RESUMEN
Cervical cancer (CC) is associated with alterations in immune system balance, which is primarily due to a shift from Th1 to Th2 and the unbalance of Th17/Treg cells. Using in silico DNA copy number analysis, we have demonstrated that ~20% of CC samples exhibit gain of 8q22.3 and 19q13.31; the regions of the genome that encodes the KLF10 and PSG genes, respectively. Gene expression studies demonstrated that there were no alterations in KLF10 mRNA expression, whilst the PSG2 and -5 genes were up-regulated by 1.76 and 3.97-fold respectively in CC compared to normal tissue controls. siRNA and ChIP experiments in SiHa cells have demonstrated that KLF10 participates in immune response through regulation of IL6, IL25 and PSG2 and PSG5 genes. Using cervical tissues from KLF10-/- mice, we have identified down-regulation of PSG17, -21 and -23 and IL11. These results suggest that KLF10 may regulate immune system response genes in cervical cancer among other functions. KLF10 and PSG copy number variations and alterations in mRNA expression levels could represent novel molecular markers in CC.
Asunto(s)
Factores de Transcripción de la Respuesta de Crecimiento Precoz/metabolismo , Regulación Neoplásica de la Expresión Génica , Factores de Transcripción de Tipo Kruppel/metabolismo , Glicoproteínas beta 1 Específicas del Embarazo/genética , Neoplasias del Cuello Uterino/genética , Animales , Línea Celular Tumoral , Variaciones en el Número de Copia de ADN , Factores de Transcripción de la Respuesta de Crecimiento Precoz/genética , Femenino , Humanos , Interleucinas/genética , Interleucinas/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Ratones , Glicoproteínas beta 1 Específicas del Embarazo/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Neoplasias del Cuello Uterino/inmunologíaRESUMEN
The hypothalamus regulates the homeostasis of the organism by controlling hormone secretion from the pituitary. The molecular mechanisms that regulate the differentiation of the hypothalamic thyrotropin-releasing hormone (TRH) phenotype are poorly understood. We have previously shown that Klf10 or TGFß inducible early gene-1 (TIEG1) is enriched in fetal hypothalamic TRH neurons. Here, we show that expression of TGFß isoforms (1-3) and both TGFß receptors (TßRI and II) occurs in the hypothalamus concomitantly with the establishment of TRH neurons during late embryonic development. TGFß2 induces Trh expression via a TIEG1 dependent mechanism. TIEG1 regulates Trh expression through an evolutionary conserved GC rich sequence on the Trh promoter. Finally, in mice deficient in TIEG1, Trh expression is lower than in wild type animals at embryonic day 17. These results indicate that TGFß signaling, through the upregulation of TIEG1, plays an important role in the establishment of Trh expression in the embryonic hypothalamus.