Matrix metalloproteinases (MMPs) have been shown to be key players in both extracellular matrix remodeling and cell migration during cancer metastasis. MMP-14, a membraneanchored MMP, in particular, is closely associated with these processes. The hemopexin (PEX) domain of MMP-14 has been proposed as the modulating region involved in the molecular cross-talk that initiates cell migration through homodimerization of MMP-14 as well as heterodimerization with the cell surface adhesion molecule CD44. In this study, minimal regions required for function within the PEX domain were investigated through a series of substitution mutations. Blades I and IV were found to be involved in cell migration. We found that blade IV is necessary for MMP-14 homodimerization and that blade I is required for CD44 MMP-14 heterodimerization. Cross-talk between MMP-14 and CD44 results in phosphorylation of EGF receptor and downstream activation of the MAPK and PI3K signaling pathways involved in cell migration. Based on these mutagenesis analyses, peptides mimicking the essential outermost strand motifs within the PEX domain of MMP-14 were designed. These synthetic peptides inhibit MMP-14-enhanced cell migration in a dose-dependent manner but have no effect on the function of other MMPs. Furthermore, these peptides interfere with cancer metastasis without affecting primary tumor growth. Thus, targeting the MMP-14 hemopexin domain represents a novel approach to inhibit MMP-14-mediated cancer dissemination.

KIAA1199 serves as a novel cell migration-promoting gene and plays a critical role in maintaining cancer mesenchymal status.

Gastric cancer is the fourth most common cancer worldwide, with a low 5-year survival rate. Epigenetic modification plays pivotal roles in gastric cancer development. However, the role of histone-modifying enzymes in gastric cancer remains largely unknown. Here we report that Sirt7, a NAD+-dependent class III histone deacetylase, is over-expressed in human gastric cancer tissues. Sirt7 level is significantly correlated with disease stage, metastasis, and survival. Knockdown of Sirt7 in gastric cancer cells inhibits cell proliferation and colony formation in vitro. In vivo subcutaneous xenograft results also show that Sirt7 knockdown can markedly repress gastric cancer cell growth. In addition, Sirt7 depletion induces apoptosis in gastric cancer cells via up-regulating expression of pro-apoptotic proteins and down-regulating anti-apoptotic proteins. Mechanically, Sirt7 binds to the promoter of miR-34a and deacetylases the H3K18ac, thus represses miR-34a expression. Reversely, depletion of miR-34a inhibits gastric cancer apoptosis induced by Sirt7 knockdown, and restores cellular capacity of proliferation and colony formation. miR-34a depletion reduces Sirt7-knockdown-induced arrest of gastric growth. Finally, miR-34a is tightly associated with survival of patients with gastric cancer.