Activated STAT3 regulates hypoxia-induced angiogenesis and cell migration in human glioblastoma.
BACKGROUND
Glioblastoma is the most common primary brain tumor, with typical histopathologic findings, pseudopalisading necrosis, and microvascular proliferation, all of which are associated with a poor prognosis. Hypoxia is known to affect these morphological features, but the underlying molecular mechanism has been poorly understood.


OBJECTIVE
To determine the role of signal transducer and activator of transcription 3 (STAT3) in the malignant progression of glioblastoma under hypoxic conditions.


METHODS
We studied STAT3 activation by hypoxic stress and its effect on hypoxia-induced angiogenesis and cell migration using U87, A172, T98, and U373 human glioblastoma cell lines.


RESULTS
All four glioblastoma cells analyzed expressed detectable levels of STAT3 phosphorylation. Hypoxic stress markedly increased phosphorylated STAT3 level in a time-dependent fashion, and activated STAT3 was translocated into the nucleus. Hypoxic conditions led to a 30-50% increase in angiogenesis and cell migration, but these effects were significantly attenuated by small interfering ribonucleic acid-mediated knockdown of STAT3. Furthermore, STAT3 activation was associated with an elevated expression of hypoxic inducible factor-1, vascular endothelial growth factor, matrix metalloproteinase 2, and TWIST messenger ribonucleic acid and protein, which may play a critical role in hypoxia-induced angiogenesis and migration.


CONCLUSIONS
STAT3 plays an important role in glioblastoma angiogenesis and migration triggered by hypoxia. Therefore, STAT3 might be a target for control of pseudopalisading necrosis and angiogenesis in glioblastoma.
Kang
Shin-Hyuk
SH
Department of Neurosurgery, Korea University Anam Hospital, College of Medicine, Korea University, Seoul, Korea. hermes23@kumc.or.kr
Yu
Mi Ok
MO
Park
Kyung-Jae
KJ
Chi
Sung-Gil
SG
Park
Dong-Hyuk
DH
Chung
Yong-Gu
YG
D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D009389:Neovascularization, Pathologic / Q000473:pathology* / Q000503:physiopathology*; D010100:Oxygen / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*
D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D010100:Oxygen