Abstract
Rho GDP dissociation inhibitor 2 (RhoGDI2) expression correlates with tumor growth, metastasis, and chemoresistance in gastric cancer. Here, we show that RhoGDI2 functions in the epithelial-mesenchymal transition (EMT), which is responsible for invasiveness during tumor progression. This tumorigenic activity is associated with repression of E-cadherin by RhoGDI2 via upregulation of Snail. Overexpression of RhoGDI2 induced phenotypic changes consistent with EMT in gastric cancer cells, including abnormal epithelial cell morphology, fibroblast-like properties, and reduced intercellular adhesion. RhoGDI2 overexpression also resulted in decreased expression of the epithelial markers E-cadherin and β-catenin and increased expression of the mesenchymal markers vimentin and fibronectin. Importantly, RhoGDI2 overexpression also stimulated the expression of Snail, a repressor of E-cadherin and inducer of EMT, but not other family members such as Slug or Twist. RNA interference-mediated knockdown of Snail expression suppressed RhoGDI2-induced EMT and invasion, confirming that the effect was Snail-specific. These results indicate that RhoGDI2 plays a critical role in tumor progression in gastric cancer through induction of EMT. Targeting RhoGDI2 may thus be a useful strategy to inhibit gastric cancer cell invasion and metastasis.
Highlights
Though incidence and mortality of gastric cancer have steadily declined in recent decades, it remains the fourth most common type of cancer and the second leading cause of cancer mortality worldwide [1]
Immunofluorescence analysis revealed less E-cadherin staining in the cell membrane region and a higher level of vimentin staining in the cytoplasmic region in Rho GDP dissociation inhibitor 2 (RhoGDI2)-overexpressing SNU-484 cells (Fig. 1C)
These results suggest that RhoGDI2 acts as a positive regulator of epithelial-mesenchymal transition (EMT) in gastric cancer cells
Summary
Though incidence and mortality of gastric cancer have steadily declined in recent decades, it remains the fourth most common type of cancer and the second leading cause of cancer mortality worldwide [1]. RhoGDI2 mRNA expression is significantly higher in ovarian adenocarcinomas than in benign adenomas [9] Consistent with this finding, RhoGDI2 is overexpressed in human breast cancer cell lines, and it increases cancer cell invasiveness and motility in vitro [10]. We have shown that RhoGDI2 expression is positively correlated with tumor progression and metastatic potential in gastric cancer [11]. The zinc finger transcription factors of the Snail family have been implicated in this repression [16,17,18] These important EMT drivers, which have a central role in the biological significance to EMT activation, are shown to correlate significantly with poor clinical prognosis in various types of cancers [19,20,21,22]. We present evidence suggesting that this tumorigenic activity is associated with the ability of RhoGDI2 to repress E-cadherin via upregulation of Snail expression
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