Zheng Li-Sheng, Yang Jun-Ping, Cao Yun, Peng Li-Xia, Sun Rui, Xie Ping, Wang Meng-Yao, Meng Dong-Fang, Luo Dong-Hua, Zou Xiong, Chen Ming-Yuan, Mai Hai-Qiang, Guo Ling, Guo Xiang, Shao Jian-Yong, Huang Bi-Jun, Zhang Wei, Qian Chao-Nan
State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Cancer Res. 2017 Jan 15;77(2):579-589. doi: 10.1158/0008-5472.CAN-16-1281. Epub 2016 Sep 26.
Nasopharyngeal carcinoma has the highest rate of metastasis among head and neck cancers, and distant metastasis is the major reason for treatment failure. The underlying molecular mechanisms of nasopharyngeal carcinoma metastasis are not fully understood. Here, we report the identification of serine protease inhibitor Kazal-type 6 (SPINK6) as a functional regulator of nasopharyngeal carcinoma metastasis via EGFR signaling. SPINK6 mRNA was upregulated in tumor and highly metastatic nasopharyngeal carcinoma cells. Immunohistochemical staining of 534 nasopharyngeal carcinomas revealed elevated SPINK6 expression as an independent unfavorable prognostic factor for overall, disease-free, and distant metastasis-free survival. Ectopic SPINK6 expression promoted in vitro migration and invasion as well as in vivo lymph node metastasis and liver metastasis of nasopharyngeal carcinoma cells, whereas silencing SPINK6 exhibited opposing effects. SPINK6 enhanced epithelial-mesenchymal transition by activating EGFR and the downstream AKT pathway. Inhibition of EGFR with a neutralizing antibody or erlotinib reversed SPINK6-induced nasopharyngeal carcinoma cell migration and invasion. Erlotinib also inhibited SPINK6-induced metastasis in vivo Notably, SPINK6 bound to the EGFR extracellular domain independent of serine protease-inhibitory activity. Overall, our results identified a novel EGFR-activating mechanism in which SPINK6 has a critical role in promoting nasopharyngeal carcinoma metastasis, with possible implications as a prognostic indicator in nasopharyngeal carcinoma patients. Cancer Res; 77(2); 579-89. ©2016 AACR.
鼻咽癌在头颈部癌症中具有最高的转移率，远处转移是治疗失败的主要原因。鼻咽癌转移的潜在分子机制尚未完全明确。在此，我们报告鉴定出丝氨酸蛋白酶抑制剂Kazal型6（SPINK6）是通过表皮生长因子受体（EGFR）信号传导调控鼻咽癌转移的功能性调节因子。SPINK6信使核糖核酸（mRNA）在肿瘤及高转移性鼻咽癌细胞中上调。对534例鼻咽癌进行免疫组织化学染色显示，SPINK6表达升高是总生存、无病生存及无远处转移生存的独立不良预后因素。异位表达SPINK6可促进鼻咽癌细胞的体外迁移和侵袭以及体内淋巴结转移和肝转移，而沉默SPINK6则表现出相反的作用。SPINK6通过激活EGFR及下游的蛋白激酶B（AKT）途径增强上皮-间质转化。用中和抗体或厄洛替尼抑制EGFR可逆转SPINK6诱导的鼻咽癌细胞迁移和侵袭。厄洛替尼在体内也抑制SPINK6诱导的转移。值得注意的是，SPINK6与EGFR胞外域结合，与丝氨酸蛋白酶抑制活性无关。总体而言，我们的研究结果确定了一种新的EGFR激活机制，其中SPINK6在促进鼻咽癌转移中起关键作用，可能作为鼻咽癌患者的预后指标。《癌症研究》；77(2)；579 - 89。©2016美国癌症研究协会。
