title: 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.
authors.affiliation: Division of Neurosurgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Ting-Chung
authors.initials: TC
authors.lastname: Wang
authors.forename: Sheng-Jie
authors.initials: SJ
authors.lastname: Luo
authors.forename: Chun-Liang
authors.initials: CL
authors.lastname: Lin
authors.forename: Pey-Jium
authors.initials: PJ
authors.lastname: Chang
authors.forename: Miao-Fen
authors.initials: MF
authors.lastname: Chen
mesh_terms: D000328:Adult; D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005353:Fibronectins / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D039842:Neural Cell Adhesion Molecule L1 / Q000096:biosynthesis; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism*; D019108:Tight Junctions / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000096:biosynthesis; D014746:Vimentin / Q000096:biosynthesis; D051176:beta Catenin / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D005353:Fibronectins; D009419:Nerve Tissue Proteins; D039842:Neural Cell Adhesion Molecule L1; D034741:RNA, Small Interfering; D017978:Receptors, Growth Factor; D051879:Twist-Related Protein 1; D014746:Vimentin; D051176:beta Catenin; C068313:Ngfr protein, rat; D019061:src-Family Kinases