Tumor-associated macrophages promote Ezrin phosphorylation-mediated epithelial-mesenchymal transition in lung adenocarcinoma through FUT4/LeY up-regulation
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Aman Wang1,*, Chang Lu2,*, Zhen Ning2,*, Wei Gao3, Yunpeng Xie4, Ningning Zhang1, Jinxiao Liang5, Faisal S. Abbasi1, Qiu Yan6, Jiwei Liu1
1Department of Oncology, The First Affiliated Hospital of Dalian Medical University, 116011, Dalian, China
2Department of Hepatobiliary Surgery, The First Affiliated Hospital of Dalian Medical University, 116011, Dalian, China
3City College, Zhejiang University, 310000, Hangzhou, China
4Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, 116011, Dalian, China
5Department of Thoracic Surgery, Zhejiang Cancer Hospital, 310000, Hangzhou, China
6Department of Biochemistry and Molecular Biology, Dalian Medical University, 116011, Dalian, China
*These authors contributed equally to this work
Jiwei Liu, email: firstname.lastname@example.org
Qiu Yan, email: email@example.com
Keywords: tumor-associated macrophages, Ezrin, epithelial-mesenchymal transition, FUT4, LeY
Received: August 24, 2016 Accepted: February 27, 2017 Published: March 08, 2017
Tumor-associated macrophages (TAMs) are key components of tumor microenvironment (TME) during tumorigenesis and progression. However, the role of TAMs in lung adenocarcinoma is still unclear. In this study, we aimed to clarify the mechanism underlying the crosstalk between TAMs and epithelial-mesenchymal transition (EMT) of lung adenocarcinoma. Fucosyltransferase IV (FUT4) and its synthetic cancer sugar antigen Lewis Y (LeY) was aberrantly elevated in various solid tumors, it plays critical role in the invasion and metastasis. Here, we found that in lung adenocarcinoma samples, the density of TAMs correlates with E-cadherin level and LeY level. In vitro assays, M2 macrophages promoted FUT4/LeY expression through the transforming growth factor-β1(TGF-β1)/Smad2/3 signaling pathway. FUT4/LeY was indispensable in M2 macrophages-mediated cytoskeletal remodeling and EMT. Furthermore, fucosylation of Ezrin mediated by FUT4/LeY can promote the phosphorylation of Ezrin, which was the critical mechanism of M2 macrophages-induced EMT. In vivo assays confirmed that M2 macrophages promoted EMT through the up-regulation of LeY and phosphorylated Ezrin. Together, our results revealed that TAMs promote Ezrin phosphorylation-mediated EMT in lung adenocarcinoma through FUT4/LeY- mediated fucosylation. Targeting this newly identified signaling may offer new possibilities for immunotherapy in lung adenocarcinoma.
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