RESUMO
Small guanosine triphosphate (GTP)-binding protein RhoB is an important stress sensor and contributes to the regulation of cytoskeletal organization, cell proliferation and survival. However, whether RhoB is involved in the hypoxic response and action of glucocorticoid (GC) is largely unknown. In this study, we investigated the effects of hypoxia or/and GC on the expression and activition of RhoB in the lung of rats and human A549 lung carcinoma cells, and further studied its mechanism and significance. We found that hypoxia and dexamethasone (Dex), a synethic GC, not only significantly increased the expression and activation of RhoB independently but also coregulated the expresion of RhoB in vitro and in vivo. Up-regulation of RhoB by hypoxia was in part through stabilizing the RhoB mRNA and protein. Inhibiting hypoxia-activated hypoxia-inducible transcription factor-1α (HIF-1α), c-Jun N-terminal kinase (JNK) or extracellular signal-regulated kinase (ERK) with their specific inhibitors significantly decreased hypoxia-induced RhoB expression, indicating that HIF-1α, JNK and ERK are involved in the up-regulation of RhoB in hypoxia. Furthermore, we found that knockdown of RhoB expression by RhoB siRNA not only significantly reduced hypoxia-enhanced cell migration and cell survival in hypoxia but also increased the sensitivity of cell to paclitaxel (PTX), a chemotherapeutic agent, and reduced Dex-enhanced resistance to PTX-chemotherapy in A549 cells. Taken together, the novel data revealed that hypoxia and Dex increased the expression and activation of RhoB, which is important for hypoxic adaptation and hypoxia-accelerated progression of lung cancer cells. RhoB also enhanced the resistance of cell to PTX-chemotherapy and mediated the pro-survival effect of Dex.
Assuntos
Glucocorticoides/farmacologia , Pulmão/metabolismo , Regulação para Cima/efeitos dos fármacos , Proteína rhoB de Ligação ao GTP/metabolismo , Células A549 , Animais , Antineoplásicos/farmacologia , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/genética , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dexametasona/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Pulmão/efeitos dos fármacos , Modelos Biológicos , Estabilidade de RNA/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteína rhoB de Ligação ao GTP/genéticaRESUMO
BACKGROUND: Mesenchymal stem cells (MSCs) came out to attract wide attention and had become one of the hotspots of most diseases' research in decades. But at present, the mechanisms of how MSCs work on chronic asthma remain undefined. Our study aims at verifying whether MSCs play a role in preventing inflammation and airway remodeling via PI3K/AKT signaling pathway in the chronic asthma rats model. METHODS: First, an ovalbumin (OVA)-induced asthma model was built. MSCs were administered to ovalbumin-induced asthma rats. The total cells in a bronchial alveolar lavage fluid (BALF) and inflammatory mediators in BALF and serum were measured. Histological examination of lung tissue was performed to estimate the pathological changes. Additionally, the expression of phosphorylated-Akt (p-Akt) in all groups was measured by western blot and immunohistochemistry (IHC). RESULTS: Compared to normal control group, the degree of airway inflammation and airway remodeling was significantly increased in asthma group. On the contrary, they were obviously inhibited in MSCs transplantation group. Moreover, the expression of p-Akt was increased in lung tissues of asthmatic rats, and suppressed by MSCs transplantation. CONCLUSION: Our results demonstrated that MSCs transplantation could suppress lung inflammation and airway remodeling via PI3K/Akt signaling pathway in rat asthma model.
