title: Astrocyte elevated gene-1 (AEG-1) functions as an oncogene and regulates angiogenesis.
abstract: Astrocyte-elevated gene-1 (AEG-1) expression is increased in multiple cancers and plays a central role in Ha-ras-mediated oncogenesis through the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Additionally, overexpression of AEG-1 protects primary and transformed human and rat cells from serum starvation-induced apoptosis through activation of PI3K/Akt signaling. These findings suggest, but do not prove, that AEG-1 may function as an oncogene. We now provide definitive evidence that AEG-1 is indeed a transforming oncogene and show that stable expression of AEG-1 in normal immortal cloned rat embryo fibroblast (CREF) cells induces morphological transformation and enhances invasion and anchorage-independent growth in soft agar, two fundamental biological events associated with cellular transformation. Additionally, AEG-1-expressing CREF clones form aggressive tumors in nude mice. Immunohistochemistry analysis of tumor sections demonstrates that AEG-1-expressing tumors have increased microvessel density throughout the entire tumor sections. Overexpression of AEG-1 increases expression of molecular markers of angiogenesis, including angiopoietin-1, matrix metalloprotease-2, and hypoxia-inducible factor 1-alpha. In vitro angiogenesis studies further demonstrate that AEG-1 promotes tube formation in Matrigel and increases invasion of human umbilical vein endothelial cells via the PI3K/Akt signaling pathway. Tube formation induced by AEG-1 correlates with increased expression of angiogenesis markers, including Tie2 and hypoxia-inducible factor-alpha, and blocking AEG-1-induced Tie2 with Tie2 siRNA significantly inhibits AEG-1-induced tube formation in Matrigel. Overall, our findings demonstrate that aberrant AEG-1 expression plays a dominant positive role in regulating oncogenic transformation and angiogenesis. These findings suggest that AEG-1 may provide a viable target for directly suppressing the cancer phenotype.
authors: Department of Neurosurgery and Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors: Luni
authors: L
authors: Emdad
authors: Seok-Geun
authors: SG
authors: Lee
authors: Zhao Zhong
authors: ZZ
authors: Su
authors: Hyun Yong
authors: HY
authors: Jeon
authors: Habib
authors: H
authors: Boukerche
authors: Devanand
authors: D
authors: Sarkar
authors: Paul B
authors: PB
authors: Fisher
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D005347:Fibroblasts; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics; D009374:Neoplasms, Experimental; D009389:Neovascularization, Pathologic / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D009857:Oncogenes / Q000502:physiology*; D016601:RNA-Binding Proteins; D051381:Rats; D014183:Transplantation, Heterologous
chemical_list: D015815:Cell Adhesion Molecules; C483039:MTDH protein, human; D008565:Membrane Proteins; D016601:RNA-Binding Proteins