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.
State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Number 15, Changle Western Road, Xi'an, China.
Jinfeng
J
Zhou
Kai
K
Li
Yong
Y
Gu
Bin
B
Feng
Gui
G
Ren
Liyun
L
Zhang
Yafang
Y
Wang
Yongzhan
Y
Nie
Daiming
D
Fan
D001483:Base Sequence; D015687:Cell Hypoxia; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008969:Molecular Sequence Data; D034741:RNA, Small Interfering / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology*; D014158:Transcription, Genetic; D020741:rho GTP-Binding Proteins / Q000235:genetics*
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C508705:RND3 protein, human; D020741:rho GTP-Binding Proteins