title: Hypoxia-induced decreases in SOCS3 increase STAT3 activation and upregulate VEGF gene expression.
abstract: Signal transducer and activator of transcription (STAT) 3 has been described as a master regulator of the signaling pathways that are involved in the mesenchymal transition of glioblastomas, which are the most aggressive type of tumors and which result in poor prognoses. Hypoxia, which is a strong inducer of vascular endothelial growth factor (VEGF), results in angiogenesis and the bulky growth of tumors. Here, we show that hypoxia induces VEGF gene expression through a STAT3 signaling cascade. Hypoxia increases the levels of aberrantly activated STAT3 by decreasing the levels of the suppressor of cytokine signaling (SOCS) 3, which is a negative regulator of the STAT3 signaling cascade. Activated STAT3 binds to the hypoxia-responsible element that is located -914 to -905 bp upstream of the transcription initiation site in the VEGF promoter and that transcriptionally regulates VEGF gene expression. This sequence closely resembled the previously defined sis-inducible element in the STAT3-binding sequences. The enforced overexpression of SOCS3 abolished the hypoxia-induced STAT3 activation and the STAT3-mediated transcriptional upregulation of the VEGF gene. In addition, activated STAT3 was found around necrotic foci in surgical specimens. These observations suggest that STAT3 is a molecular target of antiangiogenesis.
authors.affiliation: Department of Neurosurgery, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan. akatoyik8@gmail.com
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Yokogami
authors.forename: Shinji
authors.initials: S
authors.lastname: Yamashita
authors.forename: Hideo
authors.initials: H
authors.lastname: Takeshima
mesh_terms: D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D015687:Cell Hypoxia; D002478:Cells, Cultured; D015536:Down-Regulation; D005909:Glioblastoma / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D058990:Molecular Targeted Therapy; D050796:STAT3 Transcription Factor / Q000378:metabolism* / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
chemical_list: C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D042461:Vascular Endothelial Growth Factor A