Faculty Collaboration Database

uPAR and cathepsin B shRNA impedes TGF-β1-driven proliferation and invasion of meningioma cells in a XIAP-dependent pathway. Cell Death Dis 2012 Dec 06;3(12):e439

Date

12/12/2012

Pubmed ID

23222509

Pubmed Central ID

PMC3542612

DOI

10.1038/cddis.2012.170

Scopus ID

2-s2.0-84871234236 (requires institutional sign-in at Scopus site)   39 Citations

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.

Author List

Gogineni VR, Gupta R, Nalla AK, Velpula KK, Rao JS

MESH terms used to index this publication - Major topics in bold

Cathepsin B
Cell Line, Tumor
Cell Proliferation
Down-Regulation
Gene Expression Regulation, Neoplastic
Humans
Meningeal Neoplasms
Meningioma
Neoplasm Invasiveness
RNA Interference
RNA, Small Interfering
Receptors, Urokinase Plasminogen Activator
Transforming Growth Factor beta1
X-Linked Inhibitor of Apoptosis Protein