HIF-1α induces the epithelial-mesenchymal transition in gastric cancer stem cells through the Snail pathway
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Shi-wei Yang1,*, Zhi-gang Zhang1,*, Ying-xue Hao1, Yong-liang Zhao1, Feng Qian1, Yan Shi1, Ping-ang Li1, Chun-yang Liu1, Pei-wu Yu1
1Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
*These authors contributed equally to this work
Pei-Wu Yu, email: [email protected]
Ying-xue Hao, email: [email protected]
Keywords: cancer stem cells (CSCs), epithelial–mesenchymal transition (EMT), hypoxia inducible factor-1α (HIF-1α), Snail
Received: March 09, 2016 Accepted: December 16, 2016 Published: January 04, 2017
Substantial evidence suggests that the epithelial-mesenchymal transition (EMT) phenotype is associated with the invasive characteristics of cancer stem cells (CSCs),which possess an EMT phenotype that may predominate in tumor invasion and metastasis. However, the mechanisms for the generation and regulation of these CSCs have not been clearly defined. As hypoxia and EMT-related factors may have important functions in EMT-like CSCs, the aim of this study was to investigate the effects of hypoxia on these cells. CSCs were established from the gastric cancer cell lines MGC-803 and SGC7901, and the relationship between hypoxia and EMT-like CSCs was investigated in gastric cancer. After hypoxia treatment, some gastric CSCs exhibited a marked increase in hypoxia-inducible factor-1α (HIF-1α)expression and increased migration and invasion capabilities compared with the normoxic control. These CSCs were defined by activation of the mesenchymal cell marker Vimentin and by inhibition of the epithelial cell marker E-cadherin. Our analyses also show that HIF-1α was responsible for activating EMT via increased expression of the transcription factor Snail in gastric CSCs. Moreover, inhibition of Snail by shRNA reduced HIF-1α-induced EMT in gastric CSCs. The results demonstrated that hypoxia-induced EMT-like CSCs rely on HIF-1αto activate Snail, which may result in recurrence and metastasis of gastric cancer.
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