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Int J Cancer. 2018 Sep 1;143(5):1176-1187. doi: 10.1002/ijc.31404. Epub 2018 Apr 16.

A PRDX1-p38α heterodimer amplifies MET-driven invasion of IDH-wildtype and IDH-mutant gliomas.

Author information

1
Schaller Research Group, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
2
Molecular Mechanisms of Tumor Invasion, DKFZ, Heidelberg, Germany.
3
Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
4
Clinical Cooperation Unit Neuro-Oncology, German Cancer Consortium (DKTK), DKFZ, Heidelberg, Germany.
5
Schaller Research Group at Cell Networks, Department of Infectious Diseases, Virology, Heidelberg University Hospital, DKFZ, Heidelberg, Germany.
6
Neuroradiology Department, University Hospital Heidelberg, Heidelberg, Germany.
7
Clinical Cooperation Unit Neuropathology, DKTK, DKFZ, Heidelberg, Germany.
8
Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
9
Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, DKFZ, Heidelberg, Germany.
10
Division of Biostatistics (C060), DKFZ, Heidelberg, Germany.
11
Junior Research Group Computational Genome Biology, DKFZ, Heidelberg, Germany.
12
Centre for Organismal Studies, Nikon Imaging Center at the University of Heidelberg, Heidelberg, Germany.
13
Heidelberg University Biochemistry Center BZH, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
14
Division of Experimental Neurosurgery, Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany.
15
Division of Epigenomics and Cancer Risk Factors, DKFZ, Heidelberg, Germany.
16
Department of Neuroradiology, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
17
Department of Neuropathology, Heinrich Heine University Hospital Düsseldorf, and DKTK, DKFZ Heidelberg, Partner Site Essen/Düsseldorf, Düsseldorf, Germany.
18
Division of Molecular Genetics, DKFZ, Heidelberg, Germany.

Abstract

The Peroxiredoxin 1 (PRDX1) gene maps to chromosome arm 1p and is hemizygously deleted and epigenetically silenced in isocitrate dehydrogenase 1 or 2 (IDH)-mutant and 1p/19q-codeleted oligodendroglial tumors. In contrast, IDH-wildtype astrocytic gliomas including glioblastomas mostly lack epigenetic silencing and express PRDX1 protein. In our study, we investigated how PRDX1 contributes to the infiltrative growth of IDH-wildtype gliomas. Focusing on p38α-dependent pathways, we analyzed clinical data from 133 patients of the NOA-04 trial cohort to look for differences in the gene expression profiles of gliomas with wildtype or mutant IDH. Biochemical interaction studies as well as in vitro and ex vivo migration studies were used to establish a biological role of PRDX1 in maintaining pathway activity. Whole-brain high-resolution ultramicroscopy and survival analyses of pre-clinical mouse models for IDH-wildtype gliomas were then used for in vivo confirmation. Based on clinical data, we found that the absence of PRDX1 is associated with changes in the expression of MET/HGF signaling components. PRDX1 forms a heterodimer with p38α mitogen-activated protein kinase 14 (MAPK14), stabilizing phospho-p38α in glioma cells. This process amplifies hepatocyte growth factor (HGF)-mediated signaling and stimulates actin cytoskeleton dynamics that promote glioma cell migration. Whole-brain high-resolution ultramicroscopy confirms these findings, indicating that PRDX1 promotes glioma brain invasion in vivo. Finally, reduced expression of PRDX1 increased survival in mouse glioma models. Thus, our preclinical findings suggest that PRDX1 expression levels may serve as a molecular marker for patients who could benefit from targeted inhibition of MET/HGF signaling.

KEYWORDS:

c-MET; gliomas; invasion; p38α; peroxiredoxin 1

PMID:
29582423
DOI:
10.1002/ijc.31404
[Indexed for MEDLINE]
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