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Overexpression of NBS1 induces epithelial–mesenchymal transition and co-expression of NBS1 and Snail predicts metastasis of head and neck cancer

Abstract

Major causes of head and neck squamous cell carcinoma (HNSCC)-related deaths are cervical node and distant metastasis. We previously demonstrated that overexpression of the DNA double-strand break repair protein Nijmegen breakage syndrome 1 (NBS1) is a prognostic marker of advanced HNSCCs. Epithelial-mesenchymal transition (EMT) was demonstrated to be the major mechanism responsible for mediating invasiveness and metastasis of late-stage cancers. We therefore investigated the role of NBS1 overexpression in mediating EMT and metastasis. NBS1 overexpression was associated with metastasis of HNSCC patients using tissue microarray–immunohistochemistry approach. Induction of EMT was observed in an NBS1-overexpressing HNSCC cell line (FADUNBS), whereas short-interference RNA (siRNA)-mediated repression of endogenous NBS1 reversed the shift of EMT markers. Increased migration/invasiveness of FADUNBS was shown by in vitro and in vivo assays. NBS1 overexpression upregulated the expression of an EMT regulator Snail and its downstream target matrix metalloproteinase-2. EMT phenotypes and increased migration/invasiveness of FADUNBS cells were reversed by siRNA-mediated repression of Snail expression or a phosphatidylinositol 3-kinase-specific inhibitor. In HNSCC samples, co-expression of NBS1/Snail in primary tumors correlated with metastasis and the worst prognosis. These results indicate that NBS1 overexpression induces EMT through the upregulation of Snail expression, and co-expression of NBS1/Snail predicts metastasis in HNSCCs.

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Acknowledgements

We thank Drs TY Chou and WY Li of the Department of Pathology, Taipei Veterans General Hospital for providing expert opinions on pathology reading. We are grateful to Professor KW Chang of the Institute of Oral Biology, National Yang-Ming University for technical assistance on TMA construction and IHC analysis. We also thank CH Huang for excellent technical assistance on the tail vein injection procedure. This work was supported in part by Taipei Veterans General Hospital VGH 94-171, V-95-ER2-009, V-95-S5-002 (MHY), V-95-ER2-010 (SYC), National Health Research Institutes (NHRI-EX95-9329SI) (KJW), National Research Program for Genomic Medicine (NRPGM-DOH-95-TD-G-111-002) (KJW), National Science Council (NSC94-2311-B-010-011) (KJW); (NSC94-2314-B-075-077) (MHY), and a grant from Ministry of Education, Aim for the Top University Plan (95A-C-D01-PPG-05) (KJW).

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Correspondence to K-J Wu.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Yang, MH., Chang, SY., Chiou, SH. et al. Overexpression of NBS1 induces epithelial–mesenchymal transition and co-expression of NBS1 and Snail predicts metastasis of head and neck cancer. Oncogene 26, 1459–1467 (2007). https://doi.org/10.1038/sj.onc.1209929

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