59.e3, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31735403

RESUMO

Non-selective antagonists of metabotropic glutamate receptor subtypes 2 (mGlu2) and 3 (mGlu3) exert rapid antidepressant-like effects by enhancing prefrontal cortex (PFC) glutamate transmission; however, the receptor subtype contributions and underlying mechanisms remain unclear. Here, we leveraged newly developed negative allosteric modulators (NAMs), transgenic mice, and viral-assisted optogenetics to test the hypothesis that selective inhibition of mGlu2 or mGlu3 potentiates PFC excitatory transmission and confers antidepressant efficacy in preclinical models. We found that systemic treatment with an mGlu2 or mGlu3 NAM rapidly activated biophysically unique PFC pyramidal cell ensembles. Mechanistic studies revealed that mGlu2 and mGlu3 NAMs enhance thalamocortical transmission and inhibit long-term depression by mechanistically distinct presynaptic and postsynaptic actions. Consistent with these actions, systemic treatment with either NAM decreased passive coping and reversed anhedonia in two independent chronic stress models, suggesting that both mGlu2 and mGlu3 NAMs induce antidepressant-like effects through related but divergent mechanisms of action.


Assuntos
Regulação Alostérica/fisiologia , Córtex Cerebral/fisiologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Tálamo/fisiologia , Adaptação Psicológica/efeitos dos fármacos , Anedonia/efeitos dos fármacos , Animais , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/metabolismo , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/metabolismo , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Vias Neurais/fisiologia , Plasticidade Neuronal/fisiologia , Optogenética , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiologia , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Células Piramidais/fisiologia , Tálamo/metabolismo
17.
Virchows Arch ; 476(1): 3-15, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31701221

RESUMO

Although traditional morphological evaluation remains the cornerstone for the diagnosis of soft tissue tumors, ancillary diagnostic modalities such as immunohistochemistry and molecular genetic analysis are of ever-increasing importance in this field. New insights into the molecular pathogenesis of soft tissue tumors, often obtained from high-throughput sequencing technologies, has enabled significant progress in the characterization and biologic stratification of mesenchymal neoplasms, expanding the spectrum of immunohistochemical tests (often aimed towards recently discovered genetic events) and molecular genetic assays (most often fluorescence in situ hybridization and reverse transcription-polymerase chain reaction). This review discusses selected novel molecular and immunohistochemical assays with diagnostic applicability in mesenchymal neoplasms, with emphasis on diagnosis, refinement of tumor classification, and treatment stratification.


Assuntos
Neoplasias de Tecidos Moles/diagnóstico , DNA Helicases/análise , Fusão Gênica , Humanos , Imuno-Histoquímica , Proteínas Nucleares/análise , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-fos/genética , Proteína EWS de Ligação a RNA/genética , Receptor trkA/genética , Proteínas Repressoras/genética , Proteína SMARCB1/análise , Neoplasias de Tecidos Moles/química , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Fatores de Transcrição/análise
18.
Lasers Med Sci ; 35(1): 31-40, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30341668

RESUMO

This study was designed to investigate the effect of 650-nm low-level laser irradiation (LLLI) as an adjunctive treatment of experimental periodontitis. To investigate possible LLLI-mediated anti-inflammatory effects, we utilized an experimental periodontitis (EP) rat model and analyzed c-Jun, c-Fos, ICAM-1, and CCL2 gene expressions on PB leukocytes and in the gingival tissue. Total RNA was isolated from the gingivae and peripheral blood (PB) leukocytes of normal, EP, scaling, and root planing (SRP)-treated EP and LLLI + SRP-treated EP rats, and gene expressions were analyzed by real-time PCR. The productions of c-Jun, c-Fos, ICAM-1, and CCL2 in gingivae were analyzed immunohistochemically. Tartrate-resistant acid phosphatase (TRAP) staining was used to determine osteoclast activity in alveolar bone. The c-Jun and ICAM-1 messenger RNA (mRNA) levels were significantly decreased in the EP rat gingival tissue treated by SRP + LLLI than by SRP, the c-Jun, ICAM-1, and c-Fos mRNA levels on PB leukocytes reduced after LLLI treatment but did not show any significant differences in both groups. There was no significant difference in CCL2 mRNA levels on PB leukocytes and in gingivae between the SRP + LLLI and the SRP groups. The c-Fos mRNA levels in gingivae did not show significant difference in both groups. Immunohistochemistry showed that the CCL2, ICAM-1, c-Jun, and c-Fos productions were significantly reduced in rats of the SRP + LLLI group compared with the only SRP group. LLLI significantly decreased the number of osteoclasts as demonstrated by TRAP staining. The 650-nm LLLI might be a useful treatment modality for periodontitis.


