The Invasion Factor ODZ1 Is Upregulated through an Epidermal Growth Factor Receptor-Induced Pathway in Primary Glioblastoma Cells

TL;DR

This study shows that EGF activates a pathway in glioblastoma cells that increases ODZ1, a protein linked to tumor cell invasion.

Contribution

The paper identifies a novel EGFR-mediated pathway involving p38β MAPK that upregulates the invasion factor ODZ1 in glioblastoma cells.

Findings

EGF induces ODZ1 expression in EGFR-expressing glioblastoma cells at both mRNA and protein levels.

Blocking EGF-EGFR binding or inhibiting p38β MAPK reduces ODZ1 induction in response to EGF.

The EGF–EGFR pathway through p38β MAPK may drive morphological changes for tumor cell invasion.

Abstract

We have previously shown that the transmembrane protein ODZ1 promotes cytoskeletal remodeling of glioblastoma (GBM) cells and invasion of the surrounding parenchyma through the activation of a RhoA–ROCK pathway. We also described that GBM cells can control the expression of ODZ1 through transcriptional mechanisms triggered by the binding of IL-6 to its receptor and a hypoxic environment. Epidermal growth factor (EGF) plays a key role in the invasive capacity of GBM. However, the molecular mechanisms that enable tumor cells to acquire the morphological changes to migrate out from the tumor core have not been fully characterized. Here, we show that EGF is able to induce the expression of ODZ1 in primary GBM cells. We analyzed the levels of the EGF receptor (EGFR) in 20 GBM primary cell lines and found expression in 19 of them by flow cytometry. We selected two cell lines that do or do not express the EGFR and found that EGFR-expressing cells responded to the EGF ligand by increasing ODZ1 at the mRNA and protein levels. Moreover, blockade of EGF-EGFR binding by Cetuximab, inhibition of the p38 MAPK pathway, or Additionally, the siRNA-mediated knockdown of MAPK11 (p38β MAPK) reduced the induction of ODZ1 in response to EGF. Overall, we show that EGF may activate an EGFR-mediated signaling pathway through p38β MAPK, to upregulate the invasion factor ODZ1, which may initiate morphological changes for tumor cells to invade the surrounding parenchyma. These data identify a new candidate of the EGF–EGFR pathway for novel therapeutic approaches.

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