Liu Shuli, Shi Lei, Wang Yang, Ye Dongxia, Ju Houyu, Ma Hailong, Yang Wenyi, Wang Yanan, Hu Jingzhou, Deng Jiong, Zhang Zhiyuan
Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China.
Cell Physiol Biochem. 2018;47(2):567-578. doi: 10.1159/000489990. Epub 2018 May 23.
BACKGROUND/AIMS: Slug protein, a transcription factor for the induction of epithelial-mesenchymal transition (EMT) and cancer cell invasion and metastasis, is frequently upregulated in human epithelial cancers. However, mutation of this gene in cancer is rare, and the mechanism of its dysregulation remains unknown, especially in head and neck squamous cell carcinoma (HNSCC).
We examined the role of TNF-α in the stabilization of Slug by immunoprecipitation-westernblot analysis. Migration of HNSCC cells with or without knockdown of Slug gene expression was assayed by a wound healing assay. Immunohistochemical staining analysis was used to measurement Slug levels in both normal and HNSCC tumor tissues.
The inflammatory cytokine TNF-α stabilized Slug protein by inhibiting its ubiquitination through the NF-κB pathway. Inhibition of NF-κB or knockdown of p65 abrogated the TNF-α-induced stabilization of Slug. Knockdown of Slug expression inhibited cancer cell migration and EMT characteristics induced by TNF-α. Moreover, increased levels of Slug were found to correlate with lymph node metastasis and predict poor prognosis in patients with HNSCC.
NF-κB-mediated stabilization of Slug underlies the inflammation-induced EMT and metastasis in HNSCC, which may serve as a therapeutic target for metastatic HNSCC.
背景/目的：Slug蛋白是一种诱导上皮-间质转化（EMT）以及癌细胞侵袭和转移的转录因子，在人类上皮性癌中经常上调。然而，该基因在癌症中的突变很少见，其失调机制仍然未知，尤其是在头颈部鳞状细胞癌（HNSCC）中。
我们通过免疫沉淀-蛋白质印迹分析检测了肿瘤坏死因子-α（TNF-α）在稳定Slug蛋白中的作用。采用划痕实验检测Slug基因表达敲低与否的HNSCC细胞的迁移情况。免疫组化染色分析用于测量正常和HNSCC肿瘤组织中的Slug水平。
炎性细胞因子TNF-α通过NF-κB途径抑制Slug蛋白的泛素化来使其稳定。抑制NF-κB或敲低p65可消除TNF-α诱导的Slug稳定。敲低Slug表达可抑制TNF-α诱导的癌细胞迁移和EMT特征。此外，发现Slug水平升高与HNSCC患者的淋巴结转移相关，并预示预后不良。
NF-κB介导的Slug稳定是HNSCC中炎症诱导的EMT和转移的基础，这可能作为转移性HNSCC的治疗靶点。
