Abstract
Nasopharyngeal carcinoma (NPC) is a common malignant tumor with high invasive and metastatic potential. The hepatocyte growth factor (HGF)-Met signaling pathway has a critical role in mediating the invasive growth of many different types of cancer, including head and neck squamous cell carcinoma. HGF also stimulates NPC cell growth and invasion in the cell line model. In this study, we determined the inhibitory effect of Met, using a Met-targeting monoclonal antibody (SAIT301), on the invasive and growth potential of NPC cell lines. Met inhibition by SAIT301 resulted in highly significant inhibition of cell migration and invasion in both the HONE1 and HNE1 cell lines. In addition, we also found that co-treatment of SAIT301 and HGF decreased the anchorage-independent growth induced by HGF in HNE1 cell lines. After SAIT301 treatment, Met, together with its downstream signaling proteins, showed downregulation of p-Met and p-ERK, but not p-AKT, in both HONE1 and HNE1 cell lines. Interestingly, we found that HGF treatment of NPC cell lines induced early growth response protein (EGR-1) expression, which is involved in cell migration and invasion. In addition, co-treatment with SAIT301 and HGF inhibited the HGF-induced expression of EGR-1. Next, knockdown of EGR-1 using small-interfering RNA inhibited HGF-induced cell invasion in NPC cell lines, suggesting that the expression level of EGR-1 is important in HGF-induced cell invasion of NPC cells. Therefore, the results support that SAIT301 inhibited Met activation as well as the downstream EGR-1 expression and could have therapeutic potential in NPC. Taken together, we suggest that Met is an anticancer therapeutic target for NPC that warrants further investigation and clinical trials and SAIT301 may be a promising tool for NPC therapy.
Highlights
The mechanism of Nasopharyngeal carcinoma (NPC) metastasis is not fully determined
Zhou et al.[24] identified hepatocyte growth factor (HGF)-induced invasion and migration, which is mediated by JNK through regulation of matrix metalloproteinase (MMP)-9, in response to PI3K/Akt signaling in NPC cells
We further addressed the effect of SAIT301 on HONE1 and HNE1 cell invasion by using transwells, and found that co-treatment with HGF and SAIT301 significantly inhibited cell invasion compared with HGF alone (Figure 1b), indicating that SAIT301 inhibited HGF-induced NPC cell migration and invasion
Summary
The mechanism of NPC metastasis is not fully determined. While recent therapies for NPC include radiation and chemotherapy,[5] radioresistance remains a problem for successful clinical treatment. HGF binding to Met triggers receptor autophosphorylation and upregulation of Met kinase activity, which in turn stimulates a number of intracellular pathways mediating the biological effects of HGF, such as proliferation, motility, morphogenesis and angiogenesis.[11] In normal cells, Met activation is tightly controlled by a ligand-dependent transient event, whereas in tumor cells, Met is often constitutively activated.[12] Many different strategies have been exploited to inhibit aberrant Met signaling in various human cancer cells. These strategies target, directly or indirectly, the Met receptor and/or its ligand HGF. Zhou et al.[24] identified HGF-induced invasion and migration, which is mediated by JNK through regulation of matrix metalloproteinase (MMP)-9, in response to PI3K/Akt signaling in NPC cells
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