RESUMEN
Transforming growth factor-beta (TGF-beta) signaling members, TGF-beta receptor type II (TBRII), Smad2, Smad4 and Smad adaptor, embryonic liver fodrin (ELF), are prominent tumor suppressors in gastrointestinal cancers. Here, we show that 40% of elf(+/-) mice spontaneously develop hepatocellular cancer (HCC) with markedly increased cyclin D1, cyclin-dependent kinase 4 (Cdk4), c-Myc and MDM2 expression. Reduced ELF but not TBRII, or Smad4 was observed in 8 of 9 human HCCs (P<0.017). ELF and TBRII are also markedly decreased in human HCC cell lines SNU-398 and SNU-475. Restoration of ELF and TBRII in SNU-398 cells markedly decreases cyclin D1 as well as hyperphosphorylated-retinoblastoma (hyperphosphorylated-pRb). Thus, we show that TGF-beta signaling and Smad adaptor ELF suppress human hepatocarcinogenesis, potentially through cyclin D1 deregulation. Loss of ELF could serve as a primary event in progression toward a fully transformed phenotype and could hold promise for new therapeutic approaches in human HCCs.
Asunto(s)
Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/metabolismo , Proteínas Portadoras/fisiología , Ciclinas/metabolismo , Neoplasias Hepáticas Experimentales/etiología , Proteínas de Microfilamentos/fisiología , Transducción de Señal/fisiología , Espectrina/fisiología , Factor de Crecimiento Transformador beta2/antagonistas & inhibidores , Animales , Proteínas Portadoras/genética , Línea Celular Tumoral , Ciclina D , Ciclinas/antagonistas & inhibidores , Humanos , Neoplasias Hepáticas Experimentales/metabolismo , Ratones , Ratones Noqueados , Proteínas de Microfilamentos/deficiencia , Proteínas de Microfilamentos/genética , Fosforilación , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Retinoblastoma/metabolismo , Transducción de Señal/genética , Espectrina/deficiencia , Espectrina/genética , Factor de Crecimiento Transformador beta2/metabolismo , Factor de Crecimiento Transformador beta2/fisiología , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/fisiologíaRESUMEN
BACKGROUND: Symptomatic gastroesophageal reflux disease (GERD) affects a substantial proportion of the American population. The diagnosis and treatment of GERD has advanced tremendously over the past 30 years. However, there remains a lack of understanding about the differences and advantages that laparoscopic antireflux surgery offers and a lack of agreement on the ideal surgical candidate. The purpose of this study was to determine whether a significant difference exists in the practice habits and selection criteria for surgery between gastroenterologists and laparoscopic surgeons. METHODS: Surveys were sent to 1,000 randomly selected members of the American Gastroenterological Association (AGA) and to 1,000 randomly selected members of the Society of American Gastrointestinal Endoscopic Surgeons (SAGES). As a result, 20% of the AGA surveys and 33% of the SAGES surveys were completed and returned. RESULTS: The AGA group considered patients whose symptoms are not well controlled, those who have complications of disease, and those who require significant lifestyle changes to control their symptoms as the best candidates for surgical evaluation. As a group, gastroenterologists remain somewhat hesitant to refer patients for laparoscopic antireflux surgery. Surgeons considered patients whose symptoms have been well controlled with medical therapy, those who have complications of disease, and those who require significant lifestyle changes to control their symptoms as ideal candidates for fundoplication. CONCLUSION: A consensus should be reached between surgeons and gastroenterologists in establishing criteria for surgical intervention to manage GERD.