S100A14 通过抑制 NF-kB 信号通路实现抑制鼻咽癌转移的新机制

鼻咽癌高发于华南及东南亚，其远处转移是治疗失败的主要原因。我们在对比高转移和低转移鼻咽癌细胞的全基因组表达变化中发现 S100A14 在高转移细胞里的表达水平受到明显抑制。鼻咽癌原发灶S100A14低水平表达的患者其总生存时间显著缩短。预实验显示S100A14可抑制鼻咽癌细胞的迁移和侵袭能力以及抑制鼻咽癌细胞的上皮-间充质转化。RNA测序结果显示S100A14与NK-kB信号通路的激活呈负相关关系。我们因此提出科学假说：S100A14通过抑制NK-kB信号通路来实现抑制鼻咽癌细胞转移的功能。通过一系列体内外实验，本项目将进明确S100A14抑制P50和P65蛋白入核、抑制IL-1beta 的表达、抑制NK-kB信号通路中关键分子的磷酸化激活、最终抑制鼻咽癌细胞在体内的转移。本项目的开展将有助于阐明S100A14抑制鼻咽癌转移的新机制，为新药研发以及制定防治鼻咽癌转移的新策略提供理论依据。

Nasopharyngeal carcinoma (NPC) has a high incidence rate in southern China and Southeast Asia. Distant metastasis is the main reason for treatment failure. By analyzing our previously published whole genomic expression profiling data comparing low- versus high-metastasis NPC cells, we found that S100A14 expression was dramatically suppressed in high-metastasis cells. The reduced expression of S100A14 protein in the primary NPC collated with poorer overall survival of the NPC patients. Our preliminary experiments showed that S100A14 could inhibit the migratory and invasive abilities, as well as the epithelial-mesenchymal translation of NPC cells. RNA sequencing analyses found that NF-kB signaling pathway was the most dramatically influenced pathway by S100A14 with a negative relationship found between S100A14 and NF-kB signaling. We therefore propose a hypothesis that S100A14 inhibits NPC metastasis through inhibition of NF-kB signaling. In the proposed study, we will use a series of in vitro and in vivo approaches to clarify the inhibitory effects of S100A14 in terms of nuclear localization of P50 and P65, expression of IL-1beta, phosphorylation activation of the key molecules in NF-kB signaling pathway, as well as the in vivo metastasis of NPC cells. The accomplishment of the proposed study will reveal a novel mechanism of inhibiting NPC metastasis via inhibitory effects of S100A14 upon NF-kB signaling, which should be composed of drugable targets for metastasis prevention and treatment.