RESUMEN
Snail2 is a zinc finger transcription factor involved in driving epithelial to mesenchymal transitions. Snail2 null mice are viable, but display defects in melanogenesis, gametogenesis and hematopoiesis, and are markedly radiosensitive. Here, using mouse genetics, we have studied the contributions of Snail2 to epidermal homeostasis and skin carcinogenesis. Snail2 (-/-) mice presented a defective epidermal terminal differentiation and, unexpectedly, an increase in number, size and malignancy of tumor lesions when subjected to the two-stage mouse skin chemical carcinogenesis protocol, compared with controls. Additionally, tumor lesions from Snail2 (-/-) mice presented a high inflammatory component with an elevated percentage of myeloid precursors in tumor lesions that was further increased in the presence of the anti-inflammatory agent dexamethasone. In vitro studies in Snail2 null keratinocytes showed that loss of Snail2 leads to a decrease in proliferation indicating a non-cell autonomous role for Snail2 in the skin carcinogenic response observed in vivo. Bone marrow (BM) cross-reconstitution assays between Snail2 wild-type and null mice showed that Snail2 absence in the hematopoietic system fully reproduces the tumor behavior of the Snail2 null mice and triggers the accumulation of myeloid precursors in the BM, blood and tumor lesions. These results indicate a new role for Snail2 in preventing myeloid precursors recruitment impairing skin chemical carcinogenesis progression.
Asunto(s)
Inflamación/patología , Queratinocitos/patología , Células Progenitoras Mieloides/patología , Neoplasias Experimentales/patología , Neoplasias Cutáneas/patología , Factores de Transcripción/fisiología , 9,10-Dimetil-1,2-benzantraceno/toxicidad , Animales , Apoptosis , Western Blotting , Carcinógenos/toxicidad , Diferenciación Celular , Proliferación Celular , Células Cultivadas , Técnica del Anticuerpo Fluorescente , Hematopoyesis , Técnicas para Inmunoenzimas , Inflamación/inducido químicamente , Inflamación/metabolismo , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Progenitoras Mieloides/efectos de los fármacos , Células Progenitoras Mieloides/metabolismo , Neoplasias Experimentales/inducido químicamente , Neoplasias Experimentales/metabolismo , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/metabolismo , Factores de Transcripción de la Familia SnailRESUMEN
Transcriptional repression mechanisms have emerged as one of the crucial processes for the downregulation of E-cadherin expression during development and tumour progression. Recently, several E-cadherin transcriptional repressors have been characterized (Snail, E12/E47, ZEB-1 and SIP-1) and shown to act through an interaction with proximal E-boxes of the E-cadherin promoter. We have analyzed the participation of another member of the Snail family, Slug, and observed that it also behaves as a repressor of E-cadherin expression. Stable expression of Slug in MDCK cells leads to the full repression of E-cadherin at transcriptional level and triggers a complete epithelial to mesenchymal transition. Slug-induced repression of E-cadherin is mediated by its binding to proximal E-boxes, particularly to the E-pal element of the mouse promoter. Detailed analysis of the binding affinity of different repressors to the E-pal element indicates that Slug binds with lower affinity than Snail and E47 proteins. These results, together with the known expression patterns of these factors in embryonic development and carcinoma cell lines, support the idea that the in vivo action of the different factors in E-cadherin repression can be modulated by their relative concentrations as well as by specific cellular or tumour contexts.
Asunto(s)
Cadherinas/biosíntesis , Transformación Celular Neoplásica/metabolismo , Células Epiteliales/metabolismo , Epitelio/crecimiento & desarrollo , Mesodermo/metabolismo , Invasividad Neoplásica/genética , Factores de Transcripción/metabolismo , Animales , Sitios de Unión/genética , Cadherinas/genética , Adhesión Celular/genética , Línea Celular , Transformación Celular Neoplásica/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Perros , Elementos E-Box/genética , Células Epiteliales/citología , Epitelio/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , Mesodermo/citología , Regiones Promotoras Genéticas/genética , Unión Proteica/genética , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Factores de Transcripción de la Familia Snail , Factores de Transcripción TCF , Proteína 1 Similar al Factor de Transcripción 7 , Factores de Transcripción/genéticaRESUMEN
La fagocitosis es una función primordial en los padecimientos broncopulmonares. Es importante su valoración en asma bronquial porque se han encontrado alteraciones tanto congénitas como adquiridas en esta enfermedad, lo que hace importante su estudio. Utilizamos leucocitos polimorfonucleares para estudiar los cuatro pasos de la fagocitosis: adherencia inmunitaria, receptores celulares, endocitosis y digestión en 52 pacientes con asma bronquial extrínseca sin tratamiento previo que alteraran la fagocitosis. Conclusión: No encontramos diferencias significativas en los pacientes asmáticos en relación con individuos normales