Abstract
BackgroundTo investigate the influence of fibroblast activation protein alpha (FAP) derived from cancer-associated fibroblasts (CAFs), as well as potential mechanism of epithelial mesenchymal transition (EMT), on gastric cancer (GC) progression.MethodsCorrelation between CAFs-derived FAP and clinical results has been studied by using 60 GC cases. To confirm this relationship, SGC7901 cells were co-cultured with pre-established FAP-overexpressed fibroblasts in vitro and the characteristics including proliferation, migration, invasion and apoptosis abilities were detected subsequently. Meanwhile, SGC and GES1 cells cocultured with FAP-overexpressed fibroblasts were treated with cis-platinum for apoptotic analysis. The underlying EMT was detected by analyzing expression level of E-cadherin, ZO-1, N-cadherin, Vimentin, α-SMA, DKK1 and LEF-1 through western blot and immunofluorescence staining assay. Finally, the tumor-promoting ability of FAP was investigated by utlizing a xenograft gastric cancer nude mouse model.ResultsIt show that FAP has a high-risk correlation with the malignant level of clinical outcomes in GC patients. FAP promotes the ability of proliferation, migration, invasion, apoptosis-inhibition of SGC7901 cells and induces apoptosis of GES1 cells in vitro. The mechanism study shows that epithelial markers have been down-regulated and mesenchymal markers and Wnt/β-catenin signal pathway related proteins have been up-regulated. Animal assay suggests that tumor burden has been enhanced by FAP significantly in vivo.ConclusionsStromal FAP could be a potential prognostic biomarker in GC by promoting cancer progression via EMT through Wnt/ β-catenin signal pathway.
Highlights
To investigate the influence of fibroblast activation protein alpha (FAP) derived from cancer-associated fibroblasts (CAFs), as well as potential mechanism of epithelial mesenchymal transition (EMT), on gastric cancer (GC) progression
We described the tumor promoting functions of stromal FAP, which might account for GC progression
FAP was mainly expressed in cancer cells or CAFs (Fig. 1a, b)
Summary
To investigate the influence of fibroblast activation protein alpha (FAP) derived from cancer-associated fibroblasts (CAFs), as well as potential mechanism of epithelial mesenchymal transition (EMT), on gastric cancer (GC) progression. Gastric cancer (GC) remains the fourth most common cancer and the fifth leading cause of cancer-related mortality worldwide [1, 2]. The underlying mechanisms of GC PC has been a worldwide research hotspot, and more efforts were focused on the dynamic and complex PC progression. Cancer associated fibroblasts (CAFs) act as key orchestrators in TME by directly protecting cancer cells from host immune attacks, and promoting cancer progression by complex mechanisms, for instance epithelial-mesenchymal transition (EMT) [10, 11]. Whether EMT could partly explain the cross talk between GC cells and stromal CAFs required further studies [12]
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