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The transcription factor ZFHX3 is crucial for the angiogenic function of hypoxia-inducible factor 1α in liver cancer cells.

J Biol Chem. 2020 May 15;295(20):7060-7074. Epub 2020 Apr 10
Changying Fu 1 , Na An 1 , Jinming Liu 2 , Jun A 1 , Baotong Zhang 3 , Mingcheng Liu 1 , Zhiqian Zhang 1 , Liya Fu 2 , Xinxin Tian 1 , Dan Wang 1 , Jin-Tang Dong 4
Changying Fu 1 , Na An 1 , Jinming Liu 2 , Jun A 1 , Baotong Zhang 3 , Mingcheng Liu 1 , Zhiqian Zhang 1 , Liya Fu 2 , Xinxin Tian 1 , Dan Wang 1 , Jin-Tang Dong 4
+ et al

[No authors listed]

Author information
  • 1 School of Medicine, Southern University of Science and Technology, 1088 Xueyuan Road, Shenzhen, Guangdong 518055, China.
  • 2 Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, China.
  • 3 Winship Cancer Institute, Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia 30322.
  • 4 School of Medicine, Southern University of Science and Technology, 1088 Xueyuan Road, Shenzhen, Guangdong 518055, China dongjt@sustech.edu.cn.

摘要


Angiogenesis is a hallmark of tumorigenesis, and hepatocellular carcinoma (HCC) is hypervascular and therefore very dependent on angiogenesis for tumor development and progression. Findings from previous studies suggest that in HCC cells, hypoxia-induced factor 1α (HIF1A) and zinc finger homeobox 3 (ZFHX3) transcription factors functionally interact in the regulation of genes in HCC cells. Here, we report that hypoxia increases the transcription of the ZFHX3 gene and enhances the binding of HIF1A to the ZFHX3 promoter in the HCC cell lines HepG2 and Huh-7. Moreover, ZFHX3, in turn, physically associated with and was functionally indispensable for HIF1A to exert its angiogenic activity, as indicated by in vitro migration and tube formation assays of human umbilical vein endothelial cells (HUVECs) and microvessel formation in xenograft tumors of HCC cells. Mechanistically, ZFHX3 was required for HIF1A to transcriptionally activate the vascular endothelial growth factor A (VEGFA) gene by binding to its promoter. Functionally, down-regulation of ZFHX3 in HCC cells slowed their tumor growth, and addition of VEGFA to conditioned medium from ZFHX3-silenced HCC cells partially rescued the inhibitory effect of this medium on HUVEC tube formation. In human HCC, ZFHX3 expression was up-regulated, and this up-regulation correlated with both HIF1A up-regulation and worse patient survival, confirming a functional association between ZFHX3 and HIF1A in human HCC. We conclude that ZFHX3 is an angiogenic transcription factor that is integral to the HIF1A/VEGFA signaling axis in HCC cells.

KEYWORDS: Hepatocellular carcinoma cells, ZFHX3, angiogenesis, gene regulation, gene silencing, hypoxia, hypoxia-inducible factor (HIF), liver cancer, transcription factor, transcription regulation, vascular endothelial growth factor (VEGF)