Modulation of p75 neurotrophin receptor under hypoxic conditions induces migration and invasion of C6 glioma cells

Abstract

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.

Colorectal cancer mutational profiles correlate with defined microbial communities in the tumor microenvironment

“…Moreover, our finding that the abundance of Fusobacterium is depleted in tumors with LoF mutations in the PDGFR-beta pathway may be explained by the dependence of several pathogenic strains of bacteria for functionally intact PDGFR signaling for adherence to intestinal epithelium [69] . In addition, p75(NTR) signaling has been shown to operate as a tumor suppressor by mediating apoptosis in response to hypoxic conditions and reactive oxygen species [70][71][72][73] . Alterations in this pathway have also been shown to be useful as a biomarker for esophageal cancer [74,75] .…”

Synergistic Anticancer Effects of Formononetin and Temozolomide on Glioma C6 Cells

“…In normal cells, MMP-9 shows low expression, but high expression in glioma cells. 30,31) TMZ has showed effects on reducing the level of MMP-9. 29) Our work also showed that drug combination group can inhibit the migration of glioma cells by down-regulating the expression of MMP-2 and MMP-9 compared with single drug groups.…”

Retinoblastoma protein (Rb) links hypoxia to altered mechanical properties in cancer cells as measured by an optical tweezer

“…Additionally, other HIF1-regulated pathways may be sensitive to loss of Rb and contribute to this phenotype. Activation of focal adhesion kinase and phosphorylation of paxillin correlate with hypoxia-inducible migration of C6 glioma cells 49 . Up-regulation of vimentin intermediary filaments has been implicated in epithelial-to-mesenchymal transition and increased migratory capacity in lung cancer cells in an AKT-dependent fashion 50 .…”