EGFR and HER2 exert distinct roles on colon cancer cell functional properties and expression of matrix macromolecules.

Abstract

BACKGROUND:

ErbB receptors, EGFR and HER2, have been implicated in the development and progression of colon cancer. Several intracellular pathways are mediated upon activation of EGFR and/or HER2 by EGF. However, there are limited data regarding the EGF-mediated signaling affecting functional cell properties and the expression of extracellular matrix macromolecules implicated in cancer progression.

METHODS:

Functional assays, such as cell proliferation, transwell invasion assay and migration were performed to evaluate the impact of EGFR/HER2 in constitutive and EGF-treated Caco-2 cells. Signaling pathways were evaluated using specific intracellular inhibitors. Western blot was also utilized to examine the phosphorylation levels of ERK1/2. Real time PCR was performed to evaluate gene expression of matrix macromolecules.

RESULTS:

EGF increases cell proliferation, invasion and migration and importantly, EGF mediates overexpression of EGFR and downregulation of HER2. The EGF-EGFR axis is the main pathway affecting colon cancer's invasive potential, proliferative and migratory ability. Intracellular pathways (PI3K-Akt, MEK1/2-Erk and JAK-STAT) are all implicated in the migratory profile. Notably, MT1- and MT2-MMP as well as TIMP-2 are downregulated, whereas uPA is upregulated via an EGF-EGFR network. The EGF-EGFR axis is also implicated in the expression of syndecan-4 and TIMP-1. However, glypican-1 upregulation by EGF is mainly mediated via HER2.

CONCLUSIONS AND GENERAL SIGNIFICANCE:

The obtained data highlight the crucial importance of EGF on the expression of both receptors and on the EGF-EGFR/HER2 signaling network, reveal the distinct roles of EGFR and HER2 on expression of matrix macromolecules and open a new area in designing novel agents in targeting colon cancer. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.

• Authors: Maria-Ioanna Ellina, Panagiotis Bouris, Alexios J Aletras, Achilleas D Theocharis, Dimitris Kletsas, Nikos K Karamanos
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1840 Issue 8 Pg. 2651-61 (Aug 2014) ISSN: 0006-3002 [Print] Netherlands
• PMID: 24792576 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Extracellular Matrix Proteins
• Epidermal Growth Factor
• EGFR protein, human
• ERBB2 protein, human
• ErbB Receptors
• Receptor, ErbB-2

Topics

• Caco-2 Cells
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Colonic Neoplasms (genetics, metabolism, pathology)
• Epidermal Growth Factor (pharmacology)
• ErbB Receptors (genetics, metabolism)
• Extracellular Matrix Proteins (metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Intracellular Space (drug effects, metabolism)
• MAP Kinase Signaling System (drug effects)
• Models, Biological
• Neoplasm Invasiveness
• Receptor, ErbB-2 (genetics, metabolism)