Abstract
Overexpression of transforming growth factor β1 (TGF-β1) has been linked to immune suppression, tumor angiogenesis, tumor cell migration, tumor cell survival, and tumor cell invasion in many cancers. In the present study, we found abundant expression of TGF-β1 in the microenvironment of four different pathological types of meningioma tumors. TGF-β1 induced invasion in malignant meningioma cells with an associated upregulation of urokinase-type plasminogen activator (uPA), uPAR, cathepsin B, and MMP-9, and this increase in proliferation was coupled with the expression of anti-apoptotic and pro-survival signaling molecules. In addition to the intense immunoreactivity of meningioma tumors to X-linked inhibitor to apoptosis (XIAP), its knockdown abolished the TGF-β1-induced proliferation of these cells. The stimulation of XIAP expression and the activation of pSMAD-2 is mediated by phosphatidylinositol 3-kinase (PI3K)- and MEK-dependent pathways, and the addition of anti-TGF-β1 antibodies prevented their expression with a consequent decrease in invasion. Bicistronic shRNA constructs targeting uPAR and cathepsin B (pUC) quenched TGF-β1-driven invasion and survival of meningioma cells by downregulation of XIAP and pSMAD-2 expression. Animal models with intracranial tumors showed elevated levels of TGF-β1, XIAP and pSMAD-2, and pUC treatment prevented this increased expression. Thus, targeted silencing of TGF-β1-induced signaling by pUC in meningioma would provide new treatment approaches for management of meningioma.
Highlights
Transforming growth factor b (TGF-b) is involved in physiological processes, such as wound healing, tissue development, and remodeling
The cells of fibrous meningioma are usually arranged in fascicles, and TGF-b1 reactivity was seen along these fascicles of cells (Figure 1a)
In atypical meningioma, which is characterized by invasive cells, we found strong reactivity for TGF-b1 in the entire tumor section, indicating high expression (Figure 1a)
Summary
Transforming growth factor b (TGF-b) is involved in physiological processes, such as wound healing, tissue development, and remodeling. A high uPAR level portends a low 5-year survival rate.[14] It has been shown that the uPAR protein is inducible by TGF-b.15. Our investigation uses this approach to examine the therapeutic significance of RNAi-mediated simultaneous downregulation of these proteolytic networks on TGF-b1induced signaling in malignant meningiomas It has been shown that the uPAR protein is inducible by TGF-b.15 Our investigation uses this approach to examine the therapeutic significance of RNAi-mediated simultaneous downregulation of these proteolytic networks on TGF-b1induced signaling in malignant meningiomas
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