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
BACKGROUND: In patients with colorectal carcinoma, insertions or deletions of short sequences of DNA, a phenomenon called microsatellite instability, are observed. AIM: To look for microsatellite instability and mutations of MLH1 and MSH2 gene mutations in patients with colorectal carcinoma. MATERIAL AND METHODS: Ten patients with sporadic colorectal carcinoma and 31 patients fulfilling criteria for hereditary nonpolyposis colon cancer (HNPCC), aged 9 to 70 years, were studied. Microsatellite instability was studied in samples of tumor and peripheral blood mononuclear cell DNA. Six markers were amplified by polymerase chain reaction and capillary electrophoresis. In samples with microsatellite instability, mutations of MLH1 and MSH2 genes were studied by direct sequencing. RESULTS: Thirty four percent of patients had microsatellite instability and among these, 76% had a high degree of instability. BAT40 marker had the higher frequency of instability. No mutations for MLH1 and MSH2 genes were observed. However a new polymorphism, C399T, was identified in exon 3 of MSH2 gene. This polymorphism was observed both in patients with sporadic colorectal carcinoma and patients with HNPCC. CONCLUSIONS: There is a high frequency of microsatellite instability among patients with colorectal cancer. A new polymorphism, not previously reported, was identified in MSH2 gene.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Carcinoma/genética , Neoplasias Colorrectales/genética , Inestabilidad de Microsatélites , Proteína 2 Homóloga a MutS/genética , Proteínas Nucleares/genética , Polimorfismo Genético/genética , Adolescente , Adulto , Anciano , Niño , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Análisis Mutacional de ADN , Pruebas Genéticas , Humanos , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL , Reacción en Cadena de la PolimerasaRESUMEN
La leucemia mieloide crónica es un desorden clonal maligno producido por la translocación genética t(9;22)(q34;q11), que genera hiperplasia en médula ósea y proliferación incontrolada de la línea mieloide en sangre periférica. Hasta 1980, se consideró una enfermedad fatal, sin embargo gracias a los avances científicos se empezaron a dilucidar diferentes estrategias terapéuticas, que han ido desde el trasplante alogénico de médula ósea, hasta el desarrollo de fármacos de última generación como es el caso de los inhibidores tirosin kinasa de primera y segunda generación (Imanitib y Nilotinib), con los cuales se ha obtenido una respuesta positiva hasta en un 95% de los casos que ha obligado a nuevas estrategias diagnósticas y de seguimiento como la fluorescencia por hibridación in situ y las diferentes variantes de la reacción en cadena de la polimerasa; conocer estos avances es fundamental para nuestro desempeños como profesionales de la salud, ya que nos permite actuar y tomar decisiones acertadas para el beneficio del paciente, acordes con los recursos del medio.
Myeloid chronic leukemia is a malignant clonal disorder caused by genetic the translocation t(9; 22) (q34, q11) which generates hyperplasia in bone marrow and uncontrolled myeloid proliferation in peripheral blood. Until 1980, it was considered a fatal disease, however, thanks to scientific progress, scientists began to elucidate different therapeutic strategies, from allogeneic transplantation of bone marrow, to the first and second generation tyrosine kinase inhibitors (Imanitib and Nilotinib), which has provided a positive response in up to 95% of cases. Such development has enforced new diagnostic and monitoring strategies as the fluorescence in situ hybridization and different variants of the polymerase chain reaction. Knowing such advances is fundamental to our performance as health care professionals, allowing us to act and make sound decisions for the benefit of the patient, according to available resources.