title: Astrocyte elevated gene-1: a novel target for human glioma therapy.
abstract: Malignant gliomas including glioblastoma multiforme (GBM) and anaplastic astrocytomas are the most common primary brain tumors. Despite multimodal treatment including surgery, chemotherapy, and radiation, median survival for patients with GBMs is only 12 to 15 months. Identifying molecules critical for glioma progression is crucial for devising effective targeted therapy. In the present study, we investigated the potential contribution of astrocyte elevated gene-1 (AEG-1) in gliomagenesis and explored the possibility of AEG-1 as a therapeutic target for malignant glioma. We analyzed the expression levels of AEG-1 in 9 normal brain tissues and 98 brain tumor patient samples by Western blot analysis and immunohistochemistry. AEG-1 expression was significantly elevated in >90% of diverse human brain tumor samples including GBMs and astrocytic tumors, and also in human glioma cell lines compared with normal brain tissues and normal astrocytes. Knockdown of AEG-1 by small interfering RNA inhibited cell viability, cloning efficiency, and invasive ability of U87 human glioma cells and 9L rat gliosarcoma cells. We also found that matrix metalloproteases (MMP-2 and MMP-9) are involved in AEG-1-mediated invasion of glioma cells. In an orthotopic nude mouse brain tumor model using primary human GBM12 tumor cells, AEG-1 small interfering RNA significantly suppressed glioma cell growth in vivo. Taken together, these provocative results indicate that AEG-1 may play a crucial role in the pathogenesis of glioma and that AEG-1 could represent a viable potential target for malignant glioma therapy.
authors.affiliation: Departments of Neurosurgery and Oncological Sciences, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Luni
authors.initials: L
authors.lastname: Emdad
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: Seok-Geun
authors.initials: SG
authors.lastname: Lee
authors.forename: Zhao Zhong
authors.initials: ZZ
authors.lastname: Su
authors.forename: Byoung Kwon
authors.initials: BK
authors.lastname: Yoo
authors.forename: Rupesh
authors.initials: R
authors.lastname: Dash
authors.forename: Adly
authors.initials: A
authors.lastname: Yacoub
authors.forename: Christine E
authors.initials: CE
authors.lastname: Fuller
authors.forename: Khalid
authors.initials: K
authors.lastname: Shah
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Bruce
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000201:enzymology / Q000473:pathology; D005910:Glioma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D009361:Neoplasm Invasiveness; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins; D051381:Rats; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; C483039:MTDH protein, human; D008565:Membrane Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9