2 research outputs found
Short Hairpin RNA-Mediated Fibronectin Knockdown Delays Tumor Growth in a Mouse Glioma Model1
Glioblastoma multiforme is the most common and lethal primary brain tumor. Glioma progression depends on the rapid proliferation of tumor cells accompanied by an acute immunosuppressive environment, facilitated mainly by tumor infiltration of regulatory T cells (Tregs). In this study, we characterize the role of fibronectin, a high-molecular weight extracellular matrix glycoprotein secreted by tumor cells, in controlling glioma progression and in mediating immunosuppression. Fibronectin binds to membrane-spanning integrin receptors and plays an important role in cell signaling, in defining cellular shape, in mobility, and in regulating the cell cycle. We found that inhibition of fibronectin expression in glioma cells, using short hairpin RNA-mediated silencing of gene expression, delayed cell proliferation in vitro. This delayed growth is explained, in part, by the observed reduced expression of integrin β1 fibronectin receptor, which was restored by the inhibition of proteosomal activity. In our analysis of the downstream signaling targets of integrin β1, we demonstrated reduced phosphorylation of Src kinase and STAT-3. We also observed reduced survivin expression that induced a three-fold increased accumulation of fibronectin-knockdown cells in the G2/M phase. In an experimental animal model, the fibronectin knockdown tumors had a mean survival advantage of 23 days over wild-type tumors. Moreover, brain samples of animals bearing fibronectin-knockdown tumors showed delayed Treg recruitment. Collectively, we propose that fibronectin is a key mediator of glioma progression because its inhibition delays both tumor progression and immunosuppression
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Challenges in assessing the efficacy of systemic corticosteroids for severe wheezing episodes in preschool children
This letter addresses the controversial issue of the use of oral corticosteroids during wheezing exacerbations in preschool-aged children by demonstrating findings of a prematurely terminated multi-center clinical trial, discussing lessons learned, and suggesting future directions