STAT3-iNOS Signaling Mediates EGFRvIII-Induced Glial Proliferation and Transformation.
Malignant gliomas, including glioblastoma multiforme, constitute the most common and aggressive primary brain tumors in adults. The transcription factor signal transducer and activator of transcription 3 (STAT3) plays an essential role in glioblastoma pathogenesis downstream of the major oncogenic protein epidermal growth factor receptor variant III (EGFRvIII). However, the critical gene targets of STAT3 that mediate EGFRvIII-induced glial transformation have remained unknown. Here, we identify inducible nitric oxide synthase (iNOS) as a novel target gene of STAT3 in EGFRvIII-expressing mouse astrocytes. Endogenous STAT3 occupies the endogenous iNOS promoter and stimulates iNOS transcription in EGFRvIII-expressing astrocytes. STAT3 does not appear to control iNOS transcription in astrocytes deficient in the major glioblastoma tumor suppressor protein phosphatase and tensin homolog (PTEN), suggesting that STAT3 regulates iNOS transcription specifically in EGFRvIII-expressing astrocytes. Importantly, inhibition of iNOS by distinct approaches, including knockdown by RNA interference, reduces cell population growth and invasiveness of EGFRvIII-expressing astrocytes. In addition, upon iNOS knockdown or administration of a small-molecule inhibitor of iNOS, EGFRvIII-expressing astrocytes form smaller tumors in vivo. These findings suggest that inhibition of iNOS may have potential therapeutic value for EGFRvIII-activated brain tumors.
The Journal of neuroscience : the official journal of the Society for Neuroscience
June 6, 2012
Agency: NINDS NIH HHS, Id: NS064007
Agency: NINDS NIH HHS, Id: R01 NS064007
Agency: NIGMS NIH HHS, Id: T32 GM007753
Agency: Canadian Institutes of Health Research, Id:
Animals, Genetically Modified
Cell Transformation, Neoplastic
Nitric Oxide Synthase Type II
Polymerase Chain Reaction
Receptor, Epidermal Growth Factor
STAT3 Transcription Factor
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