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Int J Oncol. 2017 Aug;51(2):702-714. doi: 10.3892/ijo.2017.4051. Epub 2017 Jun 21.

Carboxypeptidase E transmits its anti-migratory function in glioma cells via transcriptional regulation of cell architecture and motility regulating factors.

Author information

1
Molecular Neuro-Oncology, Hertie Institute for Clinical Brain Research and Center Neurology, University of Tübingen, D-72076 Tübingen, Germany.
2
Luxembourg Centre of Neuropathology (LCNP), L-3555 Dudelange, Luxembourg.
3
Genomics and Proteomics Research Unit, Department of Oncology, Luxembourg Institute of Health (L.I.H.), L-1526 Luxembourg, Luxembourg.
4
NorLux Neuro-Oncology Laboratory, Luxembourg Institute of Health, L-1526 Luxembourg, Luxembourg.
5
Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, D-72076 Tübingen, Germany.

Abstract

Glioblastoma (GBM), the most frequent and aggressive malignant primary brain tumor, is characterized by a highly invasive growth. In our previous study we showed that overexpression of Carboxypeptidase E (CPE) mitigated glioma cell migration. In the present study we aimed at deciphering the regulatory mechanisms of the secreted form of CPE (sCPE). By transcriptome analysis and inhibition of signaling pathways involved in the regulation of cell growth and motility, we discovered that overexpression of sCPE was accompanied by differential regulation of mRNAs connected to the motility-associated networks, among others FAK, PAK, Cdc42, integrin, STAT3 as well as TGF-β. Especially SLUG was downregulated in sCPE-overexpressing glioma cells, paralleled by reduced expression of matrix-metalloproteinases (MMP) and, in consequence, by decreased cell migration. Expression of SLUG was regulated by ERK since inhibition of ERK reverted sCPE-mediated SLUG downregulation and enhanced cell motility. In a mouse glioma model, overexpression of sCPE significantly prolonged survival. Our results implicate a novel role for sCPE that mainly affects the expression of motility-associated genes via several signal pathways.

PMID:
28656234
DOI:
10.3892/ijo.2017.4051
[Indexed for MEDLINE]

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