Assuntos
Remodelação das Vias Aéreas/fisiologia , Asma/metabolismo , Pulmão/metabolismo , Transplante de Células-Tronco Mesenquimais , Fosfatidilinositol 3-Quinases/metabolismo , Pneumonia/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Asma/induzido quimicamente , Asma/patologia , Asma/terapia , Líquido da Lavagem Broncoalveolar , Modelos Animais de Doenças , Pulmão/patologia , Masculino , Ovalbumina , Pneumonia/induzido quimicamente , Pneumonia/patologia , Pneumonia/terapia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologiaRESUMO
This study was designed to establish a biomarker risk model for predicting brain metastasis (BM) in non-small cell lung cancer (NSCLC). The model comprises 120 cases of NSCLC that were treated and followed up for 4 years. The patients were divided into the BM (n=50) and non-BM (other visceral metastasis and those without recurrence) (n=70) groups. Immunohistochemical and western blot analyses were performed in metastatic tissues of NSCLC. Multivariate regression analysis was performed to correlate the immunoreactive cyclase-associated protein 1 (CAP1) signal with BM. Survival analyses were performed by using the Kaplan-Meier method. CAP1 protein content and immunoreactivity were significantly increased in BM specimens compared to other-metastatic specimens. The survival analysis revealed that CAP1 overexpression was significantly associated with survival (P<0.05). The ROC test suggested that the area under the curve was 73.33% (P<0.001; 95% CI, 63.5-83.2%). When P=0.466, the sensitivity and specificity reached 79.5 and 67.1%, respectively. These findings suggested that CAP1 is involved in the BM of NSCLC, and that elevated levels of CAP1 expression may indicate a poor prognosis for patients with BM. The CAP1 molecular model may be useful in the prediction of the risk of BM in NSCLC.
Assuntos
Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Ciclo Celular/metabolismo , Proteínas do Citoesqueleto/metabolismo , Neoplasias Pulmonares/patologia , Idoso , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Estudos de Casos e Controles , Proteínas de Ciclo Celular/análise , Proteínas de Ciclo Celular/genética , Proteínas do Citoesqueleto/análise , Proteínas do Citoesqueleto/genética , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Análise de Regressão , Análise de SobrevidaRESUMO
OBJECTIVE: To investigate the relationship between expression of matrix metalloproteinase (MMP)-9 and expression of adenylyl cyclase-associated protein (CAP)-1 in chronic obstructive pulmonary disease (COPD). METHODS: Patients with possible respiratory disease were recruited into the study and divided into a COPD group and a non-COPD group on diagnosis. Pulmonary function tests were performed and serum concentrations of MMP-9 were measured using an enzyme-linked immunosorbent assay. MMP-9 and CAP1 expression were analysed in lung tissue and bronchoalveolar lavage fluid in all available samples using immunohistochemistry and Western blot, respectively. In addition, expression of MMP-9 and CAP1 in vitro was investigated using immunofluorescence. Expression of CAP1 in response to MMP-9 was measured in the human alveolar epithelial cell line HP-AEpiC, using Western blot. RESULTS: A total of 90 patients were included in the study: 52 were in the COPD group and 38 in the non-COPD group. Serum MMP-9 concentrations were significantly higher in the COPD than in the non-COPD group. MMP-9 serum concentrations were negatively correlated with forced expiratory volume in 1 s (FEV1), FEV1 as a percentage of the normal predicted value and the ratio of FEV1 to forced vital capacity, and were positively correlated with residual volume (RV), total lung capacity (TLC) and RV/TLC values. In lung tissue and bronchoalveolar lavage fluid samples, MMP-9 and CAP1 expression were inversely related. This relationship was confirmed in HP-AEpiC cells. High expression of MMP-9 and low expression of CAP1 was demonstrated in the COPD group compared with the non-COPD group. CONCLUSIONS: This study demonstrated an inverse relationship between CAP1 and MMP-9 expression, and high expression of MMP-9 and low expression of CAP1 in those with COPD compared with the non-COPD group. Overexpression of MMP-9 in lung tissue and its interaction with CAP1 is likely to play a major role in airway obstruction in COPD.
