RESUMEN
Human epidermal growth factor receptor 2 (HER2) overexpression is not only closely associated with the tumor growth, but is also related to tumor invasion. We here aimed to investigate the mechanism of HER2 mediation in the pathogenesis of gastric cancer. The human gastric cancer cell lines SGC-7901, MKN-45, AGS, the immortalized cell line GES-1 derived from normal gastric mucosa. Cell transfection and selection of stable cell lines and the gene and protein levels of HER2 and Matrix metalloproteinase-9 (MMP-9) were examined to determine the molecular relationship between them in the pathogenesis of gastric cancer. The human gastric cancer cell lines SGC-7901, MKN-45, AGS, the immortalized cell line GES-1 derived from normal gastric mucosa. Cell transfection and selection of stable cell lines and the gene and protein levels of HER2 and MMP-9 were examined to determine the molecular relationship between them in the pathogenesis of gastric cancer. We demonstrated that vector-based shRNA significantly knocked down the expression of HER2 and considerably inhibited both the migration and invasion of gastric cancer cells. HER2 knockdown resulted in the downregulation of the expression of MMP-9, whereas HER2 overexpression improved the transcription of MMP-9 through the activation of an MMP-9 promoter. The promoter region of MMP-9 between -2500 and -2000 bp was found to be crucial for the upregulation of HER2-mediated transcription. Furthermore, a truncated promoter (-70 to +63) did not display any transcriptional activity. Cell invasion activity was almost completely inhibited when MMP-9 was knocked down. Conversely, the overexpression of MMP-9 partly rescued the invasion ability of cell strains with knockdown HER2. These findings help further understanding of the molecular mechanisms through which HER2 promotes malignancy, and suggest that targeting both HER2 and MMP-9 may be required to effectively block HER2 signaling in gastric cancer therapy.
Asunto(s)
Metaloproteinasa 9 de la Matriz/metabolismo , Receptor ErbB-2/fisiología , Neoplasias Gástricas/enzimología , Línea Celular Tumoral , Movimiento Celular , Inducción Enzimática , Expresión Génica , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Metaloproteinasa 9 de la Matriz/genética , Invasividad Neoplásica , Regiones Promotoras Genéticas , ARN Interferente Pequeño/genética , Neoplasias Gástricas/patología , Activación TranscripcionalRESUMEN
Ziyuglycoside II is an active compound of Sanguisorba officinalis L. that has anti-inflammation, antioxidation, antibiosis, and homeostasis properties. We report here on the anticancer effect of ziyuglycoside II on human gastric carcinoma BGC-823 cells. We investigated the effects of ziyuglycoside II on cell growth, cell cycle, and cell apoptosis of this cell line. Our results revealed that ziyuglycoside II could inhibit the proliferation of BGC-823 cells by inducing apoptosis but not cell cycle arrest, which was associated with regulation of Bax/Bcl-2 expression, and activation of the caspase-3 pathway. Our study is the first to report the antitumor potential of ziyuglycoside II in BGC-823 gastric cancer cells. Ziyuglycoside II may become a potential therapeutic agent against gastric cancer in the future.
Asunto(s)
Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Saponinas/farmacología , Transducción de Señal/efectos de los fármacos , Proteína X Asociada a bcl-2/metabolismo , Antineoplásicos/farmacología , Carcinoma/tratamiento farmacológico , Caspasa 3/efectos de los fármacos , Inhibidores de Caspasas/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Fluorometría , Fluorouracilo/farmacología , Humanos , Proteínas Proto-Oncogénicas c-bcl-2/efectos de los fármacos , Sanguisorba/química , Neoplasias Gástricas/tratamiento farmacológico , Proteína X Asociada a bcl-2/efectos de los fármacosRESUMEN
Ziyuglycoside II is an active compound of Sanguisorba officinalis L. that has anti-inflammation, antioxidation, antibiosis, and homeostasis properties. We report here on the anticancer effect of ziyuglycoside II on human gastric carcinoma BGC-823 cells. We investigated the effects of ziyuglycoside II on cell growth, cell cycle, and cell apoptosis of this cell line. Our results revealed that ziyuglycoside II could inhibit the proliferation of BGC-823 cells by inducing apoptosis but not cell cycle arrest, which was associated with regulation of Bax/Bcl-2 expression, and activation of the caspase-3 pathway. Our study is the first to report the antitumor potential of ziyuglycoside II in BGC-823 gastric cancer cells. Ziyuglycoside II may become a potential therapeutic agent against gastric cancer in the future.
