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

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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.

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Acknowledgments

The authors would like to thank Miss I-Gin Lin for technical assistance. This work was supported by grants from the Chang Gung Memorial Hospital (CMRPG 6C0021 and CMRPG 6C0022). The authors are responsible for the content of the paper.

Conflict of interest

The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Division of Neurosurgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan

    Ting-Chung Wang & Sheng-jie Luo

  2. Division of Nephrology and Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi, Taiwan

    Chun-Liang Lin

  3. Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan

    Ting-Chung Wang & Pey-Jium Chang

  4. Department of Radiation Oncology, Chang Gung Memorial Hospital at Chiayi, 6 West, Chia-Pu Road, Puzi, 613, Chiayi, Taiwan

    Miao-Fen Chen

  5. Department of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan

    Miao-Fen Chen

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  1. Ting-Chung Wang
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  2. Sheng-jie Luo
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  3. Chun-Liang Lin
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Correspondence to Miao-Fen Chen.

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Wang, TC., Luo, Sj., Lin, CL. et al. Modulation of p75 neurotrophin receptor under hypoxic conditions induces migration and invasion of C6 glioma cells. Clin Exp Metastasis 32, 73–81 (2015). https://doi.org/10.1007/s10585-014-9692-z

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  • DOI: https://doi.org/10.1007/s10585-014-9692-z

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