RESUMEN
Pancreatic cancer is the only major cancer with very low survival rates (1%). It is the fourth leading cause of cancer-related death. Hyperactivated growth hormone receptor (GHR) levels have been shown to increase the risk of cancer in general and this pathway is a master regulator of key cellular functions like proliferation, apoptosis, differentiation, metastasis, etc. However, to date there is no available data on how GHR promotes pancreatic cancer pathogenesis. Here, we used an RNA interference approach targeted to GHR to determine whether targeting GHR is an effective method for controlling pancreatic cancer growth and metastasis. For this, we used an in vitro model system consisting of HPAC and PANC-1 pancreatic cancer cells lines. GHR is upregulated in both of these cell lines and silencing GHR significantly reduced cell proliferation and viability. Inhibition of GHR also reduced the metastatic potential of pancreatic cancer cells, which was aided through decreased colony-forming ability and reduced invasiveness. Flow cytometric and western blot analyses revealed the induction of apoptosis in GHR silenced cells. GHR silencing affected phosphatidylinositol 3 kinase/AKT, mitogen extracellular signal-regulated kinase/extracellular signal-regulated kinase, Janus kinase/signal transducers and activators of transcription and mammalian target of rapamycin signaling, as well as, epithelial to mesenchymal transition. Interestingly, silencing GHR also suppressed the expression of insulin receptor-beta and cyclo-oxygenease-2. Altogether, GHR silencing controls the growth and metastasis of pancreatic cancer and reveals its importance in pancreatic cancer pathogenesis.
Asunto(s)
Humanos , Carcinoma Ductal Pancreático/genética , Línea Celular Tumoral , Movimiento Celular , Regulación Neoplásica de la Expresión Génica , Metástasis de la Neoplasia/genética , Conductos Pancreáticos/metabolismo , Neoplasias Pancreáticas/genética , Interferencia de ARN , ARN Interferente Pequeño/administración & dosificación , Receptores de Somatotropina/genética , TransfecciónRESUMEN
To investigate the protein and mRNA expression of pancreas/duodenal homeobox-1 (PDX-1), a transcription factor as a marker for pancreatic stem cells, in pancreatic ductal cells of rats after partial (90%) pancreatectomy and evaluated the significance of the PDX-1 expression. Western blot and Reverse transcriptase-polymerase chain reaction (RT-PCR) were used to detect the expression of PDX-1 protein and mRNA respectively. PDX-1 protein was only faintly detected in pancreatic ductal cells on the day 1 after partial pancreatectomy. On the day 2 and 3 after operation in operation group, a 2-3 fold increased PDX-1 protein was observed, corresponding to the characteristic 42-kD protein in Western blot. There was significant difference between operation group and sham-operation group (P0.05). RT-PCR revealed the PDX-1 mRNA expression showed no significant difference between operation group at various time points and sham-operation group (P> 0.05). These results indicate that there was overexpression of PDX-1 in the cells of pancreatic epithelium during the regeneration of remnant pancreas after partial pancreatectomy in adult rats, suggesting the pancreatic stem cells in pancreatic ductal epithelial cells are involved in the regeneration of remnant pancreas and the expression of PDX-1 in ductal cells was regulated posttranscription.
Asunto(s)
Células Epiteliales/metabolismo , Proteínas de Homeodominio/biosíntesis , Proteínas de Homeodominio/genética , Pancreatectomía/métodos , Conductos Pancreáticos/citología , Conductos Pancreáticos/metabolismo , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Ratas Sprague-Dawley , Transactivadores/biosíntesis , Transactivadores/genéticaRESUMEN
No abstract available.
Asunto(s)
Ratones , 1-Metil-3-Isobutilxantina/farmacología , Compuestos de Amonio/farmacología , Animales , Transporte Biológico/fisiología , Transporte Biológico/efectos de los fármacos , Membrana Celular/metabolismo , AMP Cíclico/metabolismo , Colforsina/farmacología , Guanidinas/farmacología , Ratones Noqueados , Conductos Pancreáticos/metabolismo , Inhibidores de Fosfodiesterasa/farmacología , Protones , Intercambiadores de Sodio-Hidrógeno/metabolismo , Intercambiadores de Sodio-Hidrógeno/genética , Sulfonas/farmacologíaRESUMEN
1. 5-HT inhibits spontaneous fluid secretion as well as stimulated secretion with secretin (cAMP mediated) or ACh (Ca2+ mediated) in the isolated guinea pig pancreatic ducts. 2. The inhibitory effect of 5-HT is reversible and is dependent on the concentration in the range 0.01-0.1 microM, which is much lower than those that affect intestinal motility and secretion. 3. The 5-HT3 receptor in duct cells appears to mediate the inhibitory effect of 5-HT. 4. [Ca2+]i is unlikely to mediate the inhibitory effect of 5-HT.
Asunto(s)
5-Metoxitriptamina/farmacología , Acetilcolina/farmacología , Animales , Calcio/metabolismo , Cobayas , Conductos Pancreáticos/metabolismo , Conductos Pancreáticos/efectos de los fármacos , Secretina/farmacología , Serotonina/farmacología , Serotonina/metabolismo , Serotonina/análogos & derivados , Vasodilatadores/farmacologíaRESUMEN
No abstract available.
Asunto(s)
Animales , Bicarbonatos/metabolismo , Transporte Biológico/fisiología , Conductos Pancreáticos/metabolismo , PerfusiónRESUMEN
É feito estudo histoquímico e ultra-estrutural das células epiteliais dos ductos intercalares e intra-lobulares da visäo. As reaçöes histoquímicas realizadas sugerem a presença de glicogênico e de mucosubstâncias sulfatadas ácidas e neutras, nas partes apicais das células epiteliasis e na luz dos ductos. Foram positivas as reaçöes para a evidenciaçäo de AcPase, esterases inespecíficas, SDH, G-6-PDH, LDH e MAO; foram negativas as reaçöes para a AlkPase, ATPase e leve para a TTPase. Os achados ultra-estruturais näo sugerem, morfologicamente, uma grande participaçäo das células epiteliais dos dúctulos pancreáticos em processos de absorçäo e secreaçäo