Abstract

BackgroundMeningiomas are the most frequent primary brain tumors of the central nervous system. The standard of treatment is surgery and radiotherapy, but effective pharmacological options are not available yet. The well-characterized genetic background stratifies these tumors in several subgroups, thus increasing diversification. We identified epidermal growth factor receptor–signal transducer and activator of transcription 1 (EGFR–STAT1) overexpression and activation as a common identifier of these tumors.MethodsWe analyzed STAT1 overexpression and phosphorylation in 131 meningiomas of different grades and locations by utilizing several techniques, including Western blots, qPCR, and immunocytochemistry. We also silenced and overexpressed wild-type and mutant forms of the gene to assess its biological function and its network. Results were further validated by drug testing.ResultsSTAT1 was found widely overexpressed in meningioma but not in the corresponding healthy controls. The protein showed constitutive phosphorylation not dependent on the JAK–STAT pathway. STAT1 knockdown resulted in a significant reduction of cellular proliferation and deactivation of AKT and ERK1/2. STAT1 is known to be activated by EGFR, so we investigated the tyrosine kinase and found that EGFR was also constitutively phosphorylated in meningioma and was responsible for the aberrant phosphorylation of STAT1. The pharmaceutical inhibition of EGFR caused a significant reduction in cellular proliferation and of overall levels of cyclin D1, pAKT, and pERK1/2.ConclusionsSTAT1–EGFR-dependent constitutive phosphorylation is responsible for a positive feedback loop that causes its own overexpression and consequently an increased proliferation of the tumor cells. These findings provide the rationale for further studies aiming to identify effective therapeutic options in meningioma.

Highlights

  • Meningiomas are the most frequent primary brain tumors of the central nervous system

  • We demonstrate that signal transducer and activator of transcription 1 (STAT1) overexpression and phosphorylation is not dependent on the Janus kinases (JAKs)–STAT pathway but it depends on a positive feedback loop caused by the constitutive activation of the epidermal growth factor receptor (EGFR).The pharmaceutical inhibition of EGFR in meningioma caused the deactivation of STAT1 and other cancer-related pathways, eventually leading to a significant reduction in cellular proliferation

  • STAT1 was found overexpressed in BM-1 and meningioma-derived primary cells (MN) compared to HMC and both pSTAT1-Y701 and -serine 727 (S727) were present across all samples while faint and undetectable

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Summary

Introduction

Meningiomas are the most frequent primary brain tumors of the central nervous system. We analyzed STAT1 overexpression and phosphorylation in 131 meningiomas of different grades and locations by utilizing several techniques, including Western blots, qPCR, and immunocytochemistry. The protein showed constitutive phosphorylation not dependent on the JAK–STAT pathway. STAT1 knockdown resulted in a significant reduction of cellular proliferation and deactivation of AKT and ERK1/2. The pharmaceutical inhibition of EGFR caused a significant reduction in cellular proliferation and of overall levels of cyclin D1, pAKT, and pERK1/2. STAT1–EGFR-dependent constitutive phosphorylation is responsible for a positive feedback loop that causes its own overexpression and an increased proliferation of the tumor cells. These findings provide the rationale for further studies aiming to identify effective therapeutic options in meningioma

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Conclusion

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