Glypican-5 suppresses Epithelial-Mesenchymal Transition of the lung adenocarcinoma by competitively binding to Wnt3a.
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.
Department 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.|The Fourth Clinical College of Nanjing Medical University, Nanjing, 210000, China.
Siwei
S
Wang
Department 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.|The Fourth Clinical College of Nanjing Medical University, Nanjing, 210000, China.
Mantang
M
Qiu
Department 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.|The Fourth Clinical College of Nanjing Medical University, Nanjing, 210000, China.
Wenjia
W
Xia
Department 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.
Youtao
Y
Xu
Department 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.|The Fourth Clinical College of Nanjing Medical University, Nanjing, 210000, China.
Qixing
Q
Mao
Department 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.
Jie
J
Wang
Department 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.
Gaochao
G
Dong
Department 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.
Lin
L
Xu
Department of Oncology, The Third Hospital of Soochow University, Changzhou, 213003, China.
Xin
X
Yang
Department 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.
Rong
R
Yin
D000072283:A549 Cells; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D000077192:Adenocarcinoma of Lung; D000818:Animals; D015703:Antigens, CD; D001667:Binding, Competitive; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement; D019295:Computational Biology; D030541:Databases, Genetic; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D053673:Glypicans / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008207:Lymphatic Metastasis; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism; D014746:Vimentin / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway; D060509:Wnt3A Protein / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D015703:Antigens, CD; C513384:CDH1 protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; C106228:GPC5 protein, human; D053673:Glypicans; D012097:Repressor Proteins; C486274:TWIST2 protein, human; D051879:Twist-Related Protein 1; D014746:Vimentin; C555510:WNT3A protein, human; D060509:Wnt3A Protein; D051176:beta Catenin; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2
Epithelial-Mesenchymal Transition (EMT); Glypican-5 (GPC5); Wnt/β-catenin signaling pathway; lung adenocarcinoma (LAC)