title: Oct-3/4 promotes tumor angiogenesis through VEGF production in glioblastoma.
abstract: Accumulating evidence shows that the expression level of Oct-3/4, a self-renewal regulator in stem cells, is positively correlated with the progression of various solid tumors. However, little is known regarding the influence of Oct-3/4 in the tumor angiogenesis of glioblastomas. In the present study, we subcutaneously transplanted Oct-3/4-overexpressing human glioblastoma U251 (U251/EGFP-Oct-3/4) cells into the right thighs of nude mice to evaluate the roles of Oct-3/4 in the tumor angiogenesis. Both tumor size and the number of large vessels growing in the tumor were markedly increased. In an in vitro model of angiogenesis, the conditioned media from U251/EGFP-Oct-3/4 cells significantly accelerated capillary-like tube formation compared with that of U251/EGFP cells. In comparison with U251/EGFP cells, U251/EGFP-Oct-3/4 cells had markedly elevated the expression of vascular endothelial growth factor mRNA under the control of hypoxia-inducible factor (HIF) 1α. In U251/EGFP-Oct-3/4 cells, enhanced protein expression and nuclear translocation of HIF1α were observed. Furthermore, we demonstrated that the involvement of AKT, an oncogenic signaling molecule, in the Oct-3/4 induced upregulation of HIF1α protein. Our findings suggest that Oct-3/4-expressing glioblastoma cells have the ability to adapt to low-oxygen environments within tumor masses by promoting tumor angiogenesis through AKT-HIF1 pathway.
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Toon, Ehime, 791-0295, Japan, hisaaki@m.ehime-u.ac.jp.
authors.forename: Hisaaki
authors.initials: H
authors.lastname: Takahashi
authors.forename: Akihiro
authors.initials: A
authors.lastname: Inoue
authors.forename: Yuya
authors.initials: Y
authors.lastname: Kawabe
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hosokawa
authors.forename: Shinji
authors.initials: S
authors.lastname: Iwata
authors.forename: Kana
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Hajime
authors.initials: H
authors.lastname: Yano
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamashita
authors.forename: Hironobu
authors.initials: H
authors.lastname: Harada
authors.forename: Shohei
authors.initials: S
authors.lastname: Kohno
authors.forename: Shiro
authors.initials: S
authors.lastname: Ohue
authors.forename: Takanori
authors.initials: T
authors.lastname: Ohnishi
authors.forename: Junya
authors.initials: J
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply* / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D005909:Glioblastoma / Q000098:blood supply* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000502:physiology; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics*; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000502:physiology*; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000502:physiology; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050814:Octamer Transcription Factor-3; D042461:Vascular Endothelial Growth Factor A; D051058:Oncogene Protein v-akt