HIFs enhance the migratory and neoplastic capacities of hepatocellular carcinoma cells by promoting EMT.
Hepatocellular carcinoma (HCC) is one of the most fatal cancers. Although the involvement of the epithelial-to-mesenchymal transition (EMT) in HCC progression is established, the mechanisms modulating this phenomenon remain unclear. Here, we demonstrate that hypoxia-inducible factors (HIFs), HIF-1α and HIF-2α, modulate the EMT through Twist1, a regulator of the EMT. The levels of HIF-1α and HIF-2α in HCC tissues were higher than those in matched, non-tumor surrounding tissues. In HCC samples, the levels of HIF-1α and HIF-2α negatively correlated with the levels of E-cadherin but positively correlated with the levels of vimentin. In highly metastatic MHCC97H cells, the levels of HIF-1α, HIF-2α, and Twist1 were higher than those in weakly metastatic HepG2 cells. In HepG2 cells, over-expression of HIFs enhanced levels of Twist1 and the EMT, which elevated the migratory and neoplastic capacities of cells. For MHCC97H cells, inhibition of HIFs reduced Twist1 levels and the EMT, which reduced their migratory and neoplastic capacity. Thus, the promotion of EMT by HIFs via Twist1 enhanced the migration and neoplastic capacities of HCC cells.
The First Clinic Medical College, Nanjing Medical University, Nanjing, 210011, Jiangsu, People's Republic of China.
Yang
Y
Liu
Yawei
Y
Liu
Xiaolu
X
Yan
Yuan
Y
Xu
Fei
F
Luo
Jing
J
Ye
Han
H
Yan
Xiaojun
X
Yang
Xiaodan
X
Huang
Jianping
J
Zhang
Guozhong
G
Ji
D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D002465:Cell Movement; D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition; D018398:Homeodomain Proteins / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D008113:Liver Neoplasms / Q000473:pathology*; D009687:Nuclear Proteins / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology; D051879:Twist-Related Protein 1 / Q000502:physiology; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000099162:Endothelial PAS Domain-Containing Protein 1; C103173:TWIST1 protein, human; C486307:ZEB1 protein, human