S100A14 suppresses metastasis of nasopharyngeal carcinoma by inhibition of NF-kB signaling through degradation of IRAK1
S100A14 suppresses metastasis of nasopharyngeal carcinoma by inhibition of NF-kB signaling through degradation of IRAK1
复制标题
S100A14 通过降解 IRAK1 抑制 NF-kB 信号传导来抑制鼻咽癌的转移
DOI：
10.1038/s41388-020-1363-8
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发表时间：
2020-06-17
期刊：
影响因子：
8
通讯作者：
Qian, Chao-Nan
中科院分区：
文献类型：
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作者：
Meng, Dong-Fang;Sun, Rui;Qian, Chao-Nan
鼻咽癌（NPC）是一种独特的头颈部肿瘤，具有高度侵袭性和转移潜力，其中远处转移是治疗失败的主要原因。到目前为止，鼻咽癌转移的潜在分子机制仍然知之甚少。在这里，我们发现S100钙结合蛋白A14 （S100A14）是一种功能调节剂，通过抑制NF-kB信号通路和逆转上皮-间质转化（EMT）来抑制鼻咽癌转移。发现S100A14在高转移性鼻咽癌细胞和组织中下调。202例鼻咽癌样本的免疫组化染色显示，S100A14低表达与患者总生存期（OS）和远端无转移生存期（DMFS）缩短显著相关。S100A14也被发现是有利生存的独立预后因素。功能获得和功能丧失研究证实，S100A14抑制鼻咽癌细胞的体外和体内运动。机制上，S100A14促进泛素蛋白酶体介导的白介素-1受体相关激酶1 （IRAK1）降解，抑制鼻咽癌细胞迁移。此外，S100A14和IRAK1建立了一个可以被IRAK1抑制剂T2457破坏的反馈回路。总之，我们的研究结果表明S100A14-IRAK1反馈回路可能是鼻咽癌转移的一个有希望的治疗靶点。
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.