Abstract
BackgroundGastric cancer (GC) is one of the most common cancers and the third leading cause of cancer related mortality worldwide. The 5-year survival rate is rather low owing to advanced unresectable and distant metastasis. The EMT has been widely implicated in the stemness, metastatic dormancy, and chemoresistance of different solid tumors. Given the fact that activating transcription factor-3 (ATF3) is a member of the ATF/CREB family of transcription factors and its role in regulation of GC recurrence and metastasis remain poorly understood, the aim of the present study was to investigate its potential impact in epithelial–mesenchymal transition (EMT) and cancer stem cell (CSC) properties and GC aggression.MethodsTo elucidate the potential role of ATF3 in gastric cancer, we utilized SGC-7901 and MGC-803 gastric cancer cell lines as research models and constructed stable cell lines overexpressing ATF3. We conducted a series of assays including cell proliferation, colony formation, cell migration, tumorsphere formation, and invasion to investigate the functional roles of ATF3 in stemness of gastric cancer. The possible effect of ATF3 on epithelial–mesenchymal transition (EMT) was assessed through flow cytometry and qRT-PCR. In vivo functional effect of upregulation of ATF3 on tumor growth was examined in a mouse xenograft model.ResultsWe found that overexpression of ATF3 inhibited cell proliferation, colony formation, cell migration and invasion. In addition, up-regulation of ATF3 attenuated tumorsphere formation, cell stemness, and potentially decreased expression of EMT markers. Moreover, ATF3 overexpression inhibited tumorigenesis in mouse xenograft model.ConclusionOur data suggest a suppressive role of ATF3 in gastric cancer development. Our findings will provide a potential therapeutic strategy and novel drug target for gastric cancer.
Highlights
Gastric cancer (GC) is one of the most common cancers and the third leading cause of cancer related mortality worldwide
Exogenous activating transcription factor-3 (ATF3) expression decreases cell proliferation in gastric cancer cells To assess the effect of ATF3 overexpression, we examined cell proliferation for the stable cell lines of both SGC7901 and MGC-803
As shown in the stained plates, overexpression of ATF3 remarkably reduced the quantity and colony size of SGC-7901 and MGC-803 stable cells (Fig. 2c, d). These findings indicated that ATF3 plays a negative role in the gastric cancer cell proliferation
Summary
Gastric cancer (GC) is one of the most common cancers and the third leading cause of cancer related mortality worldwide. The EMT has been widely implicated in the stemness, metastatic dormancy, and chemoresistance of different solid tumors. Given the fact that activating transcription factor-3 (ATF3) is a member of the ATF/CREB family of transcription factors and its role in regulation of GC recurrence and metastasis remain poorly understood, the aim of the present study was to investigate its potential impact in epithelial–mesenchymal transition (EMT) and cancer stem cell (CSC) properties and GC aggression. Accumulating evidence suggests that the EMT has been widely implicated in the stemness, metastatic dormancy, and chemoresistance of different solid tumors [6]. Hyperproliferative capacity and overproduction of gastric tumor cells are likely closely related to EMT and tumor stemness [12, 13], data about identification of molecular markers pertinent to pathogenic process and potential therapy are largely lacking
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