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Cellular prion protein (PrPC) in the development of Merlin-deficient tumours

L Provenzano1, Y Ryan1, D A Hilton2

  • 1Institute of Translational and Stratified Medicine, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK.

Oncogene
|July 11, 2017
PubMed

Insights

Loss of function mutations in the neurofibromatosis Type 2 (NF2) gene cause nervous system tumors. Researchers found increased cellular prion protein (PrPC) in these tumors, suggesting it as a potential therapeutic target.

Area of Science:

  • Oncology
  • Neuro-oncology
  • Molecular Biology

Background:

  • Neurofibromatosis Type 2 (NF2) is caused by loss-of-function mutations in the NF2 gene, leading to Merlin tumor suppressor inactivation.
  • This inactivation results in various nervous system tumors, including schwannomas, meningiomas, and ependymomas, with no current targeted drug therapies.
  • NF2 mutations and Merlin inactivation are also implicated in other cancers like mesothelioma, breast, colorectal, melanoma, and glioblastoma.

Purpose of the Study:

  • To investigate the role of Merlin deficiency in tumorigenesis using an in vitro model of human primary schwannoma cells.
  • To identify potential therapeutic targets for Merlin-deficient tumors.

Main Methods:

  • Developed an in vitro model using human primary schwannoma cells, a hallmark of NF2.
  • Analyzed the expression of cellular prion protein (PrPC) in schwannoma cells, tissues, and other Merlin-deficient tumor cell lines (mesothelioma, meningiomas).
  • Investigated the signaling pathways (LR/37/67 kDa, ERK1/2, PI3K/AKT, FAK) and release mechanisms (exosomes, free peptide) of PrPC in schwannoma cells.

Main Results:

  • Demonstrated increased expression of cellular prion protein (PrPC) in schwannoma cells and tissues.
  • Observed significant overexpression of PrPC in Merlin-deficient mesothelioma and meningioma cell lines.
  • Showed that PrPC promotes schwannoma cell proliferation, adhesion, and survival via the laminin receptor (LR/37/67 kDa) and downstream signaling pathways.
  • Found that PrPC is released from schwannoma cells via exosomes and as a free peptide, suggesting autocrine/paracrine activity.

Conclusions:

  • Cellular prion protein (PrPC) is upregulated in Merlin-deficient tumors, including schwannomas, mesothelioma, and meningiomas.
  • PrPC, acting through the laminin receptor (LR/37/67 kDa), drives key oncogenic processes like proliferation, adhesion, and survival in schwannoma cells.
  • PrPC and its interactor LR/37/67 kDa represent promising therapeutic targets for schwannomas and other Merlin-deficient malignancies.

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