Yang M-H, Chang S-Y, Chiou S-H, Liu C-J, Chi C-W, Chen P-M, Teng S-C, Wu K-J
Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
Oncogene. 2007 Mar 1;26(10):1459-67. doi: 10.1038/sj.onc.1209929. Epub 2006 Aug 28.
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.
头颈部鳞状细胞癌（HNSCC）相关死亡的主要原因是颈部淋巴结转移和远处转移。我们之前证明，DNA双链断裂修复蛋白尼氏断裂综合征1（NBS1）的过表达是晚期HNSCC的一个预后标志物。上皮-间质转化（EMT）被证明是介导晚期癌症侵袭和转移的主要机制。因此，我们研究了NBS1过表达在介导EMT和转移中的作用。使用组织芯片免疫组化方法发现，NBS1过表达与HNSCC患者的转移相关。在过表达NBS1的HNSCC细胞系（FADUNBS）中观察到了EMT的诱导，而短干扰RNA（siRNA）介导的内源性NBS1抑制逆转了EMT标志物的转变。体外和体内实验均显示FADUNBS的迁移/侵袭能力增强。NBS1过表达上调了EMT调节因子Snail及其下游靶点基质金属蛋白酶-2的表达。siRNA介导的Snail表达抑制或磷脂酰肌醇3-激酶特异性抑制剂可逆转FADUNBS细胞的EMT表型及增强的迁移/侵袭能力。在HNSCC样本中，原发肿瘤中NBS1/Snail的共表达与转移及最差预后相关。这些结果表明，NBS1过表达通过上调Snail表达诱导EMT，且NBS1/Snail的共表达可预测HNSCC的转移。