Assuntos
Quimiocina CCL2/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Terapia com Luz de Baixa Intensidade , Periodontite/metabolismo , Periodontite/radioterapia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Animais , Quimiocina CCL2/genética , Regulação da Expressão Gênica , Gengiva/metabolismo , Gengiva/patologia , Molécula 1 de Adesão Intercelular/genética , Masculino , Osteoclastos/patologia , Osteoclastos/efeitos da radiação , Periodontite/genética , Periodontite/patologia , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-jun/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley
19.
Biochem Pharmacol ; 172: 113762, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31843541

RESUMO

IKK-ß is indispensable for inflammatory osteolysis, the functional residues of IKK-ß are therapeutic drug targets for developing inhibitors to treat multiple diseases now. Thus it remains appealing to find the new residues of IKK-ß to influence osteoclasts for alleviating bone loss diseases such as rheumatoid arthritis (RA). By employing IKK-ß cysteine 46-A transgenic (IKK-ßC46A) mice, we found that mutation of cysteine 46 to alanine in IKK-ß exacerbated inflammatory bone destruction in vivo, and increased osteoclast differentiation and bone resorption ex vivo and in vitro. Consistent with these, IKK-ß kinase activity as well as c-Fos, NFATc1 were up-regulated in bone marrow macrophages (BMMs) from IKK-ßC46A mice during RANKL-induced osteoclastogenesis. Of interesting, we further identified and demonstrated that the expressions of mPGES-1 and caveolin-1 were heightened in BMMs of IKK-ßC46A mice compared to those in WT mice in RANKL-induced osteoclastogenesis. Together, it revealed that mutating cysteine 46 in IKK-ß could increase caveolin-1 and mPGES-1 expression to facilitate osteoclast differentiation and osteolysis. Cysteine 46 can serve as a novel target in IKK-ß for designing inhibitors to treat osteolysis.


Assuntos
Caveolina 1/metabolismo , Diferenciação Celular/fisiologia , Quinase I-kappa B/genética , Osteoclastos/fisiologia , Osteólise/metabolismo , Prostaglandina-E Sintases/metabolismo , Animais , Células da Medula Óssea , Caveolina 1/genética , Diferenciação Celular/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Quinase I-kappa B/metabolismo , Macrófagos , Camundongos , Camundongos Transgênicos , Monócitos , Mutação , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/metabolismo , Osteólise/genética , Prostaglandina-E Sintases/genética , Ligação Proteica , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ligante RANK/administração & dosagem , Ligante RANK/farmacologia , Regulação para Cima
20.
Cancer Lett ; 469: 256-265, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31672492

RESUMO

Stroma-derived exosomal microRNA (exomiR) contributes to tumor progression, however, which remains poorly understood. In our study, we analyzed exomiRs from the cancer-associated fibroblast (CAF) and normal fibroblast (NF) isolated from an invasive ductal carcinoma (IDC) patient and found that the level of microRNA (miR)-4516 was approximately 5-fold lower in CAF-derived exosomes than NF-derived ones. In gene annotation analysis, miR-4516 target genes were mainly associated with the regulation of proliferation. miR-4516 overexpression or mimic treatment suppressed the proliferation of breast cancer cells, especially triple negative breast cancer (TNBC) cells. Among miR-4516 targets, FOSL1 was overexpressed in TNBC cells compared to non-TNBC cells and promoted tumor proliferation. The expression of miR-4516 and FOSL1 was reversely correlated in breast cancer patient tissues. Particularly, TNBC patients with high FOSL1 expression showed a significant poorer survival than those with low FOSL1 expression. Our results show that the loss of miR-4516 from CAF-derived exosomes is associated with FOSL1-dependent TNBC progression and suggest that miR-4516 can be used as an anti-cancer drug for TNBC.


Assuntos
MicroRNAs/genética , Proteínas Proto-Oncogênicas c-fos/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antineoplásicos/farmacologia , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Progressão da Doença , Complexo Multienzimático de Ribonucleases do Exossomo/genética , Exossomos/genética , Exossomos/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células Estromais/metabolismo , Células Estromais/patologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
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