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Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the Psmad2 western blotting data shown in Fig. 7 were strikingly similar to data appearing in different form (namely, the bands appeared in the reverse orientation) in Fig. 4A in another article [Lv ZD, Na D, Liu FN, Du ZM, Sun Z, Li Z, Ma XY, Wang ZN and Xu HM: Induction of gastric cancer cell adhesion through transforming growth factorbeta1mediated peritoneal fibrosis. J Exp Clin Cancer Res 29: 139, 2010], which was written by mostly different authors at different research institutes (the author ZhengHai Qu did appear as an author on both papers). Owing to the fact that the contentious data in the above article had already been published prior to its submission to International Journal of Molecular Medicine, and due to a lack of overall confidence in the presented data, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they accepted the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 29: 564568, 2012; DOI: 10.3892/ijmm.2011.868].
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OBJECTIVE: This study aims to explore the clinical features and molecular diagnosis of FBN1-related acromelic dysplasia in Chinese patients. METHODS: The clinical and genetic features of three FBN1-related acromicric dysplasia (AD)/geleophysic dysplasia (GD) Chinese patients from two families were reviewed, and comprehensive medical evaluations were performed. Targeted next-generation sequencing was used to detect genetic mutations associated with short statures, including FBN1. Sanger sequencing was used to determine the de novo mutation origin. RESULTS: Patient 1 presented with short stature, short and stubby hands and feet, mild facial dysmorphism, hepatomegaly, delayed bone age and beak-like femoral heads. Patient 2 and this patient's father merely presented with short stature, wide and short hands, and beak-like femoral heads. One novel mutation, c.5272G>T(p.D1758Y), and one known mutation, c.5183C>T(p.A1728V), were identified in these patients. CONCLUSION: The clinical features varied among these patients. The variant c.5272G>T(p.D1758Y) is a novel mutation.
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Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. The aim of our study was to investigate the functional role of microRNA-135b (miR-135b) in TNBC. A real-time polymerase chain reaction assay was used to quantify miR-135b expression levels in 90 paired TNBC tissue and adjacent normal tissue samples. Wound-healing and transwell assays were performed to evaluate the effects of miR-135b expression on the migration and invasion of TNBC cells. Luciferase reporter and western blot analyses were used to verify whether the mRNA encoding APC is a major target of miR-135b. In the current study, we found that miR-135b was highly expressed in TNBC tissue and cells, and the expression levels were correlated with lymph node status and TNM stage. In TNBC cells, the ectopic expression of miR-135b promoted cell proliferation and invasion in vitro. In addition, our study proved that the overexpression of miR-135b significantly suppressed APC expression by targeting the 3'-untranslated region of APC, whereas enhanced APC expression could partially abrogate the miR-135b-mediated promotion of carcinogenic traits in TNBC cells. Taken together, our study demonstrated that miR-135b expression promoted the proliferation and invasion of TNBC by downregulating APC expression, indicating that miR-135b may serve as a promising target for the treatment of TNBC patients.
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Proteína de la Poliposis Adenomatosa del Colon/metabolismo , Movimiento Celular , Proliferación Celular , MicroARNs/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Proteína de la Poliposis Adenomatosa del Colon/genética , Adulto , Regulación hacia Abajo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Metástasis Linfática , Células MCF-7 , MicroARNs/genética , Persona de Mediana Edad , Estadificación de Neoplasias , Transducción de Señal , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
MicroRNAs (miRNAs) are small yet versatile gene tuners that regulate a variety of cellular processes, including cell growth and proliferation. The aim of this study was to explore how miR-448-5p affects airway remodeling and transforming growth factor-ß1 (TGF-ß1)-stimulated epithelial-mesenchymal transition (EMT) by targeting Sine oculis homeobox homolog 1 (Six1) in asthma. Asthmatic mice models with airway remodeling were induced with ovalbumin solution. MiRNA expression was evaluated using quantitative real-time polymerase chain reaction. Transfection studies of bronchial epithelial cells were performed to determine the target genes. A luciferase reporter assay system was applied to identify whether Six1 is a target gene of miR-448-5p. In the current study, we found that miR-448-5p was dramatically decreased in lung tissues of asthmatic mice and TGF-ß1-stimulated bronchial epithelial cells. In addition, the decreased level of miR-448-5p was closely associated with the increased expression of Six1. Overexpression of miR-448-5p decreased Six1 expression and, in turn, suppressed TGF-ß1-mediated EMT and fibrosis. Next, we predicted that Six1 was a potential target gene of miR-448-5p and demonstrated that miR-448-5p could directly target Six1. An SiRNA targeting Six1 was sufficient to suppress TGF-ß1-induced EMT and fibrosis in 16HBE cells. Furthermore, the overexpression of Six1 partially reversed the protective effect of miR-448-5p on TGF-ß1-mediated EMT and fibrosis in bronchial epithelial cells. Taken together, the miR-448-5p/TGF-ß1/Six1 link may play roles in the progression of EMT and pulmonary fibrosis in asthma.
