fh535 and Glioma

Epidermal Growth Factor like domain 7 (EGFL7), also known as Vascular Endothelial-statin (VE-statin), is a secreted angiogenic factor. Recent data have demonstrated the potential oncogenic role and prognostic significance of EGFL7 in several human cancers. However, the clinical signature and further mechanisms of EGFL7's function in gliomagenesis are poorly understood. In the present study, we found that increased EGFL7 expression was associated with tumor grade. High expression of EGFL7 in EGFRvIII-positive glioblastoma multiforme (GBM) was determined to be a strong and independent risk factor for reduced life expectancy. EGFRvIII cells can secrete the EGFL7 protein to improve the activity of the β-catenin/TCF4 Transcription complex in EGFRwt cells, thus promoting their own EGFL7 expression. Our research demonstrates that oncogenic activation of EGFRwt in GBM is likely maintained by a continuous EGFL7 autocrine flow line, and may be an attractive target for therapeutic intervention.

Topics: Adult; Antineoplastic Agents; Autocrine Communication; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; beta Catenin; Brain Neoplasms; Calcium-Binding Proteins; Carrier Proteins; Cell Line, Tumor; Cell Movement; Cell Proliferation; EGF Family of Proteins; Endothelial Growth Factors; ErbB Receptors; Female; Gene Expression Regulation, Neoplastic; Glioma; Humans; Kaplan-Meier Estimate; Ligands; Male; Membrane Proteins; Middle Aged; Neoplasm Grading; Neoplasm Invasiveness; Oncogenes; Protein Binding; Protein Interaction Maps; RNA Interference; Signal Transduction; Sulfonamides; Thyroid Hormone-Binding Proteins; Thyroid Hormones; Time Factors; Transcription Factor 4; Transcription Factors; Transcription, Genetic; Transfection

Identification of molecular pathways that are essential for cancer cell survival is vital for understanding the underlying biology, as well as to design effective cancer therapeutics. β-catenin, a multifunctional oncogenic protein, participates in cell development. Its multifaceted functions primarily lie to the subcellular distribution. The present study demonstrated that β-catenin accumulated in the nucleus to a greater extent in high-grade gliomas compared with low-grade gliomas. In addition, nuclear localization correlated with a worse prognosis for patients, as determined by immunohistochemical analysis of 74 glioma samples. Nuclear expression of β-catenin was down-regulated in LN229 and U87 glioma cells by a small molecule inhibitor of β-catenin/TCF4 signaling, demonstrating strongly inhibited β-catenin/TCF4 transcriptional activity and STAT3 luciferase activity, as well as decreased mRNA and protein levels of nuclear β-catenin, TCF4, EGFR, AKT1, AKT2 and STAT3. Furthermore, repressed nuclear translocation of β-catenin resulted in inhibition of proliferation and invasiveness, and also induced apoptosis of glioma cells. Similar results were also observed in vivo; intratumoral injection of such small molecule inhibitor downregulated expression of nuclear β-catenin, TCF4, and components of the EGFR pathway, and also delayed tumor growth in nude mice harboring subcutaneous U87 xenografts. Results from the present study provided evidence that nuclear accumulation of β-catenin participated in malignant progression of gliomas and implicated poor prognosis, highlighting it as a potential therapeutic target for gliomas.

Topics: Animals; Apoptosis; beta Catenin; Blotting, Western; Cell Cycle; Cell Line, Tumor; Cell Nucleus; Cell Survival; Colony-Forming Units Assay; Fluorescent Antibody Technique; Glioma; Humans; Immunohistochemistry; Luciferases; Mice; Mice, Inbred BALB C; Mice, Nude; Polymerase Chain Reaction; Sulfonamides; Translocation, Genetic; Xenograft Model Antitumor Assays