Abstract
We previously reported that loss of Nrdp1 contributes to human glioma progression by reducing apoptosis. However, the role of Nrdp1 in glioma migration and invasion has not been investigated. Here, we report that ErbB3, a substrate of Nrdp1, is undetectable in normal brain tissues and grade II/III glioma tissues, but is abundant in a certain percentage of grade IV glioma tissues and is associated with the loss of Nrdp1. This suggests that Nrdp1 may be involved in glioma migration and invasion by regulating ErbB3. Thus, the role of Nrdp1/ErbB3 signaling in glioma cell migration and invasion was investigated using Nrdp1 loss- and gain-of-function. The results show that down-regulation of Nrdp1 by use of short hairpin RNA promoted glioma cell migration and invasion. In contrast, overexpression of Nrdp1 significantly inhibited glioma cell migration and invasion. Further investigation on molecular targets revealed that Nrdp1 decreased the level of ErbB3, which resulted in decreasing p-AKT thereby reducing cytoplasmic p27Kip1. Taken together, these findings suggest that Nrdp1-mediated ErbB3 degradation suppresses glioma migration and invasion and that loss of Nrdp1 may amplify ErbB3 signaling to contribute to glioma migration and invasion. These findings suggest that Nrdp1 may be a target for glioma therapy.
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Acknowledgments
This work was supported by the National Natural Science Foundation of China (81201264, 81272777 and 81400127), the China Postdoctoral Science Foundation (2014M551662) and Jiangsu Planned Projects for Postdoctoral Research Funds.
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Hengliang Shi and Hui Gong have contributed equally to this work.
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Fig. S1
a The GFP photograph shows the stable cell line with silenced Nrdp1 in A172 cells; bar 50 μm. b The GFP photograph shows the stable cell line with silenced Nrdp1 in U118 cells; bar 50 μm. c Representative blots show the silencing efficiency of Nrdp1 shRNA and the up-regulation of ErbB3 upon silencing of Nrdp1 in A172 cells. d Representative blots show the silencing efficiency of Nrdp1 shRNA and the up-regulation of ErbB3 upon silencing of Nrdp1 in U118 cells. Supplementary material 1 (TIFF 11,096 kb)
Fig. S2
a The GFP image shows the efficiency of plasmid transfection; bar 100 μm. b The overexpression of Flag-Nrdp1 is shown by immunofluorescence staining with anti-Flag antibody; bar 100 μm. c Representative blots show the expression efficiency of Nrdp1 and the down-regulation of ErbB3 upon overexpression of Nrdp1. Supplementary material 2 (TIFF 12,574 kb)
Fig. S3
a The expression profiles of Nrdp1, ErbB3 and p27Kip1 in U251, U87, SHG44, A172, and U118 cell lines. b Knockdown of endogenous Nrdp1 in U251, U87 and SHG44 cells resulted in an increase of ErbB3 expression in these three cell lines. Supplementary material 3 (TIFF 2073 kb)
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Shi, H., Gong, H., Cao, K. et al. Nrdp1-mediated ErbB3 degradation inhibits glioma cell migration and invasion by reducing cytoplasmic localization of p27Kip1 . J Neurooncol 124, 357–364 (2015). https://doi.org/10.1007/s11060-015-1851-9
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DOI: https://doi.org/10.1007/s11060-015-1851-9