STAT3-iNOS signaling mediates EGFRvIII-induced glial proliferation and transformation

Sidharth V. Puram, Caleb M. Yeung, Arezu Jahani-Asl, Chieyu Lin, Nuria de la Iglesia, Genevieve Konopka, Laurie Jackson-Grusby, Azad Bonni

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Malignant gliomas, including glioblastoma multiforme, constitute the mostcommonand 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.

Original languageEnglish (US)
Pages (from-to)7806-7818
Number of pages13
JournalJournal of Neuroscience
Volume32
Issue number23
DOIs
StatePublished - Jun 6 2012

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STAT3 Transcription Factor
Nitric Oxide Synthase Type II
Epidermal Growth Factor Receptor
Neuroglia
Astrocytes
Glioblastoma
Brain Neoplasms
Tumor Suppressor Proteins
Phosphoprotein Phosphatases
Population Growth
RNA Interference
Glioma
Genes
Transcription Factors

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Puram, S. V., Yeung, C. M., Jahani-Asl, A., Lin, C., de la Iglesia, N., Konopka, G., ... Bonni, A. (2012). STAT3-iNOS signaling mediates EGFRvIII-induced glial proliferation and transformation. Journal of Neuroscience, 32(23), 7806-7818. https://doi.org/10.1523/JNEUROSCI.3243-11.2012

STAT3-iNOS signaling mediates EGFRvIII-induced glial proliferation and transformation. / Puram, Sidharth V.; Yeung, Caleb M.; Jahani-Asl, Arezu; Lin, Chieyu; de la Iglesia, Nuria; Konopka, Genevieve; Jackson-Grusby, Laurie; Bonni, Azad.

In: Journal of Neuroscience, Vol. 32, No. 23, 06.06.2012, p. 7806-7818.

Research output: Contribution to journalArticle

Puram, SV, Yeung, CM, Jahani-Asl, A, Lin, C, de la Iglesia, N, Konopka, G, Jackson-Grusby, L & Bonni, A 2012, 'STAT3-iNOS signaling mediates EGFRvIII-induced glial proliferation and transformation', Journal of Neuroscience, vol. 32, no. 23, pp. 7806-7818. https://doi.org/10.1523/JNEUROSCI.3243-11.2012
Puram, Sidharth V. ; Yeung, Caleb M. ; Jahani-Asl, Arezu ; Lin, Chieyu ; de la Iglesia, Nuria ; Konopka, Genevieve ; Jackson-Grusby, Laurie ; Bonni, Azad. / STAT3-iNOS signaling mediates EGFRvIII-induced glial proliferation and transformation. In: Journal of Neuroscience. 2012 ; Vol. 32, No. 23. pp. 7806-7818.
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