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.
Department of Neurobiology and Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts 02115, USA.
Sidharth V
SV
Puram
Caleb M
CM
Yeung
Arezu
A
Jahani-Asl
Chieyu
C
Lin
Nuria
N
de la Iglesia
Genevieve
G
Konopka
Laurie
L
Jackson-Grusby
Azad
A
Bonni
D000818:Animals; D030801:Animals, Genetically Modified; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D001665:Binding Sites; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000502:physiology*; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology; D007150:Immunohistochemistry; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D009457:Neuroglia / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000502:physiology; D010957:Plasmids / Q000235:genetics; D016133:Polymerase Chain Reaction; D034622:RNA Interference; D050796:STAT3 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014158:Transcription, Genetic
D004791:Enzyme Inhibitors; D050796:STAT3 Transcription Factor; C410723:epidermal growth factor receptor VIII; D052247:Nitric Oxide Synthase Type II; D066246:ErbB Receptors; D051059:PTEN Phosphohydrolase