Asunto(s)
Humanos , Apoptosis/efectos de los fármacos , /metabolismo , /metabolismo , Saponinas/farmacología , Transducción de Señal/efectos de los fármacos , /metabolismo , Antineoplásicos/farmacología , Línea Celular Tumoral , Carcinoma/tratamiento farmacológico , /efectos de los fármacos , Inhibidores de Caspasas/metabolismo , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Fluorometría , Fluorouracilo/farmacología , /efectos de los fármacos , Sanguisorba/química , Neoplasias Gástricas/tratamiento farmacológico , /efectos de los fármacosRESUMEN
BACKGROUND: Peripheral venous pressure (PVP) is strongly correlated with central venous pressure (CVP) during various surgeries. Laparoscopic surgery in the Trendelenburg position with pneumoperitoneum typically increases CVP. To determine whether PVP convincingly reflects changes in CVP, we evaluated the correlation between PVP and CVP in patients undergoing laparoscopic colorectal surgery. METHODS: Both CVP and PVP were measured simultaneously at predetermined time intervals during elective laparoscopic colorectal surgery in 42 patients without cardiac disease. The pairs of venous pressure measurements were analysed for correlation, and the Bland-Altman plots of repeated measures were used to evaluate the agreement between CVP and PVP. RESULTS: A total of 420 data pairs were obtained. The overall mean CVP was 11.3 (sd 4.5) mm Hg, which was significantly lower than the measured PVP of mean 12.1 (4.5) mm Hg (P=0.005). There was a strong positive correlation between overall CVP and PVP (correlation coefficient=0.96, P<0.0001). The mean bias (PVP-CVP) corrected for repeated measurements using random-effects modelling was 0.9 mm Hg [95% confidence interval (CI) 0.54-1.19 mm Hg] with 95% limits of agreement of -1.2 mm Hg (95% CI -1.75 to -0.62 mm Hg) to 2.9 mm Hg (95% CI 2.35-3.48 mm Hg). CONCLUSIONS: PVP displays a strong correlation and agreement with CVP under the increased intrathoracic pressure of pneumoperitoneum in the Trendelenburg position and may be used as an alternative to CVP in patients without cardiac disease undergoing laparoscopic colorectal surgery.
Asunto(s)
Neoplasias Colorrectales/cirugía , Monitoreo Intraoperatorio/métodos , Presión Venosa/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Resistencia de las Vías Respiratorias/fisiología , Determinación de la Presión Sanguínea/métodos , Presión Venosa Central/fisiología , Femenino , Antebrazo/irrigación sanguínea , Mano/irrigación sanguínea , Humanos , Laparoscopía/métodos , Masculino , Persona de Mediana Edad , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Desflurane at more than 1 minimum alveolar concentration (MAC) has been shown to prolong the QT interval, but it is unclear whether this is the case at lower concentrations. The aim of this study was to determine whether desflurane concentrations of <1 MAC affect tracheal intubation-induced prolongation of the QT interval. METHODS: Forty-four subjects received either inspired desflurane at 1 MAC in oxygen 100% at a fresh gas flow rate of 6 litre min(-1) (desflurane group) or only oxygen 100% (control group) beginning at anaesthesia induction with propofol, before tracheal intubation. The QT intervals were corrected by Bazett's (QTcB) and Fridericia's (QTcF) formulae. The primary outcome was the QTcB immediately after tracheal intubation. Secondary outcomes were the interval from the peak to the end of the T wave (Tp-e), mean arterial pressure (MAP), heart rate (HR), and bispectral index (BIS) score. RESULTS: The QTc interval immediately after tracheal intubation did not differ between the control and the desflurane groups [QTcB, 451 (sd 23) vs 456 (27) ms, P=0.56; QTcF, 422 (24) vs 429 (22) ms, P=0.31, control vs desflurane group, respectively]. There was no difference in Tp-e or HR between the two groups in this study. However, MAP and the BIS score were significantly lower in the desflurane group until 1 min after tracheal intubation. CONCLUSIONS: The administration of desflurane at an inspiratory concentration of 1 MAC during manually controlled ventilation after anaesthesia induction with propofol did not affect tracheal intubation-induced QTc prolongation.
