Bone morphogenetic protein 4 (BMP-4) and epidermal growth factor (EGF) inhibit metalloproteinase-9 (MMP-9) expression in cancer cells.

Nathalie Bibens Laulan,Yves St-Pierre

doi:10.18632/oncoscience.144

Abstract

Matrix metalloproteinase-9 (MMP-9) plays a central role in the progression of the cancer. While a large number of studies have contributed to our understanding of the molecular mechanisms responsible for upregulating MMP-9 gene expression in normal and cancer cells, our knowledge on the signals that suppress MMP-9 expression is much more limited. Here, we report that EGF and BMP-4 cooperate to inhibit MMP-9 expression in cancer cells. Treatment with EGF reduces the expression of MMP-9 at both mRNA while augmenting BMP-4 expression. Interestingly, recombinant BMP-4 suppressed constitutive and PMA-induced MMP-9 expression in both fibrosarcoma and breast cancer cells. Addition of gremlin a natural inhibitor of BMP-4, inhibited the suppression of MMP-9 by EGF. The suppression of MMP-9 by BMP-4 likely occurs at the transcriptional level since BMP-4 suppressed MMP-9 mRNA expression and activation of a reporter vector encoding the human MMP-9 promoter. The suppressive effect of BMP-4 occurs via Smad1/5/8 and is specific since BMP-4 did not inhibit MMP-2 while BMP-2 was ineffective in suppressing MMP-9. Taken together, these results are consistent with a new paradigm for the role of EGF and BMPs in controlling MMP gene expression in cancer cells.

Highlights

Tumor cell proliferation, invasion and metastasis are mediated, at least in part, through the degradation of the extracellular matrix by metalloproteinases (MMPs) locally produced by tumor and stromal cells
We found that suppression of Matrix metalloproteinase-9 (MMP-9) by EGF in HT1080 cells correlated with increased Bone morphogenetic proteins (BMPs)-4 gene expression (Fig. 2A)
We tested whether treatment of HT1080 cells with recombinant BMP-4 could www.impactjournals.com/oncoscience downregulate MMP-9 expression in HT1080 cells

Summary

Introduction

Invasion and metastasis are mediated, at least in part, through the degradation of the extracellular matrix by metalloproteinases (MMPs) locally produced by tumor and stromal cells. A point in case is MMP-9, which plays a significant role in cell invasion and metastasis in several cancers [1,2,3,4]. A large number of studies have focused their attention on identifying and characterizing the molecular mechanisms that are responsible for increased expression of MMP-9 in cancer. Our knowledge on the molecular mechanisms that suppress MMP-9 remains largely unexplored and largely focused on epigenetic mechanisms, including DNA methylation [5,6,7]. Using an experimental mouse lymphoma model, where MMP-9 plays a central role, our group has recently shown that the EGF/EGR1 (epidermal growth factor/ early growth response 1) pathway was involved in the repression of MMP-9 expression by stromal cells [8].

Methods

Results

Conclusion