p75 neurotrophin receptor (p75NTR) has been reported to play important roles in various
cancer types. However, the exact mechanism of
tumorigenesis involving p75NTR is unknown. In this study, we investigated the relationship between the expression of p75NTR in
malignant glioma and the impact on
tumor cell migration and invasion. p75NTR and
hypoxia-inducible factor-1α (HIF-1α) expression was down-regulated by
short-hairpin RNA and up-regulated with expression vectors. By immunohistochemical staining and Western blot analysis, we found that p75NTR was expressed in both human and rat
malignant gliomas. Knockdown of p75NTR increased the expression of
vimentin,
vascular endothelial growth factor,
Matrix metalloproteinase 9, and TWIST, and enhanced the invasion and migration abilities assessed by transwell assay in the C6
tumor cells. Inverse expressions of p75NTR and HIF-1α were detected in
glioma cell lines under hypoxic conditions, while increased HIF-1α significantly downregulated the expression of p75NTR, suggesting a HIF-1α-p75NTR-EMT pathway that may regulate
glioma cells invasion and migration. Downregulation of p75NTR increased phosphorylation of Src,
focal adhesion kinase (FAK) and
paxillin. Knockdown of p75NTR also dysregulated β-
catenin-mediated cell junctions, and up-regulated the expressions of
fibronectin and
L1CAM in the cell-cell junctions, thus suggesting that p75NTR knockdown contributed to a more aggressive migration phenotype via FAK signaling pathway. Our studies suggested that modulation of p75NTR under hypoxic condition could enhance C6 cells migration and invasion by induction of EMT, and activation of the FAK pathway. The HIF-1α-p75NTR-EMT axis may play a central role in
glioma tumorigenesis.