STAT3 activation promotes oncolytic HSV1 replication in glioma cells

PLoS One. 2013 Aug 2;8(8):e71932. doi: 10.1371/journal.pone.0071932. Print 2013.


Recent studies report that STAT3 signaling is a master regulator of mesenchymal transformation of gliomas and that STAT3 modulated genes are highly expressed in the mesenchymal transcriptome of gliomas. A currently studied experimental treatment for gliomas consists of intratumoral injection of oncolytic viruses (OV), such as oncolytic herpes simplex virus type 1 (oHSV). We have described one particular oHSV (rQNestin34.5) that exhibits potent anti-glioma activity in animal models. Here, we hypothesized that alterations in STAT3 signaling in glioma cells may affect the replicative ability of rQNestin34.5. In fact, human U251 glioma cells engineered to either over-express STAT3 or with genetic down-regulation of STAT3 supported oHSV replication to a significantly higher or lesser degree, respectively, when compared to controls. Administration of pharmacologic agents that increase STAT3 phosphorylation/activation (Valproic Acid) or increase STAT3 levels (Interleukin 6) also significantly enhanced oHSV replication. Instead, administration of inhibitors of STAT3 phosphorylation/activation (LLL12) significantly reduced oHSV replication. STAT3 led to a reduction in interferon signaling in oHSV infected cells and inhibition of interferon signaling abolished the effect of STAT3 on oHSV replication. These data thus indicate that STAT3 signaling in malignant gliomas enhances oHSV replication, likely by inhibiting the interferon response in infected glioma cells, thus suggesting avenues for possible potentiation of oncolytic virotherapy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anticonvulsants / pharmacology
  • Blotting, Western
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / therapy
  • Brain Neoplasms / virology*
  • Cell Proliferation
  • Combined Modality Therapy
  • Glioma / metabolism
  • Glioma / therapy
  • Glioma / virology*
  • Herpes Simplex / genetics
  • Herpes Simplex / therapy
  • Herpes Simplex / virology*
  • Herpesvirus 1, Human / physiology*
  • Humans
  • Interferon Type I / genetics
  • Interferon Type I / metabolism
  • Luciferases / metabolism
  • Oncolytic Virotherapy*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT3 Transcription Factor / antagonists & inhibitors
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Tumor Cells, Cultured
  • Valproic Acid / pharmacology
  • Virus Replication*


  • Anticonvulsants
  • Interferon Type I
  • RNA, Messenger
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Valproic Acid
  • Luciferases