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Asma/inducido químicamente , Células Epiteliales/metabolismo , MicroARNs/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Animales , Línea Celular , Transición Epitelial-Mesenquimal , Femenino , Fibrosis/metabolismo , Técnicas de Silenciamiento del Gen , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Ratones , MicroARNs/genética , Ovalbúmina/toxicidad , Distribución Aleatoria , Mucosa Respiratoria/metabolismo , Factor de Crecimiento Transformador beta1/genéticaRESUMEN
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Our study investigated the functional role of DLC-3 in TNBC. The expression of DLC-3 was assessed by immunohistochemistry in TNBC to evaluate the clinicopathologic significance of DLC-3. Recombinant lentiviral vectors encoding the DLC-3 gene were constructed for transfection into MDA-MB-231. Real-time qPCR and western blot analysis were employed to evaluate the expression of DLC-3, ß-catenin, GSK-3ß and c-myc in DLC-3-transfected cells. Moreover, cell proliferation assays, cell colony formation assays, and cell migration and invasion assays were performed to elucidate the role of DLC-3 in TNBC development and progression. Our data revealed that DLC-3 was downregulated in TNBC, and its expression level was associated with lymph node status and differentiation grade in breast cancer. Both real-time qPCR and western blot analyses showed that the DLC-3 gene and protein were overexpressed in the DLC-3-transfected MDA-MB-231 cells. In addition, the expression of GSK-3ß was upregulated and the expression of ß-catenin and c-myc gene was downregulated in the DLC-3-transfected cells. Furthermore, DLC-3 overexpression inhibited cell proliferation, colony formation, migration, and invasion in vitro. DLC-3, functioning as a tumor-suppressor gene, inhibits cell growth and invasion in TNBC, possibly through regulation of the Wnt/ß-catenin signaling pathway.
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BACKGROUND/AIMS: Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Our study investigated the functional role of miR-212-5p in TNBC. METHODS: Realtime PCR was used to quantify miR-212-5p expression levels in 30 paired TNBC samples and adjacent normal tissues. Wound healing and Transwell assays were used to evaluate the effects of miR-212-5p expression on the invasiveness of TNBC cells. Luciferase reporter and Western blot assays were used to verify whether the mRNA encoding Prrx2 is a major target of miR-212-5p. RESULTS: MiR-212-5p was downregulated in TNBC, and its expression levels were related to tumor size, lymph node status and vascular invasion in breast cancer. We also observed that the miR-212-5p expression level was significantly correlated with a better prognosis in TNBC. Ectopic expression of miR-212-5p induced upregulation of E-cadherin expression and downregulation of vimentin expression. The expression of miR212-5p also suppressed the migration and invasion capacity of mesenchymal-like cancer cells accompanied by a morphological shift towards the epithelial phenotype. Moreover, our study observed that miR-212-5p overexpression significantly suppressed Prrx2 by targeting its 3'-untranslated region (3'-UTR) region, and Prrx2 overexpression partially abrogated miR-212-5p-mediated suppression. CONCLUSIONS: Our study demonstrated that miR-212-5p inhibits TNBC from acquiring the EMT phenotype by downregulating Prrx2, thereby inhibiting cell migration and invasion during cancer progression.
