Hepatocyte growth factor induces breast cancer cell invasion via the PI3K/Akt and p38 MAPK signaling pathways to up-regulate the expression of COX2.

Hepatocyte growth factor (HGF) is a multifunctional growth factor that plays important roles in promoting the invasion and metastasis of various tumor cells. However, there are few reports about the exact mechanisms of HGF involved in the regulation of cell invasion via the induction of COX2. In this study, we found that HGF could activate its receptor c-Met and up-regulate COX2 expression in a dose- and time-dependent manner, which resulted in an increase in MMP-9 expression and subsequent invasiveness of the breast cancer cell lines MDA-MB-231 and MCF-7. The HGF-induced expression of COX2 and MMP-9 and cell invasion were partially suppressed by COX2 gene silencing. The PI3K/Akt and p38 MAPK signaling pathways were activated by HGF in both cell lines. However, PI3K/Akt or p38 MAPK-specific inhibition alone partially attenuated HGF-induced COX2 and MMP-9 expression and the invasiveness of the two breast cancer cell lines, and these HGF-induced effects were almost completely abolished by simultaneous treatment with both inhibitors. Therefore, we concluded that HGF mediates the up-regulation of COX2 predominantly through the PI3K/Akt and p38 MAPK signaling pathways, leading to MMP-9 expression and the subsequent invasion of two breast cancer cell lines. This study improves our understanding of the signal transduction mechanisms in the HGF-induced invasion and progression of breast cancer.