Coexpression of Matrix Metalloproteinase-7 (MMP-7) and Epidermal Growth Factor (EGF) Receptor in Colorectal Cancer

Abstract

Purpose: Matrix metalloproteinase-7 (MMP-7) plays an important role in carcinoma invasion and metastasis of cancer. Recent studies focus on diverse roles of MMP-7, other than as a protease, during cancer progression. MMP-7 activates the epidermal growth factor (EGF) receptor by releasing an EGF ligand, tumor growth factor (TGF)-␣.Experimental Design: We examined expression of MMP-7 and EGF receptor in an immunohistochemical study of 40 colorectal cancer (CRC) cases. To determine the relationship between the EGF receptor and MMP-7, with a potential curative application, we compared the antitumor activity of the EGF receptor tyrosine kinase inhibitor (gefitinib) between MMP-7 transfectant, KYSE150 and HT29, and control cells.Results: We found a statistically significant correlation (P ‫؍‬ 0.04) between MMP-7 and activated (phosphorylated) EGF receptor expression, both being positive in six (15%) cases. Gefitinib reduced the cell number ratio more for MMP-7 transfectant than mock cells, and the proportion of apoptotic cells was 1.5 times higher in MMP-7 transfectant than mock cells by annexin/propidium iodide staining. This was mediated by activation of a TGF-␤ signal as confirmed by the abundant expression of TGF-␤ protein, the cytoplasmic to nuclear translocation of Smad4 protein by the administration of gefitinib, and the quantitative assay of the plasminogen activator inhibitor-1 promoter/luciferase construction.Conclusions: We propose that there are some cancers with up-regulated MMP-7 expression that leads to the activation of apoptotic activity of TGF-␤, which is susceptible to treatment with EGF receptor tyrosine kinase inhibitor.

Contribution of sialidase NEU1 to suppression of metastasis of human colon cancer cells through desialylation of integrin β4

“…In addition, we found downregulation of MMP-7 probably through NEU1-mediated attenuation of integrin b4 signaling, which may result in processing inhibition of laminin-5 and lead to suppression of cell invasion and metastasis. MMP-7 overexpression in cancers is associated with advanced clinicopathological stages, especially with colorectal cancer liver metastasis (Zeng et al, 2002), and MMP-7 production occurs through activation of epidermal growth factor (EGF) receptor-mediated MEK/Erk signaling pathway (Mimori et al, 2004). In this context, this study suggests that NEU1-mediated repression of Erk subsequent to decreased integrin b4 phosphorylation presumably contributes to reduced MMP-7 expression.…”

MMP-7 overexpression is an independent prognostic marker in gastric cancer

“…MMP-7 inhibition by an antisense expression vector or antisense nucleotides can suppress the in vitro invasiveness and in vivo metastatic potential of pancreatic cancer and Ewing's sarcoma cells [11]. Clinical use of MMP7 inhibitors has however been disappointing because of their poor therapeutic effect and undesirable side-effects [25]. Colon cancer patients have been treated with the tyrosine kinase inhibitors gefitinib or with its derivatives known to be effective against MMP-7-positive tumour cells [25].…”

Colorectal carcinoma: from tumorigenesis to treatment

“…Proteolysis of the insulin-like growth factor binding protein 3 (IGFBP-3) by this protease has been shown to play a crucial role in promoting the survival of colon cancer cells via regulating IGF-I bioavailability [58]. MMP-7 may play a role in EGF receptor activation in colon cancer cells [59]. Finally, MMP-7 may confer resistance to FasL-induced apoptosis to colon cancer cells by cleaving Fas, the cognate death receptor for this ligand [60].…”