Transcriptional up-regulation of RhoE by hypoxia-inducible factor (HIF)-1 promotes epithelial to mesenchymal transition of gastric cancer cells during hypoxia

被引：67

作者：

Zhou, Jinfeng ^{[1
,2
]}

Li, Kai ^{[1
,2
]}

Gu, Yong ^{[1
,2
]}

Feng, Bin ^{[1
,2
]}

Ren, Gui ^{[1
,2
]}

Zhang, Liyun ^{[1
,2
]}

Wang, Yafang ^{[1
,2
]}

Nie, Yongzhan ^{[1
,2
]}

Fan, Daiming ^{[1
,2
]}

机构：

[1] Fourth Mil Med Univ, State Key Lab Canc Biol, 15 Changle Western Rd, Xian 710032, Peoples R China

[2] Fourth Mil Med Univ, Xijing Hosp Digest Dis, Xian 710032, Peoples R China

来源：

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS | 2011年 / 415卷 / 02期

基金：

中国国家自然科学基金;

关键词：

Hypoxia; Gastric cancer; RhoE; HIF-1; alpha; EMT; Invasion; TUMOR; MIGRATION; HIF-1; PROGRESSION; METASTASIS; APOPTOSIS; MELANOMA; TENSION; GROWTH;

D O I：

10.1016/j.bbrc.2011.10.065

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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)-1 alpha induction, and that HIF-1 alpha a 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-1 alpha 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 upregulation 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. (C) 2011 Elsevier Inc. All rights reserved.

引用

页码：348 / 354

页数：7

共 27 条

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