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A new key player in VEGF-dependent angiogenesis in human hepatocellular
carcinoma: dimethylarginine dimethylaminohydrolase 1
#MMPMID28741166
Buijs N
; Oosterink JE
; Jessup M
; Schierbeek H
; Stolz DB
; Houdijk AP
; Geller DA
; van Leeuwen PA
Angiogenesis
2017[Nov]; 20
(4
): 557-565
PMID28741166
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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.
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