Overexpression of NBS1 induces epithelial-mesenchymal transition and co-expression of NBS1 and Snail predicts metastasis of head and neck cancer.
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.
Yang
M-H
MH
Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
Chang
S-Y
SY
Chiou
S-H
SH
Liu
C-J
CJ
Chi
C-W
CW
Chen
P-M
PM
Teng
S-C
SC
Wu
K-J
KJ
D018797:Cell Cycle Proteins / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic; D053903:DNA Breaks, Double-Stranded; D004848:Epithelium; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008648:Mesoderm; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D018307:Neoplasms, Squamous Cell / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D011379:Prognosis; D034741:RNA, Small Interfering / Q000494:pharmacology; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D018797:Cell Cycle Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D020778:Matrix Metalloproteinase 2