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http://purl.uniprot.org/citations/28741166http://www.w3.org/2000/01/rdf-schema#comment"

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."xsd:string
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http://purl.uniprot.org/citations/28741166http://purl.uniprot.org/core/author"Stolz D.B."xsd:string
http://purl.uniprot.org/citations/28741166http://purl.uniprot.org/core/author"Geller D.A."xsd:string
http://purl.uniprot.org/citations/28741166http://purl.uniprot.org/core/author"van Leeuwen P.A."xsd:string
http://purl.uniprot.org/citations/28741166http://purl.uniprot.org/core/author"Schierbeek H."xsd:string
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http://purl.uniprot.org/citations/28741166http://purl.uniprot.org/core/author"Houdijk A.P."xsd:string
http://purl.uniprot.org/citations/28741166http://purl.uniprot.org/core/author"Jessup M."xsd:string
http://purl.uniprot.org/citations/28741166http://purl.uniprot.org/core/author"Oosterink J.E."xsd:string
http://purl.uniprot.org/citations/28741166http://purl.uniprot.org/core/date"2017"xsd:gYear
http://purl.uniprot.org/citations/28741166http://purl.uniprot.org/core/name"Angiogenesis"xsd:string
http://purl.uniprot.org/citations/28741166http://purl.uniprot.org/core/pages"557-565"xsd:string
http://purl.uniprot.org/citations/28741166http://purl.uniprot.org/core/title"A new key player in VEGF-dependent angiogenesis in human hepatocellular carcinoma: dimethylarginine dimethylaminohydrolase 1."xsd:string
http://purl.uniprot.org/citations/28741166http://purl.uniprot.org/core/volume"20"xsd:string
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