Assuntos
Adenilil Ciclases/biossíntese , Proteínas de Ciclo Celular/biossíntese , Proteínas do Citoesqueleto/biossíntese , Metaloproteinase 9 da Matriz/sangue , Doença Pulmonar Obstrutiva Crônica/metabolismo , Adenilil Ciclases/genética , Líquido da Lavagem Broncoalveolar/química , Proteínas de Ciclo Celular/genética , Linhagem Celular , Proteínas do Citoesqueleto/genética , Células Epiteliais/metabolismo , Volume Expiratório Forçado/fisiologia , Humanos , Pulmão/metabolismo , Metaloproteinase 9 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/genética , Doença Pulmonar Obstrutiva Crônica/genética , Testes de Função Respiratória , Mucosa Respiratória/metabolismo , Capacidade Pulmonar Total/fisiologiaRESUMO
PURPOSE: To determine the role of brain metastases (BM) and overall survival (OS) in patients with non-small cell lung cancer (NSCLC) by performing a meta-analysis of the RCTs (randomized controlled clinical trials) and non-RCTs (non-randomized controlled clinical trials) published in the literature. METHODS: A meta-analysis was performed using trials identified through PubMed, EMBASE and Cochrane databases. Two investigators independently assessed the quality of the trials and extracted data. The outcomes included BM, OS, median survival (MS), response rate (RR), Hazard ratios (HRs) and odds ratios (ORs), and their 95% confidence intervals (CIs) were pooled using ReMan software. RESULTS: Twelve trials (6 RCTs and 6 non-RCTs) involving 1,718 NSCLC patients met the inclusion criteria. They were grouped on the basis of study design for separate Meta-analyses. The results showed that prophylactic cranial irradiation (PCI) reduced the risk of BM as compared with non-PCI in NSCLC patients (ORâ=â0.30, 95% [CI]: 0.21-0.43, p<0.00001). However, HRs for OS favored non-PCI (HRâ=â1.19, 95% [CI]: 1.06-1.33, pâ=â0.004), without evidence of heterogeneity between the studies. CONCLUSION: Our results suggest that although PCI decreased the risk of BM, it may impose a detrimental effect on OS of NSCLC patients.
Assuntos
Neoplasias Encefálicas/prevenção & controle , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Irradiação Craniana , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Pré-Medicação , Estudos de Casos e Controles , Humanos , Ensaios Clínicos Controlados não Aleatórios como Assunto , Razão de Chances , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Adiposity is a well-recognized risk factor of type 2 diabetes and cardiovascular disease, and recently there is increasing evidence that excess body weight is an avoidable cause of cancer, including gastrointestinal, endometrial, esophageal adenocarcinoma, colorectal, postmenopausal breast, prostate, and renal malignancies. The mechanisms whereby adiposity is associated with tumor development remains not well understood. There are some most studied hypothesized mechanisms such as, high levels of insulin and free levels of insulin-like growth factors, sex hormones, adipocytokines, and inflammatory cytokines, adiposity-induced hypoxia, and so on. The potential mechanisms and conclusions in adiposity associated with increased risk for developing malignancy, and the underlying cellular and molecular mechanisms will be studied very well in the near future.
Assuntos
Adiposidade , Neoplasias/etiologia , Obesidade/complicações , Humanos , Neoplasias/mortalidade , Neoplasias/patologia , Obesidade/mortalidade , Obesidade/patologia , Prognóstico , Fatores de Risco , Taxa de SobrevidaRESUMO
BACKGROUND: The usual transbronchial coagulation techniques include microwave, argon plasma coagulation (APC), electrocautery and cryotherapy. However, there are serious clinical problems in the safety of each. By analyzing the experimental data and clinical observations, we observed the variable effects of different coagulation techniques via bronchofibroscopy, to look for an optimal interventional management of luminal bronchus diseases, and evaluate the safety and the equivalent point. METHODS: Four kinds of coagulation techniques under bronchoscopy were performed on the fresh bronchus of healthy sheep, and the pathologic changes in all groups were observed under the microscope. The different treatment parameters were as follows: microwave 60 W×1 second, 3 seconds, 5 seconds and 40 W×1 second, 3 seconds, 5 seconds; APC 40 W×1 second, 3 seconds, 5 seconds; electrocautery 40 W×1 second, 3 seconds, 5 seconds; cryotherapy 100 Ω×60 seconds, 120 seconds. RESULTS: After treatment, ovine bronchial mucosa in all groups showed pathologic changes such as local necrosis and amotio of the mucosa lining epithelium, local submucosa coagulative necrosis or tissue defects, while inflammation in the surrounding tissue was not obvious. Under the same output power and action time, different methods had different outcomes. The damage by APC was the most superficial, microwave was the second, and electrocautery caused the worst damage. The study also found that effects of electrocautery at 40 W×3 seconds, microwave at 40 W×5 seconds or 60 W×3 seconds, APC at 40 W×5 seconds and cryotherapy at 100 Ω×120 seconds were the equivalent point conditions. The appearance included mucosa absence, partial submucosa absence, and collagen fiber coagulation in treatment areas. CONCLUSIONS: Each coagulation technique has its own characteristic. It is very important to choose the appropriate power and action time of the suitable method according to the therapy requirement.
