Oct-3/4 promotes tumor angiogenesis through VEGF production in glioblastoma.

Hisaaki Takahashi, Akihiro Inoue, Yuya Kawabe, Yuki Hosokawa, Shinji Iwata, Kana Sugimoto, Hajime Yano, Daisuke Yamashita, Hironobu Harada, Shohei Kohno, Shiro Ohue, Takanori Ohnishi, Junya Tanaka

Index: Brain Tumor Pathol. 32(1) , 31-40, (2015)

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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.