Effects of tetrahydrobiopterin on the angiogenesis in hepatocellular carcinoma
10.3760/cma.j.issn.0253-3766.2016.11.002
- VernacularTitle:四氢生物蝶呤促进肝细胞癌肿瘤血管形成的机制
- Author:
Youguo DAI
1
;
Ping GAN
;
Weiming LI
;
Qian YAO
;
Yong LI
;
Bo PEI
;
Jin CUI
Author Information
1. 650118,昆明医科大学第三附属医院云南省肿瘤医院腹部外科
- Keywords:
Liver neoplasms;
Nude mice;
Tetrahydrobiopterin;
Nitric oxide;
Nitric oxide synthase;
Angiogenesis
- From:
Chinese Journal of Oncology
2016;38(11):806-811
- CountryChina
- Language:Chinese
-
Abstract:
Objective To investigate the effect and mechanism of tetrahydrobiopterin ( BH4) on the angiogenesis in hepatocellular carcinoma ( HCC) .Methods BALBc/-nu mice were subcutaneously injected with HepG-2 cells and randomly divided into control and BH 4 groups.The BH4 group and control group received 20 mg/kg BH4 or saline by intraperitoneal injection daily for two weeks , respectively .The level of BH4was measured by high performance liquid chromatography (HPLC), the level of nitric oxide (NO) was measured by Griess test array , the transcriptional level of K-ras was measured by quantitative RT-PCR, and the protein expressions of guanosine triphosphate cyclohydrolase Ⅰ( GTPCH ) , endothelial nitric oxide synthase ( eNOS) , phospho-Akt and Akt were determined by Western blot .Results BH4 level in the tumor tissues of BH4 group was (0.24±0.02) μg/ml, significantly higher than the (0.17±0.01) μg/ml in the control group (P<0.01).The level of NO in the tumor tissues of BH4group was (51.44±2.90) mmol/L, significantly higher than the (24.77±0.54) mmol/L in the control group( P<00.1 ).The tumor volume of BH4 group was (191.05±8.70) mm3, significantly higher than the (103.10±5.03) mm3 in the control group (P<0.01).The expressions of CD34 , K-ras, phospho-eNOS, phospho-Akt and GTPCH were significantly up-regulated in the tumor tissues of BH4 group when compared with those of the control group (P<0.01). Conclusions BH4 recognized as an essential cofactor of eNOS can increase tumor-produced NO by activating the wild-type Ras-PI3K/Akt pathway, thus induces angiogenesis .This might provide a novel and promising way to control the progression of hepatocellular carcinoma through targeting BH 4 synthesis pathway and inhibiting angiogenesis .
