RESUMEN
To investigate the role of the transcription factor nuclear factor kappaB (NFkappaB) in tumor metastasis, we generated a murine lung alveolar carcinoma cell line (Line 1) defective in NFkappaB-signaling by retroviral delivery of a dominant negative inhibitor of NFkappaB. The NFkappaB signal blockade resulted in the down-regulation of prometastatic matrix metalloproteinase 9, a urokinase-like plasminogen activator, and heparanase and reciprocal up-regulation of antimetastatic tissue inhibitors of matrix metalloproteinases 1 and 2 and plasminogen activator inhibitor 2. NFkappaB signal blockade did not affect tumor cell proliferation in vitro or in vivo but prevented intravasation of tumor cells in an in vivo chick chorioallantoic membrane model of metastasis as well as spontaneous metastasis in a murine model. These findings suggest that NFkappaB plays a central and specific role in the regulation of tumor metastasis and may be an important therapeutic target for development of antimetastatic cancer treatments.
Asunto(s)
Regulación Neoplásica de la Expresión Génica/fisiología , FN-kappa B/fisiología , Metástasis de la Neoplasia/genética , Adenocarcinoma Bronquioloalveolar/enzimología , Adenocarcinoma Bronquioloalveolar/genética , Adenocarcinoma Bronquioloalveolar/secundario , Alantoides/irrigación sanguínea , Animales , División Celular/fisiología , Embrión de Pollo , Corion/irrigación sanguínea , Regulación hacia Abajo , Glucuronidasa/biosíntesis , Glucuronidasa/genética , Humanos , Proteínas I-kappa B/genética , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundario , Metaloproteinasa 9 de la Matriz/biosíntesis , Metaloproteinasa 9 de la Matriz/genética , Ratones , Ratones Endogámicos BALB C , FN-kappa B/antagonistas & inhibidores , Fenotipo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/fisiología , Inhibidor Tisular de Metaloproteinasa-1/biosíntesis , Inhibidor Tisular de Metaloproteinasa-1/genética , Inhibidor Tisular de Metaloproteinasa-2/biosíntesis , Inhibidor Tisular de Metaloproteinasa-2/genética , Transfección , Regulación hacia Arriba , Activador de Plasminógeno de Tipo Uroquinasa/biosíntesis , Activador de Plasminógeno de Tipo Uroquinasa/genéticaRESUMEN
BACKGROUND: Dominant negative inhibition of nuclear factor kappa B (NF kappa B) signalling activity in a human osteosarcoma cell line (Saos2) results in malignant reversion and the induction of the osteoblast differentiating transcription factor, Runx2/Cbfa1. This observation suggests that there is an inverse relation between a transcription factor associated with malignant progression and chemoresistance (NF kappa B) and an osteoblast differentiating transcription factor (Runx2/Cbfa1). AIMS: To assess and correlate Runx2/Cbfa1 and NF kappa B (p65) immunoreactivity in human osteosarcoma. METHODS: Runx2/Cbfa1 and NFkappaB (p65) immunoreactivity was assessed on 11 paraffin wax embedded archival specimens of human primary osteosarcoma by standard immunohistochemical methods and scored on a scale of 0-3. A Pearson correlation analysis between Runx2/Cbfa1 and NF kappa B (p65) scores was established. RESULTS: Runx2/Cbfa1 was expressed constitutively in all pathology specimens of human osteosarcoma. Of note, a chondroblastic osteosarcoma showed the highest Runx2/Cbfa1 immunoreactivity. A Pearson correlation did not support an inverse correlation between Runx2/Cbfa1 and NF kappa B (p65) scores (r = 0.57) in human osteosarcoma. CONCLUSION: Runx2/Cbfa1 immunoreactivity does not inversely correlate with NF kappa B immunoreactivity, and thus cannot serve as an indirect measure of NF kappa B activity or an independent predictive or prognostic indicator.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Óseas/metabolismo , Proteínas de Unión al ADN/metabolismo , FN-kappa B/metabolismo , Osteosarcoma/metabolismo , Factores de Transcripción/metabolismo , Neoplasias Óseas/patología , Subunidad alfa 1 del Factor de Unión al Sitio Principal , Humanos , Técnicas para Inmunoenzimas , Proteínas de Neoplasias/metabolismo , Osteosarcoma/patología , Factor de Transcripción AP-2RESUMEN
Hyper-activation of nuclear factor kappa B (NF-kappaB) is germane to carcinogenesis by its fundamental implication in cellular de-differentiation and proliferation, the subversion of apoptosis, the promotion of neo-angiogenesis, invasive growth and metastases. Conversely, the expression of multiple nuclear receptors (NRs), arbiters of cellular differentiation, decreases with progressive carcinogenesis. This review is a conceptual discussion of evidence to support NF-kappaB as the nexus between carcinogenesis and decreased NR expression. Furthermore, it synthesizes the thesis and antithesis of NR function in carcinogenesis and expounds on the functional antagonism between NRs and NF-kappaB as a basis for the chemopreventive activity of NR ligands. Finally, strategies for optimal chemopreventive interventions with NR ligands are discussed.