Activated STAT3 Regulates Hypoxia-Induced Angiogenesis and Cell Migration in Human Glioblastoma

作者：Kang Shin Hyuk^*; Yu Mi Ok; Park Kyung Jae; Chi Sung Gil; Park Dong Hyuk; Chung Yong Gu

来源：Neurosurgery, 2010, 67(5): 1386-1395.

DOI：10.1227/NEU.0b013e3181f1c0cd

• Angiogenesis
• Glioblastoma
• Hypoxia
• Migration
• Signal transducer and activator of transcription 3

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.
CONCLUSION: 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.

• 出版日期2010-11