RESUMEN
Despite recent insights into prostate cancer (PCa)-associated genetic changes, full understanding of prostate tumorigenesis remains elusive owing to complexity of interactions among various cell types and soluble factors present in prostate tissue. We found the upregulation of nuclear factor of activated T cells c1 (NFATc1) in human PCa and cultured PCa cells, but not in normal prostates and non-tumorigenic prostate cells. To understand the role of NFATc1 in prostate tumorigenesis in situ, we temporally and spatially controlled the activation of NFATc1 in mouse prostate and showed that such activation resulted in prostatic adenocarcinoma with features similar to those seen in human PCa. Our results indicate that the activation of a single transcription factor, NFATc1 in prostatic luminal epithelium to PCa can affect expression of diverse factors in both cells harboring the genetic changes and in neighboring cells through microenvironmental alterations. In addition to the activation of oncogenes c-MYC and STAT3 in tumor cells, a number of cytokines and growth factors, such as IL1ß, IL6 and SPP1 (osteopontin, a key biomarker for PCa), were upregulated in NFATc1-induced PCa, establishing a tumorigenic microenvironment involving both NFATc1 positive and negative cells for prostate tumorigenesis. To further characterize interactions between genes involved in prostate tumorigenesis, we generated mice with both NFATc1 activation and Pten inactivation in prostate. We showed that NFATc1 activation led to acceleration of Pten null-driven prostate tumorigenesis by overcoming the PTEN loss-induced cellular senescence through inhibition of p21 activation. This study provides direct in vivo evidence of an oncogenic role of NFATc1 in prostate tumorigenesis and reveals multiple functions of NFATc1 in activating oncogenes, in inducing proinflammatory cytokines, in oncogene addiction, and in overcoming cellular senescence, which suggests calcineurin-NFAT signaling as a potential target in preventing PCa.
Asunto(s)
Transformación Celular Neoplásica/genética , Factores de Transcripción NFATC/genética , Próstata/metabolismo , Neoplasias de la Próstata/genética , Animales , Western Blotting , Línea Celular , Línea Celular Tumoral , Proliferación Celular/genética , Transformación Celular Neoplásica/metabolismo , Senescencia Celular/genética , Citocinas/genética , Citocinas/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Ratones Noqueados , Ratones Desnudos , Ratones Transgénicos , Factores de Transcripción NFATC/metabolismo , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Neoplasias de la Próstata/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Trasplante Homólogo , Células Tumorales Cultivadas , Microambiente Tumoral/genéticaAsunto(s)
Dolor de Espalda/cirugía , Vértebras Lumbares/cirugía , Enfermedad de Paget Extramamaria/cirugía , Manejo del Dolor , Neoplasias de la Columna Vertebral/cirugía , Anciano , Dolor de Espalda/etiología , Humanos , Masculino , Enfermedad de Paget Extramamaria/complicaciones , Neoplasias de la Columna Vertebral/complicacionesRESUMEN
The newborn daughter of a diabetic mother developed neonatal gangrene of an upper extremity with massive muscle necrosis of the forearm, and required early dorsal and volar fasciotomies with subsequent debridements to salvage the limb. Decreased perfusion and local ischemia resulting in neonatal gangrene may result from the greater propensity for intravascular thrombosis in infants whose mothers have diabetes mellitus. While previous investigators have suggested that surgical intervention should be avoided in neonatal gangrene, in more severe cases early fasciotomy may be required to salvage a limb and avoid life-threatening complications.