四氢生物蝶呤促进肝细胞癌肿瘤血管形成的 机制.

Objective To investigate the effect and mechanism of tetrahydrobiopterin (BII4) on the angiogenesis in hepatocellular carcinoma (IICC). Methods BALB/c-nu mice were subcutaneously injected with IIepG-2 cells and randomly divided into control and BII4 groups. The BII4 group and control group received 20 mg/kg BII4 or saline by intraperitoneal injection daily or two weeks, respectively. The level of BII4 was 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 cyolohydrolase I (GTPCH), endothelial nitric oxide synthase (eNOS), phospho-Akt and Akt were determined by Western blot. Results B1I4 level in the tumor tissues of BII4 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 BH4 group was (51.44±2.90) mmol/L, significantly higher than the (24.77±0.54) mmol/L in the control group (P<0.06 ). The tumor volume of BII4 group was (191.05 + 8.70) mm3, significantly higher than the (103.IO±5.03) mm in the control group (P<0.01). The expressions of CD34, K-ras, phospho-eNOS, phospho-Akt and GTPCII were significantly up-regulated in the tumor tissues of BII4 group when compared with those of the control group (P<0.01). Conclusions B114 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 BH4 synthesis pathway and inhibiting angiogenesis. [ABSTRACT FROM AUTHOR]