S897 phosphorylation of EphA2 is indispensable for EphA2-dependent nasopharyngeal carcinoma cell invasion, metastasis and stem properties.

Abstract

Our phosphoproteomics identified that phosphorylation of EphA2 at serine 897 (pS897-EphA2) was significantly upregulated in the high metastatic nasopharyngeal carcinoma (NPC) cells relative to non-metastatic NPC cells. However, the role and underlying mechanism of pS897-EphA2 in cancer metastasis and stem properties maintenance remain poorly understood. In this study, we established NPC cell lines with stable expression of exogenous EphA2 and EphA2-S897A using endogenous EphA2 knockdown cells, and observed that pS897-EphA2 maintained EphA2-dependent NPC cell in vitro migration and invasion, in vivo metastasis and cancer stem properties. Using phospho-kinase antibody array to identify signaling downstream of pS897-EphA2, we found that AKT/Stat3 signaling mediated pS897-EphA2-promoting NPC cell invasion, metastasis and stem properties, and Sox-2 and c-Myc were the effectors of pS897-EphA2. Immunohistochemistry showed that pS897-EphA2 was positively correlated with NPC metastasis and negatively correlated with patient overall survival. Moreover, ERK/RSK signaling controlled serum-induced pS897-EphA2 in NPC cells. Collectively, our results demonstrate that pS897-EphA2 is indispensable for EphA2-dependent NPC cell invasion, metastasis and stem properties by activating AKT/Stat3/Sox-2 and c-Myc signaling pathway, suggesting that pS897-EphA2 can serve as a therapeutic target in NPC and perhaps in other cancers.

• Authors: Jiao-Yang Li, Ta Xiao, Hong-Mei Yi, Hong Yi, Juan Feng, Jin-Feng Zhu, Wei Huang, Shan-Shan Lu, Yan-Hong Zhou, Xin-Hui Li, Zhi-Qiang Xiao
• Journal: Cancer letters (Cancer Lett) Vol. 444 Pg. 162-174 (03 01 2019) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 30583071 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Biomarkers, Tumor
• Receptor, EphA2

Topics

• Animals
• Apoptosis
• Biomarkers, Tumor (genetics, metabolism)
• Cell Proliferation
• Follow-Up Studies
• Gene Expression Regulation, Neoplastic
• Humans
• Lung Neoplasms (genetics, metabolism, secondary)
• Lymphatic Metastasis
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Nasopharyngeal Neoplasms (genetics, metabolism, pathology)
• Neoplasm Invasiveness
• Neoplastic Stem Cells (metabolism, pathology)
• Phosphorylation
• Prognosis
• Receptor, EphA2 (genetics, metabolism)
• Survival Rate
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays