PT  - JOURNAL ARTICLE
AU  - Sidharth V. Puram
AU  - Caleb M. Yeung
AU  - Arezu Jahani-Asl
AU  - Chieyu Lin
AU  - Nuria de la Iglesia
AU  - Genevieve Konopka
AU  - Laurie Jackson-Grusby
AU  - Azad Bonni
TI  - STAT3-iNOS Signaling Mediates EGFRvIII-Induced Glial Proliferation and Transformation
AID  - 10.1523/JNEUROSCI.3243-11.2012
DP  - 2012 Jun 06
TA  - The Journal of Neuroscience
PG  - 7806--7818
VI  - 32
IP  - 23
4099  - http://www.jneurosci.org/content/32/23/7806.short
4100  - http://www.jneurosci.org/content/32/23/7806.full
SO  - J. Neurosci.2012 Jun 06; 32
AB  - 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.