Epidermal Growth Factor Receptor Regulates MT1-MMP and MMP-2 Synthesis in SiHa Cells via Both PI3-K/AKT and MAPK/ERK Pathways

Abstract

Matrix metalloproteinase 2 (MMP-2) and membrane type 1 matrix metalloproteinase (MT1-MMP) have been identified as important participants in tumor invasion, metastasis, and angiogenesis. Membrane type 1 matrix metalloproteinase has also been recognized as a major activator of MMP-2. The purpose of this study was to investigate epidermal growth factor (EGF) mediating signal pathways in the regulation of MMP-2 and MT1-MMP in SiHa cells, a cervical cancer cell line. We showed here that EGF induced the expression of MT1-MMP and inhibited the expression of MMP-2 at both the mRNA and protein levels. Membrane type 1 matrix metalloproteinase induction was blocked by mitogen-activated protein kinase or extracellular signal-regulated kinase inhibitors PD98059 and U0126 but not by phosphatidylinositol-3 kinase (PI3-K) inhibitors LY294002 and wortmannin. Interestingly, the mitogen-activated protein kinase or extracellular signal-regulated kinase inhibitors PD98059 and U0126 actually increased MMP-2 mRNA and protein synthesis, whereas the PI3-K inhibitors LY294002 and wortmannin further suppressed the expression of MMP-2. Our results suggest that EGF receptor up-regulated the expression of MT1-MMP and down-regulated the synthesis of MMP-2 through the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway while concomitantly transmitting a mild positive regulatory signal to the expression of MMP-2 via the PI3-K/AKT pathway in SiHa cells. Furthermore, we found that EGF elevated the activity of MMP-2 in culture media.

Lipid raft localization of epidermal growth factor receptor alters matrix metalloproteinase-1 expression in SiHa cells via the MAPK/ERK signaling pathway

“…It was previously demonstrated by the present authors that EGFR regulates MT1-MMP and MMP-2 synthesis in SiHa cells via both the PI3-K/AKT and MAPK/ERK pathways in SiHa cells (22). To further indicate a role for EGFR in the synthesis and function of other MMP members in SiHa cells, the changes in MMP-1 expression were investigated at the mRNA and protein levels following EGF treatment in the present study.…”

“…Our analyses previously demonstrated that EGFR regulates melatonin receptor type 1A (MT1)-MMP and MMP-2 synthesis in the SiHa cervical cancer cell line via both the PI3-K/AKT and MAPK/ERK pathways (22). However, the effects of EGFR localization to lipid rafts on signaling pathways involved in the regulation of MMP-1 expression are unknown.…”

Fibulin-3 promoter methylation alters the invasive behavior of non-small cell lung cancer cell lines via MMP-7 and MMP-2 regulation

“…Therefore, we examined the activation states of various signalling molecules related to cell growth, including ERK, AKT and NF-κB. Activation of these signalling pathways is also involved in metastasis (21)(22)(23)(24). As expected, these signalling molecules were seemed to be more activated by phosphorylation in A549 cells than in H460 cells (Fig.…”

Oxytocin Increases Invasive Properties of Endometrial Cancer Cells Through Phosphatidylinositol 3-Kinase/AKT-Dependent Up-Regulation of Cyclooxygenase-1, -2, and X-Linked Inhibitor of Apoptosis Protein1

“…Because MMP14 and MMP2 have been identified as important participants in tumor cell invasion [27], we have examined whether OT-induced invasiveness of Hec-1-A cells also occurs via these two matrix metalloproteinases. We found that resting Hec-1-A cells expressed detectable levels of both MMP14 and MMP2, but exposure to OT induced an upregulation of their transcripts (Fig.…”