Journal
FRONTIERS IN PHARMACOLOGY
Volume 12, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2021.755394
Keywords
angiogenesis; hepatocellular carcinoma; hypoxia; HIF-1 alpha; IL-8
Categories
Funding
- National Natural Science Foundation of China [82074203, 81774077, 82030117]
- Scientific Research Project of Science and Technology Commission of Shanghai Municipality [18401901400]
- Changhai Hospital [2019QNA11]
- Talent Training Plan of Baoshan Hospital of Integrated Traditional Chinese and Western Medicine
Ask authors/readers for more resources
This study found that ursodeoxycholic acid (UDCA) can inhibit hypoxic hepatocellular carcinoma (HCC) cell-induced angiogenesis by suppressing HIF-1 alpha/VEGF/IL-8-mediated intercellular signaling.
Background: A hypoxic microenvironment may induce angiogenesis and promote the development of hepatocellular carcinoma (HCC). The aim of this study was to evaluate whether ursodeoxycholic acid (UDCA) may inhibit hypoxic HCC cell-induced angiogenesis and the possible mechanisms.Methods: Tube formation and matrigel plug angiogenesis assays were used to evaluate angiogenesis in vitro and in vivo, respectively. Real-time PCR, enzyme-linked immunosorbent assay, and Western blot were used to evaluate the mRNA and protein expressions of hypoxia-inducible factor-1 alpha (HIF-1 alpha), vascular endothelial growth factor (VEGF), and IL-8, respectively. Dual-luciferase reporter assay was applied to assess the reporter gene expression of hypoxia-response element (HRE).Results: UDCA antagonized hypoxic Huh 7 cell-induced tube formation of EA.hy 926 cells. In HCC cells, UDCA inhibited hypoxia-induced upregulation of VEGF and IL-8 both in mRNA and protein levels. UDCA also inhibited IL-8-induced angiogenesis in vitro and in vivo through suppressing IL-8-induced phosphorylation of ERK. The levels of HIF-1 alpha mRNA and protein and HRE-driven luciferase activity in HCC cells were upregulated by hypoxia and were all inhibited by UDCA. The proteasome inhibitor MG132 antagonized the effect of UDCA on HIF-1 alpha degradation. In hypoxic condition, the phosphorylation of ERK and AKT was obviously increased in HCC cells, which was suppressed by UDCA. Transfection of the HIF-1 alpha overexpression plasmid reversed the effects of UDCA on hypoxic HCC cell-induced angiogenesis, HRE activity, and expressions of IL-8 and VEGF.Conclusions: Our results demonstrated that UDCA could inhibit hypoxic HCC cell-induced angiogenesis through suppressing HIF-1 alpha/VEGF/IL-8-mediated intercellular signaling between HCC cells and endothelial cells.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available