Theranostics 2017; 7(15):3700-3714. doi:10.7150/thno.19712

Research Paper

Epiregulin Promotes Lung Metastasis of Salivary Adenoid Cystic Carcinoma

Wen-Wen Yang1, Lin-Qian Yang1, Fei Zhao1, Chu-Wen Chen1, Li-Hua Xu1, Jia Fu2, Sheng-Lin Li1,2✉, Xi-Yuan Ge1,2✉

1. Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, PR China;
2. Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, PR China.

Abstract

Salivary adenoid cystic carcinoma (SACC) is a peculiar malignant tumor, characterized by its slow but inexorable growth, with a high incidence of lung metastasis and poor prognosis. Here, we show the upregulated expression of EGFR ligand epiregulin in a subset of SACC cells correlates with lung metastasis and unfavorable outcome in patients with SACC. We found that upregulation of epiregulin in SACC cells induced epithelial-mesenchymal transition by regulating GLI1/E-cadherin. Elevated epiregulin increased the expression of pro-angiogenic factors, such as VEGFA, bFGF, and IL-8. We also show that epiregulin can be delivered via exosomes and was enriched in exosomes derived from epiregulin-overexpressing SACC cells. Furthermore, treating immunodeficient mice with these epiregulin-enriched exosomes greatly enhanced SACC metastasis to lung. These epiregulin-enriched exosomes significantly enhanced angiogenesis in the neighboring tumor microenvironment and increased vascular permeability in the pre-metastatic lung microenvironment in vivo. Therefore, epiregulin, as well as epiregulin-containing exosomes, may be a novel target for controlling SACC lung metastasis.

Keywords: adenoid cystic cacinoma, epiregulin, lung metastasis, exosomes, pre-metastatic niche

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How to cite this article:
Yang WW, Yang LQ, Zhao F, Chen CW, Xu LH, Fu J, Li SL, Ge XY. Epiregulin Promotes Lung Metastasis of Salivary Adenoid Cystic Carcinoma. Theranostics 2017; 7(15):3700-3714. doi:10.7150/thno.19712. Available from http://www.thno.org/v07p3700.htm