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Transición Epitelial-Mesenquimal , Proteínas de Homeodominio/metabolismo , MicroARNs/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Adulto , Animales , Cadherinas/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Supervivencia sin Enfermedad , Regulación hacia Abajo , Femenino , Proteínas de Homeodominio/antagonistas & inhibidores , Proteínas de Homeodominio/genética , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/genética , Persona de Mediana Edad , Pronóstico , Trasplante Heterólogo , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/mortalidad , Regulación hacia Arriba , Vimentina/metabolismoRESUMEN
Asthma is an inflammatory disease of the airways, characterized by lung eosinophilia, mucus hypersecretion by goblet cells and airway hyperresponsiveness to inhaled allergens. The purpose of this study was to evaluate the effects of Six1 on airway inflammation and remodeling and the underlying mechanisms in a murine model of chronic asthma. Female BALB/c mice were randomly divided into four groups: phosphate-buffered saline control, ovalbumin (OVA)-induced asthma group, OVA+siNC and OVA+siSix1. In this mice model, Six1 expression level was significantly elevated in OVA-induced asthma of mice. Additionally, downregulation of Six1 dramatically decreased OVA-challenged inflammation, infiltration, and mucus production. Moreover, silencing of Six1 resulted in decreased levels of immunoglobulin E and inflammatory mediators and reduced inflammatory cell accumulation, as well as inhibiting the expression of important mediators including matrix metalloproteinase MMP-2 and MMP-9, which is related to airway remodeling. Further analysis indicated that silencing of Six1 can significantly inhibit NF-kB pathway activation in the lungs. .In conclusion, these findings indicated that the downregulation of Six1 effectively inhibited airway inflammation and reversed airway remodeling, which suggest that Six1 represents a promising therapeutic strategy for human allergic asthma.
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Remodelación de las Vías Aéreas (Respiratorias) , Asma/prevención & control , Silenciador del Gen , Terapia Genética/métodos , Proteínas de Homeodominio/metabolismo , Pulmón/metabolismo , Animales , Asma/inducido químicamente , Asma/genética , Asma/metabolismo , Asma/fisiopatología , Líquido del Lavado Bronquioalveolar/química , Modelos Animales de Enfermedad , Regulación hacia Abajo , Femenino , Técnicas de Transferencia de Gen , Proteínas de Homeodominio/genética , Inmunoglobulina E/metabolismo , Mediadores de Inflamación/metabolismo , Pulmón/fisiopatología , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones Endogámicos BALB C , FN-kappa B/metabolismo , Ovalbúmina , Transducción de SeñalRESUMEN
Triple-negative breast cancer (TNBC) is a highly aggressive tumour subtype associated with poor prognosis. The mechanisms involved in TNBC progression remains largely unknown. To date, there are no effective therapeutic targets for this tumour subtype. Paired-related homeobox 1b (Prrx1b), one of major isoforms of Prrx1, has been identified as a new epithelial-mesenchymal transition (EMT) inducer. However, the function of Prrx1b in TNBC has not been elucidated. In this study, we found that Prrx1b was significantly up-regulated in TNBC and associated with tumour size and vascular invasion of breast cancer. Silencing of Prrx1b suppressed the proliferation, migration and invasion of basal-like cancer cells. Moreover, silencing of Prrx1b prevented Wnt/ß-catenin signaling pathway and induced the mesenchymal-epithelial transition (MET). Taken together, our data indicated that Prrx1b may be an important regulator of EMT in TNBC cells and a new therapeutic target for interventions against TNBC invasion and metastasis.
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Movimiento Celular/genética , Transición Epitelial-Mesenquimal/genética , Silenciador del Gen , Proteínas de Homeodominio/genética , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Animales , Cadherinas/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Forma de la Célula/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/metabolismo , Humanos , Ratones , Persona de Mediana Edad , Invasividad Neoplásica , Regulación hacia Arriba/genética , Vimentina/metabolismo , Vía de Señalización Wnt/genéticaRESUMEN
PURPOSE: Several studies have investigated the associations between XRCC2 R188H polymorphism and the susceptibility to breast cancer, but the results have been inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. METHODS: PubMed and China National Knowledge Infrastructure (CNKI) searches were carried out for relevant studies published before March 2015. Meta-analysis was performed with the Stata, version 11.0. RESULTS: A total of 17 case-control studies, including 17,986 cases and 17,436 controls, were selected. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association in the homozygous model, dominant model, and recessive model. When all the studies were pooled into the meta-analysis, there was no evidence showing a significant association between XRCC2 R188H polymorphism and breast cancer risk (for homozygous model, OR=0.84, 95% CI=0.62-1.14; for dominant model: OR=0.76, 95% CI=0.53-1.09; and for recessive model: OR=1.04, 95% CI=0.98-1.10). In the subgroup analysis by ethnicity, no significant association was found between the polymorphism and breast cancer risk. CONCLUSIONS: In conclusion, this meta-analysis indicates that the XRCC2 R188H polymorphism is not a risk factor for developing of breast cancer.