Asunto(s)
Anestésicos por Inhalación/farmacología , Intubación Intratraqueal/efectos adversos , Isoflurano/análogos & derivados , Síndrome de QT Prolongado/etiología , Adulto , Anestésicos por Inhalación/administración & dosificación , Concienciación/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Colecistectomía Laparoscópica , Desflurano , Esquema de Medicación , Electrocardiografía/efectos de los fármacos , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Isoflurano/administración & dosificación , Isoflurano/farmacología , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
In cancer cells, glucose is often converted into lactic acid, which is known as the 'Warburg effect'. The reason that cancer cells have a higher rate of aerobic glycolysis, but not oxidative phosphorylation, remains largely unclear. Herein, we proposed an epigenetic mechanism of the Warburg effect. Fructose-1,6-bisphosphatase-1 (FBP1), which functions to antagonize glycolysis was downregulated through NF-kappaB pathway in Ras-transformed NIH3T3 cells. Restoration of FBP1 expression suppressed anchorage-independent growth, indicating the relevance of FBP1 downregulation in carcinogenesis. Indeed, FBP1 was downregulated in gastric carcinomas (P<0.01, n=22) and gastric cancer cell lines (57%, 4/7). Restoration of FBP1 expression reduced growth and glycolysis in gastric cancer cells. Moreover, FBP1 downregulation was reversed by pharmacological demethylation. Its promoter was hypermethylated in gastric cancer cell lines (57%, 4/7) and gastric carcinomas (33%, 33/101). Inhibition of NF-kappaB restored FBP1 expression, partially through demethylation of FBP1 promoter. Notably, Cox regression analysis revealed FBP1 promoter methylation as an independent prognosis predicator for gastric cancer (hazard ratio: 3.60, P=0.010). In summary, we found that NF-kappaB functions downstream of Ras to promote epigenetic downregulation of FBP1. Promoter methylation of FBP1 can be used as a new biomarker for prognosis prediction of gastric cancer. Such an important epigenetic link between glycolysis and carcinogenesis partly explains the Warburg effect.
