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Angiogenesis. 2017 Nov;20(4):557-565. doi: 10.1007/s10456-017-9567-4. Epub 2017 Jul 24.

A new key player in VEGF-dependent angiogenesis in human hepatocellular carcinoma: dimethylarginine dimethylaminohydrolase 1.

Author information

1
Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. n.buijs@vumc.nl.
2
Department of Surgery, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, The Netherlands. n.buijs@vumc.nl.
3
Department of Surgery, Medical Center Alkmaar, Trial Center Holland Health, Alkmaar, The Netherlands. n.buijs@vumc.nl.
4
Department of Pediatrics, Academic Medical Center, Emma Children's Hospital, Amsterdam, The Netherlands.
5
Department of Cell Biology and Physiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
6
Department of Surgery, Medical Center Alkmaar, Trial Center Holland Health, Alkmaar, The Netherlands.
7
Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
8
Department of Surgery, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, The Netherlands.

Abstract

BACKGROUND:

Anti-angiogenic therapies, targeting VEGF, are a promising treatment for hepatocellular carcinoma (HCC). To enhance this potential therapy, identification of novel targets in this pathway is of major interest. Nitric oxide (NO) plays a crucial role in VEGF-dependent angiogenesis. NO production depends on arginine as substrate and asymmetric dimethylarginine (ADMA) as inhibitor. Dimethylarginine dimethylaminohydrolase 1 (DDAH-1) catabolizes ADMA and therefore regulates NO and VEGF expression. This study unravels additional mechanisms to improve VEGF targeting therapies.

METHODS:

The expression of DDAH-1 was examined in HCC specimen and non-tumorous background liver of 20 patients undergoing liver resection. Subsequently, arginine/ADMA balance, NO production, and VEGF expression were analyzed. The influence of hypoxia on DDAH-1 and angiogenesis promoting factors was evaluated in HepG2 cells and primary human hepatocytes.

RESULTS:

DDAH-1 expression was significantly induced in primary HCC tumors compared to non-tumorous background liver. This was associated with an increased arginine/ADMA ratio, higher NO formation, and higher VEGF expression in human HCC compared to non-tumorous liver. Hypoxia induced DDAH-1, iNOS, and VEGF expression in a time-dependent manner in HepG2 cells.

CONCLUSIONS:

Our results indicate that DDAH-1 expression is increased in human HCC, which is associated with an increase in the arginine/ADMA ratio and enhanced NO formation. Hypoxia may be an initiating factor for the increase in DDAH-1 expression. DDAH-1 expression is associated with promotion of angiogenesis stimulating factor VEGF. Together, our findings for the first time identified DDAH-1 as a key player in the regulation of angiogenesis in human HCC, and by understanding this mechanism, future therapeutic strategies targeting VEGF can be improved.

KEYWORDS:

Angiogenesis; Arginine; Asymmetric dimethylarginine; Dimethylarginine dimethylaminohydrolase; Hepatocellular carcinoma; Hypoxia; Nitric oxide; VEGF

PMID:
28741166
PMCID:
PMC5660142
DOI:
10.1007/s10456-017-9567-4
[Indexed for MEDLINE]
Free PMC Article

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