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Breast cancer metastasis suppressor 1 (BRMS1) is a metastasis suppressor gene in several solid tumors. However, the expression and function of BRMS1 in triple-negative breast cancer (TNBC) have not been reported. In this study, we found that BRMS1 was down-regulation in breast cancer cell lines and primary TNBC, while decreased expression of BRMS1 mRNA was significantly associated with lymph node metastasis. And this down-regulation was found to be in accordance with aberrant methylation of the gene. Hypermethylation of the gene was observed in 53.4% (62/116) of the TNBC primary breast carcinomas, while it was found in only 24.1% (28/116) of the corresponding nonmalignant tissues. In addition, BRMS1 expression was restored in MDA-MB-231 after treatment with the demethylating agent, 5-aza-2-deoxycytidine (5-Aza-dC), and demethylation of the highly metastatic cells MDA-MB-231 induced invasion suppression of the cells. Furthermore, the suppression of BRMS1 by siRNA transfection enhanced cancer cells invasion. Collectively, our results suggest that the aberrant methylation of BRMS1 frequently occurs in the down-regulation of BRMS1 in TNBC and that it may play a role in the metastasis of breast cancer.
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Movimiento Celular , Metilación de ADN , Epigénesis Genética , Proteínas Represoras/genética , Neoplasias de la Mama Triple Negativas/genética , Adulto , Azacitidina/análogos & derivados , Azacitidina/farmacología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Metilación de ADN/efectos de los fármacos , Metilasas de Modificación del ADN/antagonistas & inhibidores , Metilasas de Modificación del ADN/metabolismo , Decitabina , Progresión de la Enfermedad , Regulación hacia Abajo , Inhibidores Enzimáticos/farmacología , Epigénesis Genética/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Metástasis Linfática , Persona de Mediana Edad , Invasividad Neoplásica , Interferencia de ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Represoras/metabolismo , Transfección , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
Airway remodeling is characterized by airway wall thickening, subepithelial fibrosis, increased smooth muscle mass, angiogenesis and an increase in mucous glands, which may lead to a chronic and obstinate asthma with pulmonary function depression. In the present study, we observed substantially thickened lung tissue with extensive fibrosis in ovalbumin-sensitized mice, which was interrelated with transforming growth factor-ß1 (TGF-ß1) expression in bronchoalveolar lavage fluid. In vitro experiments further demonstrated that TGF-ß1 resulted in epithelial-mesenchymal transition (EMT) in bronchial epithelial cells, which was characterized by the expected decrease in E-cadherin expression and the increase in vimentin and α-smooth muscle actin expression, as well as the associated increase in Snail expression at mRNA and protein levels. Furthermore, the downregulation of Snail by small interfering RNA (siRNA) attenuated the TGF-ß1induced EMT-like phenotype. Of note, a significantly increased synthesis of fibronectin was observed following TGF-ß1 treatment, which further supported the hypothesis that EMT is a pivotal factor in peribronchial fibrosis. In combination, the results indicated that myofibroblasts deriving from bronchial epithelial cells via EMT may contribute to peribronchial fibrosis and that Snail may be an important factor in this phenomenon.
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Remodelación de las Vías Aéreas (Respiratorias) , Asma/metabolismo , Bronquios/patología , Células Epiteliales/metabolismo , Transición Epitelial-Mesenquimal , Factores de Transcripción/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Animales , Asma/patología , Asma/fisiopatología , Regulación hacia Abajo , Fibronectinas/metabolismo , Silenciador del Gen , Humanos , Ratones , Miofibroblastos/metabolismo , Miofibroblastos/patología , Fenotipo , Transducción de Señal , Factores de Transcripción de la Familia Snail , Regulación hacia ArribaRESUMEN
Peritoneal metastases are one reason for the poor prognosis of scirrhous gastric cancer (SGC), and myofibroblast provides a favorable environment for the peritoneal dissemination of gastric cancer. The aim of this study was to determine whether myofibroblast originates from peritoneal mesothelial cells under the influence of the tumor microenvironment. Immunohistochemical studies of peritoneal biopsy specimens from patients with peritoneal lavage cytological (+) status demonstrate the expression of the epithelial markers cytokeratin in fibroblast-like cells entrapped in the stroma, suggesting that these cells stemmed from local conversion of mesothelial cells. To confirm this hypothesis in vitro, we co-incubated mesothelial cells with SGC or non-SGC to investigate morphology and function changes. As we expected, mesothelial cells undergo a transition from an epithelial phenotype to a mesenchymal phenotype with loss of epithelial morphology and decrease in the expression of cytokeratin and E-cadherin when exposed to conditioned medium from HSC-39, and the induction of mesothelial cells can be abolished using a neutralizing antibody to transforming growth factor-beta1 (TGF-ß1) as well as by pre-treatment with SB431542. Moreover, we found that these mesothelial cells-derived cells exhibit functional properties of myofibroblasts, including the ability to increase adhesion and invasion of SGC. In summary, our current data demonstrated that mesothelial cells are a source of myofibroblasts under the SGC microenvironment which provide a favorable environment for the dissemination of gastric cancer; TGF-ß1 produced by autocrine/paracrine in peritoneal cavity may play a central role in this pathogenesis.
