C/EBPβ promotes angiogenesis through secretion of IL-6, which is inhibited by genistein, in EGFRvIII-positive glioblastoma.
To study the mechanisms underlying the IL-6-promoted angiogenic microenvironment in EGFRvIII-positive glioblastoma, VEGF expression in EGFRvIII-positive/negative tumors was determined by optical molecular imaging. Next, the HUVEC tube formation assay, Western blot, qPCR, RNA silencing, chromatin immunoprecipitation, luciferase reporter and ELISA assays were performed to examine the role of IL-6 and C/EBPβ in the formation of the angiogenic microenvironment in EGFRvIII-positive tumors. Finally, in vitro and in vivo genistein treatment experiments were conducted to challenge the interaction between the IL-6 promoter and C/EBPβ. Optical imaging revealed greater VEGF expression in EGFRvIII-positive tumor-bearing mice, suggesting an angiogenic microenvironment. In vitro experiments demonstrated that C/EBPβ-mediated regulation of IL-6 was indispensable for maintenance of this angiogenic microenvironment. In contrast, genistein-mediated upregulation of CHOP impeded C/EBPβ interaction with the IL-6 promoter, thus disturbing the angiogenic microenvironment. This more malignant microenvironment in EGFRvIII glioblastoma is generated, at least in part, by greater VEGF, IL-6 and C/EBPβ expression. Interaction of C/EBPβ with the IL-6 promoter maintains this angiogenic microenvironment, while disturbance of this dynamically balanced interaction inhibits EGFRvIII tumor proliferation by reducing both VEGF and IL-6 expression.
Department of Cell Biology, Peking University Health Science Center, Beijing, People's Republic of China; Peking University Stem Cell Research Center, Beijing, People's Republic of China.
Xujie
X
Liu
Kaiyu
K
Liu
Jiazhen
J
Qin
Limin
L
Hao
Xiaoxia
X
Li
Yinan
Y
Liu
Xiaoyan
X
Zhang
Xiuxiu
X
Liu
Peng
P
Li
Shuo
S
Han
Zebin
Z
Mao
Li
L
Shen
D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology*; D005909:Glioblastoma / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D011401:Promoter Regions, Genetic; D051742:Transcription Factor CHOP / Q000378:metabolism*; D059016:Tumor Microenvironment; D000093242:Interleukin-6 Inhibitors
D022782:CCAAT-Enhancer-Binding Protein-beta; D066246:ErbB Receptors; D019833:Genistein; D015850:Interleukin-6; D051742:Transcription Factor CHOP; D000093242:Interleukin-6 Inhibitors
C/EBPβ; EGFRvIII; GBM; IL-6; angiogenesis