Transcriptional Up-regulation of RhoE by Hypoxia-inducible Factor (HIF)-1 Promotes Epithelial to Mesenchymal Transition of Gastric Cancer Cells During Hypoxia

Epithelial-mesenchymal transition (EMT) is a key process that drives cancer invasion. Recently, hypoxia has been reported to induce EMT, accompanied by cytoskeleton remodeling. As RhoE is a key regulator in cytoskeleton formation, we hypothesized that RhoE may play a role in hypoxia-induced EMT. For the first time, we report that RhoE protein levels increase in gastric cancer cells under hypoxic conditions. Rigorous analysis revealed that RhoE up-regulation is at the transcriptional levels and requires hypoxia-inducible factor (HIF)-1α induction, and that HIF-1α binds a hypoxia-responsive element (HRE) on the RhoE promoter. Additionally, we discovered that hypoxia or overexpression of RhoE in normoxia up-regulates the mesenchymal marker Vimentin, down-regulates the epithelial marker E-cadherin, and significantly increases cell invasion in vitro. Silencing of HIF-1α or RhoE by specific siRNAs rescued these hypoxia-induced effects. Ectopic expression of RhoE also induced up-regulation of MMP2/MMP-9 in gastric cancer cells. This study identifies RhoE as a direct target for HIF-1 in gastric cancer cells. In addition, RhoE up-regulation represents a pivotal cellular adaptive response to hypoxia with implications in gastric cancer cell EMT and invasion. We propose that RhoE-targeted therapy might inhibit the high invasive potential of gastric cancer cells in hypoxic regions.