Abstract
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.
Highlights
In recent years, lung cancer rates and deaths are increasing dramatically around the world
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)
GPC5 mRNA expression is correlated with lung adenocarcinoma (LAC) lymphatic metastasis
Summary
Lung cancer rates and deaths are increasing dramatically around the world. According to the reports in 2014, the overall rate of incidence of lung cancer is still high and lung cancer is the most common cause of cancer death [1]. Lung adenocarcinoma (lung adenocarcinoma, LAC) and squamous cell carcinoma (squamous cell carcinoma, SCC) are the two main pathological types of non-small cell lung cancer (NSCLC). According to the world health organization (WHO), due to increasing national tobacco control and variation of the environment pollutants, the incidence of lung cancer of different pathological types is quietly changing. The incidence of LAC (31.5%) has gradually exceeded SCC (29.4%), and it presents rapid growth www.impactjournals.com/oncotarget trend [2]. The trend is more obvious in China (LAC vs SCC: 52% vs 33%) [3]
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