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Hypoxia Induces Epithelial-Mesenchymal Transition in Follicular Thyroid Cancer: Involvement of Regulation of Twist by Hypoxia Inducible Factor-1α

 Yeon Ju Yang  ;  Hwi Jung Na  ;  Michelle J. Suh  ;  Myung Jin Ban  ;  Hyung Kwon Byeon  ;  Won Shik Kim  ;  Jae Wook Kim  ;  Eun Chang Choi  ;  Hyeong Ju Kwon  ;  Jae Won Chang  ;  Yoon Woo Koh 
 YONSEI MEDICAL JOURNAL, Vol.56(6) : 1503-1514, 2015 
Journal Title
Issue Date
Adenocarcinoma, Follicular/genetics* ; Adenocarcinoma, Follicular/metabolism ; Animals ; Cadherins/genetics ; Epithelial-Mesenchymal Transition/genetics* ; Gene Expression Regulation, Neoplastic ; Hypoxia/genetics* ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics* ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Lymphokines ; Mice ; Neoplasm Invasiveness ; Phenotype ; Real-Time Polymerase Chain Reaction ; Signal Transduction/drug effects ; Thyroid Neoplasms/genetics* ; Thyroid Neoplasms/metabolism ; Transcriptional Activation ; Twist-Related Protein 1/genetics* ; Twist-Related Protein 1/metabolism ; Vimentin/metabolism
Hypoxia ; hypoxia inducible factor-1α ; epithelial-mesenchymal transition ; Twist ; orthotopic thyroid cancer model ; follicular thyroid cancer
PURPOSE: Although follicular thyroid cancer (FTC) has a relatively fair prognosis, distant metastasis sometimes results in poor prognosis and survival. There is little understanding of the mechanisms contributing to the aggressiveness potential of thyroid cancer. We showed that hypoxia inducible factor-1α (HIF-1α) induced aggressiveness in FTC cells and identified the underlying mechanism of the HIF-1α-induced invasive characteristics. MATERIALS AND METHODS: Cells were cultured under controlled hypoxic environments (1% O₂) or normoxic conditions. The effect of hypoxia on HIF-1α, and epithelial-to-mesenchymal transition (EMT) related markers were evaluated by quantitative real-time PCR, Western blot analysis and immunocytochemistry. Invasion and wound healing assay were conducted to identify functional character of EMT. The involvement of HIF-1α and Twist in EMT were studied using gene overexpression or silencing. After orthotopic nude mouse model was established using the cells transfected with lentiviral shHIF-1α, tissue analysis was done. RESULTS: Hypoxia induces HIF-1α expression and EMT, including typical morphologic changes, cadherin shift, and increased vimentin expression. We showed that overexpression of HIF-1α via transfection resulted in the aforementioned changes without hypoxia, and repression of HIF-1α with RNA interference suppressed hypoxia-induced HIF-1α and EMT. Furthermore, we also observed that Twist expression was regulated by HIF-1α. These were confirmed in the orthotopic FTC model. CONCLUSION: Hypoxia induced HIF-1α, which in turn induced EMT, resulting in the increased capacity for invasion and migration of cells via regulation of the Twist signal pathway in FTC cells. These findings provide insight into a possible therapeutic strategy to prevent invasive and metastatic FTC.
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1. College of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
Kho, Yoon Woo(고윤우)
Kim, Won Shik(김원식)
Na, Hwi Jung(나휘정)
Ban, Myung Jin(반명진)
Byeon, Hyung Kwon(변형권)
Choi, Eun Chang(최은창)
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