CXCR4 and SDF-1 Production Are Stimulated by Hepatocyte Growth Factor and Promote Glioma Cell Invasion

Background: Hepatocyte growth factor (HGF) and its receptor play an important role in the formation and progression of glioma and can promote tumor proliferation. In this study, we investigated the ability of HGF to promote the proliferation and invasion of U251n cells; we also tested the effects of HGF on stromal cell-derived factor 1 (SDF-1) and CXCR4 mRNA expression. Methods: We measured the effect of HGF on the proliferation of U251n cells using enzyme-linked immunosorbent assays (ELISAs) to detect incorporated bromodeoxyuridine (BrdU) as a marker of DNA synthesis. The effects of HGF and SDF-1 on U251n cell invasion and proliferation were measured using the inhibitors K252a to c-Met and AMD3100 to CXCR4. SDF-1 and CXCR4 mRNA and protein expression were measured using quantitative polymerase chain reaction (PCR) and fluorescence-activated cell sorter (FACS) analysis. Small interfering (si) RNAs were also used to down-regulate HGF and c-Met expression in U251n cells. Results: HGF significantly increased U251n cell proliferation and invasion in a dose-dependent manner; K252a blocked this. AMD3100 blocked invasion but not proliferation. CXCR4 and SDF-1 mRNAs were up-regulated when cells were treated with HGF. CXCR4 and SDF-1 mRNA levels and HGF and c-Met protein levels were down-regulated after cells were transfected with siRNAs. Conclusions: HGF has a direct effect on glioma cell proliferation and invasion. HGF up-regulates SDF-1 and CXCR4 mRNA expression and contributes to cell invasion.