2. Academic Validation
  3. SPINK6 Promotes Metastasis of Nasopharyngeal Carcinoma via Binding and Activation of Epithelial Growth Factor Receptor

SPINK6 Promotes Metastasis of Nasopharyngeal Carcinoma via Binding and Activation of Epithelial Growth Factor Receptor

  • Cancer Res. 2017 Jan 15;77(2):579-589. doi: 10.1158/0008-5472.CAN-16-1281.
Li-Sheng Zheng 1,  Jun-Ping Yang 1,  Yun Cao 1 2,  Li-Xia Peng 1,  Rui Sun 1 3,  Ping Xie 1,  Meng-Yao Wang 1 4,  Dong-Fang Meng 1,  Dong-Hua Luo 1 3,  Xiong Zou 1 3,  Ming-Yuan Chen 1 3,  Hai-Qiang Mai 1 3,  Ling Guo 1 3,  Xiang Guo 1 3,  Jian-Yong Shao 1 5,  Bi-Jun Huang 1,  Wei Zhang 6 7,  Chao-Nan Qian 8 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
  • 2 Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
  • 3 Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, China.
  • 4 Radiotherapy Department, Affiliated Cancer Hospital of Guangzhou Medical University, Guangzhou, China.
  • 5 Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, Guangzhou, China.
  • 6 Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 7 Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest Baptist Medical Center, Winston-Salem, North Carolina.
  • 8 State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China. qianchn@sysucc.org.cn.
PMID: 27671677 DOI: 10.1158/0008-5472.CAN-16-1281
Abstract

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.

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