title: uPAR and cathepsin B shRNA impedes TGF-β1-driven proliferation and invasion of meningioma cells in a XIAP-dependent pathway.
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.
authors.affiliation: Department of Cancer Biology & Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA.
authors.forename: V R
authors.initials: VR
authors.lastname: Gogineni
authors.forename: R
authors.initials: R
authors.lastname: Gupta
authors.forename: A K
authors.initials: AK
authors.lastname: Nalla
authors.forename: K K
authors.initials: KK
authors.lastname: Velpula
authors.forename: J S
authors.initials: JS
authors.lastname: Rao
mesh_terms: D002401:Cathepsin B / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008577:Meningeal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008579:Meningioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D009361:Neoplasm Invasiveness; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics* / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D055293:Receptors, Urokinase Plasminogen Activator; D053773:Transforming Growth Factor beta1; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D002401:Cathepsin B