Oct-3/4 promotes tumor angiogenesis through VEGF production in glioblastoma
Oct-3/4 promotes tumor angiogenesis through VEGF production in glioblastoma
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DOI：
10.1007/s10014-014-0203-3
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发表时间：
2014
影响因子：
3.3
通讯作者：
Hisaaki Takahashi;Akihiro Inoue;Yuya Kawabe;Y. Hosokawa;S. Iwata;K. Sugimoto;Hajime Yano;Daisuke Yamashita;H. Harada;S. Kohno;S. Ohue;T. Ohnishi;Junya Tanaka
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文献类型：
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作者：
Hisaaki Takahashi;Akihiro Inoue;Yuya Kawabe;Y. Hosokawa;S. Iwata;K. Sugimoto;Hajime Yano;Daisuke Yamashita;H. Harada;S. Kohno;S. Ohue;T. Ohnishi;Junya Tanaka
越来越多的证据表明，干细胞中自我更新调节因子Oct-3/4的表达水平与多种实体瘤的进展呈正相关。然而，Oct-3/4在胶质母细胞瘤血管生成中的作用尚不清楚。本研究将过表达Oct-3/4的人胶质母细胞瘤U251 （U251/EGFP-Oct-3/4）细胞皮下移植至裸鼠右大腿，探讨Oct-3/4在肿瘤血管生成中的作用。肿瘤大小和肿瘤内生长的大血管数量均明显增加。在体外血管生成模型中，与U251/EGFP细胞相比，U251/EGFP- oct -3/4细胞的条件培养基显著加速了毛细血管样管的形成。与U251/EGFP细胞相比，U251/EGFP- oct -3/4细胞在缺氧诱导因子（HIF） 1α的调控下，血管内皮生长因子mRNA的表达明显升高。在U251/EGFP-Oct-3/4细胞中，HIF1α蛋白表达增强，核易位增加。此外，我们证明了AKT（一种致癌信号分子）参与了10 -3/4诱导的HIF1α蛋白上调。我们的研究结果表明，表达oct -3/4的胶质母细胞瘤细胞通过AKT-HIF1途径促进肿瘤血管生成，从而具有适应肿瘤肿块内低氧环境的能力。
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.