RESUMEN
Glioblastoma (GBM) is characterized by extensive tumor cell invasion, angiogenesis, and proliferation. We previously established subclones of GBM cells with distinct invasive phenotypes and identified annexin A2 (ANXA2) as an activator of angiogenesis and perivascular invasion. Here, we further explored the role of ANXA2 in regulating phenotypic transition in GBM. We identified oncostatin M receptor (OSMR) as a key ANXA2 target gene in GBM utilizing microarray analysis and hierarchical clustering analysis of the Ivy Glioblastoma Atlas Project and The Cancer Genome Atlas datasets. Overexpression of ANXA2 in GBM cells increased the expression of OSMR and phosphorylated signal transducer and activator of transcription 3 (STAT3) and enhanced cell invasion, angiogenesis, proliferation, and mesenchymal transition. Silencing of OSMR reversed the ANXA2-induced phenotype, and STAT3 knockdown reduced OSMR protein expression. Exposure of GBM cells to hypoxic conditions activated the ANXA2-STAT3-OSMR signaling axis. Mice bearing ANXA2-overexpressing GBM exhibited shorter survival times compared with control tumor-bearing mice, whereas OSMR knockdown increased the survival time and diminished ANXA2-mediated tumor invasion, angiogenesis, and growth. Further, we uncovered a significant relationship between ANXA2 and OSMR expression in clinical GBM specimens, and demonstrated their correlation with tumor histopathology and patient prognosis. Our results indicate that the ANXA2-STAT3-OSMR axis regulates malignant phenotypic changes and mesenchymal transition in GBM, suggesting that this axis is a promising therapeutic target to treat GBM aggressiveness.
Asunto(s)
Anexina A2/genética , Neoplasias Encefálicas/genética , Glioblastoma/genética , Subunidad beta del Receptor de Oncostatina M/genética , Factor de Transcripción STAT3/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Anexina A2/metabolismo , Neoplasias Encefálicas/irrigación sanguínea , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Proliferación Celular/genética , Niño , Perros , Transición Epitelial-Mesenquimal/genética , Femenino , Técnicas de Silenciamiento del Gen , Silenciador del Gen , Glioblastoma/irrigación sanguínea , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Invasividad Neoplásica/genética , Trasplante de Neoplasias , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Subunidad beta del Receptor de Oncostatina M/metabolismo , Fenotipo , Receptores de Oncostatina M/genética , Receptores de Oncostatina M/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Tasa de Supervivencia , Hipoxia Tumoral/genéticaRESUMEN
In this paper, we describe stimuli-responsive hydrogels prepared from a rigid rod-like polyelectrolyte 'imogolite' and a dicarboxylic acid. The hydrogel exhibited thixotropy in response to mechanical shock within the order of seconds or sub-seconds. Here, using the latest structural/rheological characterisation techniques, the relationship between the structural transition processes and the shear thinning was estimated. The evidence obtained by the experiments revealed for the first time the direct relationship between the microscopic structural change and the macroscopic thixotropic behavior that have been extensively discussed. The thixotropic hydrogel has the hierarchical architecture in the combination of imogolite and dicarboxylic acid, i.e., sheathed nanotubes/hydroclusters of cross-bridged nanotubes/frameworks. The formation and disintegration of the network structure upon resting and agitating, respectively, were the origin of gel/sol transition (thixotropy), although the hydroclusters of cross-bridged nanotubes were maintained throughout the transition.
