HGF mediated upregulation of lipocalin 2 regulates MMP9 through nuclear factor-κB activation

Abstract

Lipocalin 2 (LCN2) is a member of lipocalin family that binds and transports a small lipophilic ligand, sharing a highly conserved tertiary structure and can be found as a monomer, homodimer, heterodimer with matrix metalloproteinase 9 (MMP9). The high molecule LCN2/ MMP9 complex was found in several cancer types. Yet, the mechanisms of regulation between LCN2 with MMP9 in tumorigenesis is unclear. The aims of the present study were to identify the function of LCN2 associated with MMP9 in gastric cancer growth and metastasis. First, we confirmed that the expression level of LCN2 and MMP9 was upregulated by hepatocyte growth factor (HGF). To identify the association pathway of HGF-induced LCN2, the cells were treated with PI3-kinase inhibitor (LY294002), or MEK inhibitor (PD098059), or p38 inhibitor (SB203580) and then analyzed using western blotting. The HGF-mediated LCN2 protein level was decreased with LY294002. Also, the HGF-mediated MMP9 was decreased with LY294002. The role for LCN2 with HGF mediated MMP9 was determined by knockdown of LCN2. LCN2-sh RNA cells showed a decreased level of HGF-mediated MMP9. The HGF-mediated LCN2 protein level was decreased with treatment of the NFκB inhibitor. We confirmed the role of HGF-mediated LCN2. HGF-mediated cell proliferation and in vitro invasion was decreased in LCN2 knockdown cell. In conclusion, the present study showed that LCN2 upregulated MMP9 through PI3K/AKT/NFκB pathway in gastric cancer. LCN2 has a role in cell proliferation and cell invasion in gastric cancer, which may be a possible target for developing gastric cancer therapy.