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

Abstract

BackgroundAnti-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.MethodsThe 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.ResultsDDAH-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.ConclusionsOur 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.

Transcriptional and Metabolomic Analysis of L-Arginine/Nitric Oxide Pathway in Inflammatory Bowel Disease and Its Association with Local Inflammatory and Angiogenic Response: Preliminary Findings

“…Nonetheless, in addition to DDAH overexpression, DDAH1 was associated with IBD angiogenesis as VEGFA and TP53 were independent predictors of its expression in both quiescent and inflamed bowel. Those findings corroborate recent reports on DDAH1 being a new player in VEGF-dependent angiogenesis in human hepatocellular carcinoma [48] and glioma [49]. DDAH2, in turn, has been implicated in angiogenesis in lung adenocarcinoma [50].…”

RRM2 elicits the metastatic potential of breast cancer cells by regulating cell invasion, migration and VEGF expression via the PI3K/AKT signaling

“…VEGF is a critical driver of sprouting angiogenesis that functions by regulating vascular formation, remodeling and permeability. Aberrant expression and activation of VEGF usually occurs in most solid tumor microenvironments, including breast cancer (20,21). The present study next clarified the effects of RRM2 on VEGF levels and found that RRM2 knockdown dampened the expression and release of VEGF in breast cancer cells.…”

DDAH1 regulates apoptosis and angiogenesis in human fetal pulmonary microvascular endothelial cells

“…; Buijs et al. ). Studies in transgenic mice over‐expressing DDAH1 showed lower plasma levels of ADMA, increased NO production, and NOS activity (Dayoub et al.…”

“…There are two isoforms encoded by two different genes DDAH1 and DDAH2 (Leiper et al 1999;Tran et al 2003;Vallance and Leiper 2004;Pope et al 2009b;Janssen et al 2013). DDAH1 is the main isoform for ADMA degradation in vivo (Pope et al 2009a;Buijs et al 2017). Studies in transgenic mice over-expressing DDAH1 showed lower plasma levels of ADMA, increased NO production, and NOS activity (Dayoub et al 2003;Jacobi et al 2005), as well as enhanced angiogenesis after ischemia or inflammation (Jacobi et al 2005).…”