Research Papers:

Glypican-5 suppresses Epithelial-Mesenchymal Transition of the lung adenocarcinoma by competitively binding to Wnt3a

Siwei Wang, Mantang Qiu, Wenjia Xia, Youtao Xu, Qixing Mao, Jie Wang, Gaochao Dong, Lin Xu, Xin Yang _ and Rong Yin

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Oncotarget. 2016; 7:79736-79746. https://doi.org/10.18632/oncotarget.12945

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Siwei Wang1,2,*, Mantang Qiu1,2,*, Wenjia Xia1,2,*, Youtao Xu1, Qixing Mao1,2, Jie Wang1, Gaochao Dong1, Lin Xu1, Xin Yang3, Rong Yin1

1Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Jiangsu Biobank of Clinical Resources, Cancer Institute of Jiangsu Province, Nanjing 210009, China

2The Fourth Clinical College of Nanjing Medical University, Nanjing, 210000, China

3Department of Oncology, The Third Hospital of Soochow University, Changzhou, 213003, China

*These authors have contributed equally to this work

Correspondence to:

Xin Yang, email: yangxindoctor@163.com

Rong Yin, email: yinhero001@126.com

Keywords: Glypican-5 (GPC5), lung adenocarcinoma (LAC), Epithelial-Mesenchymal Transition (EMT), Wnt/β-catenin signaling pathway

Received: June 30, 2016    Accepted: October 14, 2016    Published: October 27, 2016


We previously demonstrated that Glypican-5 (GPC5), one of the members of heparan sulfate proteoglycan, was a novel tumor metastasis suppressor in lung adenocarcinoma (LAC). However, it remains unclear how GPC5 suppresses lung cancer metastasis. Here, we found over-expression GPC5 induced significant Epithelial-Mesenchymal Transition (EMT) process of A549 cells in vitro. Bioinformatic analysis of RNA sequencing data indicated that GPC5 was co-expressed with EMT related markers, E-cadherin and Vimentin. Wnt/β-catenin signaling pathway was also significantly enriched after overexpressing GPC5. Further in vitro experiments demonstrated that overexpressing GPC5 could block the translocation of β-catenin from cytoplasm to nucleus and therefore inactivate the Wnt/β-catenin signaling pathway by competitively binding to Wnt3a. Subsequent rescue experiments demonstrated that GPC5-induced metastatic phenotype and EMT process suppression were significantly reversed when cells cultured in Wnt3a conditioned media. By establishing the metastatic model in severe combined immune deficiency (SCID) mice, we also demonstrated that overexpressing GPC5 suppressed LAC migration and accordingly alerted EMT related markers, which including up-regulated E-cadherin and down-regulated Vimentin in both lung and liver metastasis. Finally, clinical samples of LAC further validated that GPC5 expression was positively correlated with E-cadherin, and negatively correlated with both Twist1 and MMP2. Taken together, these data suggested that GPC5 is able to suppress the LAC metastasis by competitively binding to Wnt3a and inactivating the Wnt/β-catenin signaling pathway. Our findings expanded the role and the molecular mechanism of GPC5 on malignant bionomics of LAC.

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