Asunto(s)
Epigénesis Genética , Fructosa-Bifosfatasa/genética , Glucólisis , Neoplasias Gástricas/patología , Anciano , Animales , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Metilación de ADN , Regulación hacia Abajo , Femenino , Fructosa-Bifosfatasa/metabolismo , Glucosa/metabolismo , Humanos , Estimación de Kaplan-Meier , Ácido Láctico/metabolismo , Masculino , Ratones , Persona de Mediana Edad , FN-kappa B/genética , FN-kappa B/metabolismo , Células 3T3 NIH , Pronóstico , Regiones Promotoras Genéticas/genética , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismoRESUMEN
BACKGROUND: MicroRNAs (miRNAs) are 19-25-nucleotides regulatory non-protein-coding RNA molecules that regulate the expressions of a wide variety of genes, including some involved in cancer development. In this study, we investigated the possible role of miR-143 in colorectal cancer (CRC). METHODS: Expression levels of human mature miRNAs were examined using real-time PCR-based expression arrays on paired colorectal carcinomas and adjacent non-cancerous colonic tissues. The downregulation of miR-143 was further evaluated in colon cancer cell lines and in paired CRC and adjacent non-cancerous colonic tissues by qRT-PCR. Potential targets of miR-143 were defined. The functional effect of miR-143 and its targets was investigated in human colon cancer cell lines to confirm miRNA-target association. RESULTS: Both real-time PCR-based expression arrays and qRT-PCR showed that miR-143 was frequently downregulated in 87.5% (35 of 40) of colorectal carcinoma tissues compared with their adjacent non-cancerous colonic tissues. Using in silico predictions, DNA methyltranferase 3A (DNMT3A) was defined as a potential target of miR-143. Restoration of the miR-143 expression in colon cell lines decreased tumour cell growth and soft-agar colony formation, and downregulated the DNMT3A expression in both mRNA and protein levels. DNMT3A was shown to be a direct target of miR-143 by luciferase reporter assay. Furthermore, the miR-143 expression was observed to be inversely correlated with DNMT3A mRNA and protein expression in CRC tissues. CONCLUSION: Our findings suggest that miR-143 regulates DNMT3A in CRC. These findings elucidated a tumour-suppressive role of miR-143 in the epigenetic aberration of CRC, providing a potential development of miRNA-based targeted approaches for CRC therapy.
Asunto(s)
Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , MicroARNs/metabolismo , Western Blotting , Línea Celular Tumoral , ADN Metiltransferasa 3A , Regulación hacia Abajo , Silenciador del Gen , Humanos , MicroARNs/genética , ARN Interferente Pequeño , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Regional anesthesia for laparoscopic cholecystectomy has been reported in patients with severe respiratory disease and is a safe alternative to general anesthesia. Hemodynamic instability can occur on initiating pneumoperitoneum and the respiratory acidosis can last into the post-operative period without careful monitoring and management. This case report describes such an episode in an elderly patient with severely impaired respiratory function who was given thoracic epidural anesthesia for laparoscopic cholecystectomy.
Asunto(s)
Anestesia Epidural , Colecistectomía Laparoscópica , Tórax , Anciano de 80 o más Años , Femenino , Humanos , Pruebas de Función RespiratoriaRESUMEN
Cadherin function is required for normal keratinocyte intercellular adhesion and stratification. In the present study, we have investigated whether cadherin-cadherin interactions may also modulate keratinocyte differentiation, as evidenced by alterations in the levels of several differentiation markers. Confluent keratinocyte cultures, propagated in low Ca(2+) medium in which cadherins are not active, were pre-incubated with antibodies that block the function of E-cadherin and/or P-cadherin; Ca(2+ )was then elevated to 1 mM to activate the cadherins and induce differentiation. In control cultures (incubated with no antibody or with antibodies to other cell surface molecules), Ca(2+) elevation induced an increase in type 1 transglutaminase, profilaggrin, and loricrin, as measured by western blotting and in agreement with previous results. However, the concurrent addition of antibodies against both E- and P-cadherin prevented this increase in transglutaminase 1 protein. Incubation with either antibody alone had no consistent effect. Profilaggrin and loricrin, which are later markers of keratinocyte differentiation, responded differently from transglutaminase 1 to addition of antibodies. In the presence of anti-E-cadherin antibody, both loricrin and profilaggrin levels were dramatically enhanced compared to the high Ca(2+) control cells, while addition of antibody to P-cadherin slightly attenuated the Ca(2+)-induced increase. In the presence of both antibodies, loricrin and profilaggrin protein levels were intermediate between those observed in the presence of either antibody alone. The expression of involucrin, however, was unaffected by addition of antibodies. In addition, effects of the anti-cadherin antibodies were not secondary to alterations in proliferation or programmed cell death, as determined by several independent assays of these processes. Thus, the consequences of cadherin inhibition depend upon both the particular cadherin and the differentiation marker under study. Taken together, these data suggest that E-cadherin and P-cadherin contribute to the orderly progression of terminal differentiation in the epidermis in multiple ways.