Assuntos
Coagulação com Plasma de Argônio/efeitos adversos , Broncopatias/terapia , Crioterapia/efeitos adversos , Eletrocoagulação/efeitos adversos , Micro-Ondas/efeitos adversos , Animais , Broncopatias/patologia , Broncoscopia , OvinosRESUMO
Myopericytoma is a benign tumor composed of cells that show apparent differentiation towards putative perivascular myoid cells called myopericytes. To date, only a small number of series describing myopericytomas have been reported. Here, we report a case of pulmonary myopericytoma presenting as multiple nodules in a 26-year-old man. Clinical presentation, radiological features and histopathologic findings of the patient are also discussed. The result of the histology combined with the immunohistochemical analysis led to a diagnosis of myopericytomas. To our knowledge, this is the first report of myopericytoma showing pulmonary involvement.
Assuntos
Neoplasias Pulmonares/diagnóstico , Neoplasias Primárias Múltiplas/diagnóstico , Pericitos/patologia , Neoplasias de Tecidos Moles/diagnóstico , Actinas/análise , Adulto , Antígenos CD34/análise , Biomarcadores Tumorais/análise , Biópsia , Diagnóstico Diferencial , Humanos , Neoplasias Pulmonares/química , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Imageamento por Ressonância Magnética , Masculino , Neoplasias Primárias Múltiplas/química , Neoplasias Primárias Múltiplas/diagnóstico por imagem , Neoplasias Primárias Múltiplas/patologia , Neoplasias Primárias Múltiplas/cirurgia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/análise , Pneumonectomia , Neoplasias de Tecidos Moles/química , Neoplasias de Tecidos Moles/diagnóstico por imagem , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/cirurgia , Tomografia Computadorizada por Raios X , Vimentina/análiseRESUMO
BACKGROUND: Microwaves have other biological effects on cancer as well besides killing tumor cells by coagulation. Some studies showed that microwaves may induce apoptosis in some tumor cells. The apoptotic effect of microwaves may help in clinic to remove residual malignant cells nearby the primary lesion and avoid relapse subsequently. However, there is little evidence on this subject from lung cancer. We studied the effect of microwaves on inducing apoptosis in the human lung carcinoma cell line A549 cells, aiming to identify its effect on apoptosis. METHODS: A549 cells were radiated by various intensities and durations of microwaves. Apoptosis induction in A549 cells was analyzed by morphological observations, tetrazolium blue color method (MTT) assays, flow cytometry, immunohistochemistry, and image analyses. RESULTS: Morphological changes in A549 cells, including cell shrinking and nuclear pyknosis, were observed after microwave radiation. Microwaves significantly inhibited metabolic activities and induced apoptosis in A549 cells. The results of the MTT assay showed a significant decrease of cell activities in all the radiation groups compared with the normal control (P < 0.01). The low point of cell activities often appeared at 6 - 12 hours after radiation. Apoptosis was also confirmed by flow cytometry. The early stage apoptotic rate reached 6.10% - 17.98% and the advanced stage apoptotic rate + necrosis rate reached 8.04% - 44.06% at 6 hours after microwave irradiation, in contrast to 2.32% and 4.10% in the respective control groups. Down-regulation of Bcl-2 expression and up-regulation of p53 expression were observed by immunohistochemistry after radiation. In most treated groups, the down-regulation of Bcl-2 expression reached its lowest level at 3 - 6 hours after radiation (integrated optical density (IOD)-6 hours: 2.13 ± 0.08 - 5.14 ± 0.13 vs. control: 5.79 ± 0.10, P < 0.01) and the up-regulation of P53 expression peaked at about 3 hours (IOD-3 hours: 2.61 ± 0.13 - 8.07 ± 0.11 vs. control: 1.29 ± 0.07, P < 0.01). Cell damage, apoptosis, and protein expression levels in the samples differed depending on the radiation intensity and duration. CONCLUSIONS: Microwaves can promote apoptosis in A549 cells. The effect depends on the duration and dosage of microwave radiation. Bcl-2 and p53 proteins may be involved in the apoptotic process of A549 cells induced by microwaves.