鼻咽癌 EGFR 信号通路的全新激活机制

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。我们已发现具备高转移能力的鼻咽癌细胞往往同时具备干细胞的特性。已知EGFR的激活是肿瘤细胞得以维持其干细胞特性的重要因素。基于全基因组表达谱分析，我们发现SPINK6在高转移的鼻咽癌细胞中表达水平升高。预实验显示SPINK6可结合EGFR并导致EGFR磷酸化。SPINK6在原发肿瘤的高表达预示着患者的不良预后。我们因此提出科学假说：鼻咽癌细胞的EGFR信号通路可被SPINK6激活，从而促使癌细胞获得干细胞特性及高转移能力。通过一系列体内外实验，本项目将进一步收集SPINK6促进鼻咽癌细胞运动的系列证据、确认SPINK6与EGFR的结合位点、阐明SPINK6/EGFR信号通路在促进鼻咽癌转移方面的重要作用。本项目的开展将有助于阐明鼻咽癌细胞EGFR的全新激活机制，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. Our previous studies have found that high-metastasis NPC cells always possess stem cell characteristics. It has been reported that activating EGFR signaling is the key factor for the maintenance of stem cell characteristics in NPC cells. Our high through-put whole genome expression profiling showed that SPINK6 was highly expressed in high-metastasis cells. Further studies showed that SPINK6 could directly bind to EGFR resulting in EGFR phosphorylation. Elevated SPINK6 protein expression in the primary NPCs significantly correlated with poorer patient survival. We therefore propose a hypothesis that in NPC cells, EGFR signaling could be activated by SPINK6, and SPINK6/EGFR signaling is critical for NPC metastasis. In the present proposal, we will apply lymph-node metastasis model, proteomic analyses, as well as some other biochemical approaches to further collect the evidence of SPINK6-promoting cellular mobility, the binding site of SPINK6 on EGFR, and the critical role of SPINK6/EGFR signaling in NPC metastasis. The completion of the present proposal will reveal a novel mechanism of EGFR activation by direct binding of SPINK6, which is a potential target for drug development and metastasis prevention in NPC patients.