S100A14 suppresses metastasis of nasopharyngeal carcinoma by inhibition of NF-kB signaling through degradation of IRAK1

• Published in: Oncogene Vol. 39; no. 30; pp. 5307 - 5322
• Main Authors: Meng, Dong-Fang, Sun, Rui, Liu, Guo-Ying, Peng, Li-Xia, Zheng, Li-Sheng, Xie, Ping, Lin, Si-Ting, Mei, Yan, Qiang, Yuan-Yuan, Li, Chang-Zhi, Xu, Liang, Peng, Xing-Si, Hu, Hao, Lang, Yan-Hong, Liu, Zhi-Jie, Wang, Ming-Dian, Guo, Ling-Ling, Xie, De-Huan, Shu, Di-Tian, Li, Hai-Feng, Luo, Fei-Fei, Niu, Xing-Tang, Huang, Bi-Jun, Qian, Chao-Nan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.07.2020; Nature Publishing Group
• Subjects: 13/2; 14/5; 38/89; 42/70; 631/67/1536; 64/60; 692/53/2422; 82/51; 96; 96/109; Animals; Apoptosis; Calcium-binding protein; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Cancer; Carcinoma; Cell Biology; Cell Line, Tumor; Cell Movement - genetics; Epithelial-Mesenchymal Transition - genetics; Feedback; Feedback, Physiological; Gene Expression Regulation, Neoplastic; Head & neck cancer; Health aspects; Heterografts; Human Genetics; Humans; Immunohistochemistry; Interleukin 1; Interleukin-1 Receptor-Associated Kinases - genetics; Interleukin-1 Receptor-Associated Kinases - metabolism; Internal Medicine; IRAK protein; Kinases; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Medicine; Medicine & Public Health; Mesenchyme; Metastases; Metastasis; Mice, Nude; Molecular modelling; Nasopharyngeal carcinoma; Nasopharyngeal Carcinoma - genetics; Nasopharyngeal Carcinoma - metabolism; Nasopharyngeal Carcinoma - pathology; Nasopharyngeal Neoplasms - genetics; Nasopharyngeal Neoplasms - metabolism; Nasopharyngeal Neoplasms - pathology; NF-kappa B - genetics; NF-kappa B - metabolism; NF-κB protein; Oncology; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Protein binding; RNA Interference; Signal transduction; Signal Transduction - genetics; Survival Analysis; Therapeutic applications; Throat cancer; Ubiquitin
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-020-1363-8

Nasopharyngeal carcinoma (NPC) is a unique head and neck cancer with highly aggressive and metastatic potential in which distant metastasis is the main reason for treatment failure. Till present, the underlying molecular mechanisms of NPC metastasis remains poorly understood. Here, we identified S100 calcium-binding protein A14 (S100A14) as a functional regulator suppressing NPC metastasis by inhibiting the NF-kB signaling pathway and reversing the epithelial–mesenchymal transition (EMT). S100A14 was found to be downregulated in highly metastatic NPC cells and tissues. Immunohistochemical staining of 202 NPC samples revealed that lower S100A14 expression was significantly correlated with shorter patient overall survival (OS) and distant metastasis-free survival (DMFS). S100A14 was also found as an independent prognostic factor for favorable survival. Gain- and loss-of-function studies confirmed that S100A14 suppressed the in vitro and in vivo motility of NPC cells. Mechanistically, S100A14 promoted the ubiquitin-proteasome-mediated degradation of interleukin-1 receptor-associated kinase 1 (IRAK1) to suppress NPC cellular migration. Moreover, S100A14 and IRAK1 established a feedback loop that could be disrupted by the IRAK1 inhibitor T2457. Overall, our findings showed that the S100A14-IRAK1 feedback loop could be a promising therapeutic target for NPC metastasis.