title: Hypoxia Induces Epithelial-Mesenchymal Transition in Follicular Thyroid Cancer: Involvement of Regulation of Twist by Hypoxia Inducible Factor-1α.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Yeon Ju
authors.initials: YJ
authors.lastname: Yang
authors.affiliation: Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hwi Jung
authors.initials: HJ
authors.lastname: Na
authors.affiliation: Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Suh
authors.affiliation: Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Myung Jin
authors.initials: MJ
authors.lastname: Ban
authors.affiliation: Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hyung Kwon
authors.initials: HK
authors.lastname: Byeon
authors.affiliation: Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Won Shik
authors.initials: WS
authors.lastname: Kim
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Soonchunhyang University College of Medicine, Seoul, Korea.
authors.forename: Jae Wook
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Eun Chang
authors.initials: EC
authors.lastname: Choi
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hyeong Ju
authors.initials: HJ
authors.lastname: Kwon
authors.affiliation: Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Korea. strive1005@yuhs.ac.
authors.forename: Jae Won
authors.initials: JW
authors.lastname: Chang
authors.affiliation: Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Korea. ywkohent@yuhs.ac.
authors.forename: Yoon Woo
authors.initials: YW
authors.lastname: Koh
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D000860:Hypoxia / Q000235:genetics*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D008222:Lymphokines; D051379:Mice; D009361:Neoplasm Invasiveness; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D051879:Twist-Related Protein 1 / Q000235:genetics* / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
chemical_list: D015820:Cadherins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines; D051879:Twist-Related Protein 1; D014746:Vimentin; C043874:tumor migration inhibition factor
keywords: Hypoxia; Twist; epithelial-mesenchymal transition; follicular thyroid cancer; hypoxia inducible factor-1α; orthotopic thyroid cancer model