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Adenocarcinoma Escirroso/secundario , Transición Epitelial-Mesenquimal , Epitelio/patología , Fibroblastos/patología , Neoplasias Peritoneales/secundario , Neoplasias Gástricas/patología , Adenocarcinoma Escirroso/metabolismo , Adhesión Celular , Técnicas de Cocultivo , Medios de Cultivo Condicionados , Fibroblastos/metabolismo , Humanos , Invasividad Neoplásica , Neoplasias Peritoneales/metabolismo , Peritoneo/patología , Proteína Smad2/metabolismo , Neoplasias Gástricas/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Células Tumorales Cultivadas , Microambiente TumoralRESUMEN
BACKGROUND: Astragalus membranaceus from traditional Chinese herbal medicines previously showed that it possesses a strong anti-inflammatory activity. The purpose of this study was to elucidate the effect of astragalus on allergen-induced airway inflammation and airway hyperresponsiveness and investigate its possible molecular mechanisms. METHODS: Female BALB/c mice sensitized and challenged with ovalbumin (OVA) developed airway inflammation. Bronchoalveolar lavage fluid was assessed for total and differential cell counts and cytokine and chemokine levels. In vivo airway responsiveness to increasing concentrations of methacholine was measured 24 hours after the last OVA challenge using whole-body plethysmography. The expression of inhibitory κB-α and p65 in lung tissues was measured by Western blotting. RESULTS: Astragalus extract attenuated lung inflammation, goblet cell hyperplasia and airway hyperresponsiveness in OVA-induced asthma and decreased eosinophils and lymphocytes in bronchoalveolar lavage fluid. In addition, astragalus extract treatment reduced expression of the key initiators of allergic T(H)2-associated cytokines (interleukin 4, interleukin 5) (P < 0.05). Furthermore, astragalus extract could inhibit nuclear factor κB (NF-κB) expression and suppress NF-κB translocation from the cytoplasm to the nucleus in lung tissue samples. CONCLUSIONS: Taken together, our current study demonstrated a potential therapeutic value of astragalus extract in the treatment of asthma and it may act by inhibiting the expression of the NF-κB pathway.
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Asma/metabolismo , Planta del Astrágalo , Hiperreactividad Bronquial/prevención & control , FN-kappa B/antagonistas & inhibidores , Extractos Vegetales/uso terapéutico , Neumonía/prevención & control , Animales , Asma/patología , Hiperreactividad Bronquial/inducido químicamente , Hiperreactividad Bronquial/metabolismo , Líquido del Lavado Bronquioalveolar , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Hiperplasia , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Ratones , Ratones Endogámicos BALB C , FN-kappa B/metabolismo , Ovalbúmina/efectos adversos , Extractos Vegetales/farmacología , Pletismografía , Neumonía/inducido químicamente , Neumonía/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Metastasis is unequivocally the most lethal aspect of breast cancer and the most prominent feature associated with disease recurrence, the molecular mechanisms whereby epithelial-to-mesenchymal transition (EMT) mediates the initiation and resolution of breast cancer metastasis remains poorly understood. Transforming growth factor-ß1 (TGF-ß1) is a multifunctional cytokine that is intimately involved in regulating numerous physiological processes, including cellular differentiation, homeostasis and EMT. Recent findings have implicated high levels of TGF-ß1 were associated with poor outcome, whereas inhibition of TGF-ß signaling reduces metastasis in breast cancer, suggesting that the chemo-therapeutic targeting of TGF-ß1 or TGF-ß signaling may offer new inroads in ameliorating metastatic disease in breast cancer patients. In this study, we showed immunohistochemical evidence for EMT, which is associated with TGF-ß1 expression, at the invasion front of breast cancer in vivo. The data also indicated that human breast cancer cell lines, MCF-7 and MDA-MB-435S, of epithelial cell characteristics were induced to undergo EMT by TGF-ß1 and dependent on the Smad2 signaling pathway. Following TGF-ß1 treatment, cells showed dramatic morphological changes assessed by phase contrast microscopy, accompanied by decreased epithelial marker and increased mesenchymal markers. Importantly, cell invasion was also enhanced in the EMT process, while knockdown of the Smad2 gene by silencing siRNA partially inhibited these effects in MDA-MB435S (P<0.05). These data suggested that EMT of breast cancer induced by TGF-ß1 is dependent on Smad2 signaling and promotes breast cancer cell metastasis.
