A miR-297/hypoxia/DGK-α axis regulating glioblastoma survival.

Background: Despite advances in the treatment of the most aggressive form of brain tumor, glioblastoma, patient prognosis remains disappointing. This failure in treatment has been attributed to dysregulated oncogenic pathways, as observed in other tumors. We and others have suggested the use of microRNAs (miRs) as therapeutic tools able to target multiple pathways in glioblastoma.

Hepatocyte growth factor sensitizes brain tumors to c-MET kinase inhibition.

Purpose: The receptor tyrosine kinase (RTK) c-MET and its ligand hepatocyte growth factor (HGF) are deregulated and promote malignancy in cancer and brain tumors. Consequently, clinically applicable c-MET inhibitors have been developed. The purpose of this study was to investigate the not-well-known molecular determinants that predict responsiveness to c-MET inhibitors and to explore new strategies for improving inhibitor efficacy in brain tumors.

Epidermal growth factor receptor-mediated regulation of urokinase plasminogen activator expression and glioblastoma invasion via C-SRC/MAPK/AP-1 signaling pathways.

One of the major pathophysiological features of malignant astrocytomas is their ability to infiltrate surrounding brain tissue. The epidermal growth factor receptor (EGFR) and proteases are known to be overexpressed in glioblastomas (GBMs), but the interaction between the activation of the EGFR and urokinase plasminogen activator (uPA) in promoting astrocytic tumor invasion has not been fully elucidated. Here, we characterized the signal transduction pathway(s) by which EGF regulates uPA expression and promotes astrocytoma invasion.

An extensive invasive intracranial human glioblastoma xenograft model: role of high level matrix metalloproteinase 9.

The lack of an intracranial human glioma model that recapitulates the extensive invasive and hypervascular features of glioblastoma (GBM) is a major hurdle for testing novel therapeutic approaches against GBM and studying the mechanism of GBM invasive growth. We characterized a high matrix metalloproteinase-9 (MMP-9) expressing U1242 MG intracranial xenograft mouse model that exhibited extensive individual cells and cell clusters in a perivascular and subpial cellular infiltrative pattern, geographic necrosis and infiltrating tumor-induced vascular proliferation closely resembling the human GBM phenotype. MMP-9 silencing cells with short hairpin RNA dramatically blocked the cellular infiltrative pattern, hypervascularity, and cell proliferation in vivo, and decreased cell invasion, colony formation, and cell motility in vitro, indicating that a high level of MMP-9 plays an essential role in extensive infiltration and hypervascularity in the xenograft model.

The neuronal microRNA miR-326 acts in a feedback loop with notch and has therapeutic potential against brain tumors.

Little is known of microRNA interactions with cellular pathways. Few reports have associated microRNAs with the Notch pathway, which plays key roles in nervous system development and in brain tumors. We previously implicated the Notch pathway in gliomas, the most common and aggressive brain tumors.

ADAM-10-mediated N-cadherin cleavage is protein kinase C-alpha dependent and promotes glioblastoma cell migration.

MMPs (matrix metalloproteinases) and the related "a disintegrin and metalloproteinases" (ADAMs) promote tumorigenesis by cleaving extracellular matrix and protein substrates, including N-cadherin. Although N-cadherin is thought to regulate cell adhesion, migration, and invasion, its role has not been characterized in glioblastomas (GBMs). In this study, we investigated the expression and function of posttranslational N-cadherin cleavage in GBM cells as well as its regulation by protein kinase C (PKC).

H-Ras increases urokinase expression and cell invasion in genetically modified human astrocytes through Ras/Raf/MEK signaling pathway.

Previous study reported that the activation of Ras pathway cooperated with E6/E7-mediated inactivation of p53/pRb to transform immortalized normal human astrocytes (NHA/hTERT) into intracranial tumors strongly resembling human astrocytomas. The mechanism of how H-Ras contributes to astrocytoma formation is unclear. Using genetically modified NHA cells (E6/E7/hTERT and E6/E7/hTERT/Ras cells) as models, we investigated the mechanism of Ras-induced tumorigenesis.

Protein kinase C-alpha-mediated regulation of low-density lipoprotein receptor related protein and urokinase increases astrocytoma invasion.

Aggressive and infiltrative invasion is one of the hallmarks of glioblastoma. Low-density lipoprotein receptor-related protein (LRP) is expressed by glioblastoma, but the role of this receptor in astrocytic tumor invasion remains poorly understood. We show that activation of protein kinase C-alpha (PKC-alpha) phosphorylated and down-regulated LRP expression.

Ultrastructural changes of neuronal mitochondria after transient and permanent cerebral ischemia.

Background And Purpose: Mitochondrial swelling is one of the most striking and initial ultrastructural changes after acute brain ischemia. The purpose of the present study was to examine the role of reperfusion of the cerebral cortex after transient focal cerebral ischemia on neuronal mitochondrial damage.

Methods: Male Sprague-Dawley rats (n=16) were subjected to either temporary or permanent occlusion of the middle cerebral artery and bilateral carotid arteries.