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Apoptosis , Neoplasias de la Mama/patología , Movimiento Celular , Transición Epitelial-Mesenquimal , Proteína Smad2/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Western Blotting , Neoplasias de la Mama/metabolismo , Adhesión Celular , Proliferación Celular , Femenino , Humanos , Técnicas para Inmunoenzimas , Invasividad Neoplásica , Fosforilación , ARN Interferente Pequeño/genética , Proteína Smad2/antagonistas & inhibidores , Proteína Smad2/genética , Análisis de Matrices Tisulares , Células Tumorales CultivadasRESUMEN
Peritoneal dissemination is one of the main causes of death in gastric cancer patients. We have previously reported that gastric cancer cells can induce peritoneal apoptosis, lead to damage of peritoneum integrity, and therefore promote peritoneal metastasis. However, the soluble factors secreted by cancer cells to trigger the damaging cascade remain unclear. TGF-ß1, a cytokine known for its capacity to induce proliferative and transformative changes of cells is found in significantly higher quantities correlated with peritoneal metastasis and TNM stages of gastric cancer. High levels of TGF-ß1 in the subperitoneal milieu may affect the morphology and function of mesothelial cells, so that the resulting environment becomes favorable for peritoneal metastases. We observed apoptosis induced by TGF-ß1 in mesothelial cells in peritoneal carcinomatosis. Knockdown of the smad2 gene by siRNA silencing can partially inhibit these effects. TGF-ß1 could upregulate the expressions of Bax and suppress Bcl-2 in mesothelial cells. We conclude that TGF-ß1 could induce apoptosis of mesothelial cells, which involves the smad2 signaling pathway in peritoneal carcinomatosis. Bcl-2 and Bax may contribute to this phenomenon.
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Apoptosis , Epitelio/metabolismo , Neoplasias Peritoneales/metabolismo , Proteína Smad2/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Epitelio/efectos de los fármacos , Epitelio/patología , Humanos , Neoplasias Peritoneales/patología , Peritoneo/patología , Interferencia de ARN , ARN Interferente Pequeño , Transducción de Señal , Proteína Smad2/genética , Proteína X Asociada a bcl-2/biosíntesis , Proteína Letal Asociada a bcl/biosíntesis , Proteína Letal Asociada a bcl/metabolismoRESUMEN
Airway remodeling is characterized by airway wall thickening, subepithelial ï¬brosis, increased smooth muscle mass, angiogenesis and increased mucous glands, which can lead to a chronic and obstinate asthma with pulmonary function depression. In the present study, we investigated whether the astragalus extract inhibits airway remodeling in a mouse asthma model and observed the effects of astragalus extract on the transforming growth factor-ß1 (TGF-ß1)/Smad signaling pathway in ovalbumin-sensitized mice. Mice were sensitized and challenged by ovalbumin to establish a model of asthma. Treatments included the astragalus extract and budesonide. Lung tissues were obtained for hematoxylin and eosin staining and Periodic acid-Schiff staining after the ï¬nal ovalbumin challenge. Levels of TGF-ß1 were assessed by immunohistology and ELISA, levels of TGF-ß1 mRNA were measured by RT-PCR, and levels of P-Smad2/3 and T-Smad2/3 were assessed by western blotting. Astragalus extract and budesonide reduced allergen-induced increases in the thickness of bronchial airway and mucous gland hypertrophy, goblet cell hyperplasia and collagen deposition. Levels of lung TGF-ß1, TGF-ß1 mRNA and P-Smad2/3 were signiï¬cantly reduced in mice treated with astragalus extract and budesonide. Astragalus extract improved asthma airway remodeling by inhibiting the expression of the TGF-ß1/Smad signaling pathway, and may be a potential drug for the treatment of patients with a severe asthma airway.