Novel mechanism for the angiogenesis in hepatocellular carcinoma

des - γ羧基凝血酶原（DCP）刺激人脐静脉上皮细胞KDR；增强细胞迁移2.2倍，增强细胞增殖1.5倍。KDR抑制剂消除了这些影响。序列分析显示，外显子2跳剪接变异γ -谷氨酰羧化酶（Δ2-GGCX）在dcp阳性的肝细胞癌（HCC）中表达。dcp阳性HCC细胞占Δ2-GGCX的69%，而dcp阴性HCC细胞占Δ2-GGCX的8%。Δ2-GGCX的引入将dcp阴性HCC细胞转化为dcp阳性HCC细胞。另一方面，野生型(WT)-GGCX的引入将dcp阳性HCC细胞转化为dcp阴性HCC细胞。将表达Hep3B的WT-GGCX和Δ2-GGCX细胞皮下注射到裸鼠体内。Δ2-GGCX-Hep3B形成的血管生成肿瘤比WT-GGCX-Hep3B大4.2倍。肝细胞癌组织样本显示，CD31指数测定的DCP生成与血管生成呈正相关。高血管型肝细胞癌血清DCP水平明显高于低血管型肝细胞癌。综上所述，DCP的表达与HCC中的肿瘤血管生成有关。

Des-gamma carboxy prothrombin (DCP) stimulated KDR in human umbilical vein epithelial cell ; enhanced cell migration by 2.2-fold and enhanced cell proliferation by 1.5-fold. KDR inhibitor abrogated these effects. Sequence analysis revealed that exon 2 skipping splice variant gamma-glutamyl carboxylase (Δ2-GGCX) was expressed in DCP-positive hepatocellular carcinoma (HCC) cells. DCP-positive HCC cells expressed 69% of Δ2-GGCX, while DCP-negative HCC cells expressed 8% of Δ2-GGCX. The introduction of Δ2-GGCX converted DCP-negative HCC cells into DCP-positive HCC cells. On the other hand, the introduction of wild type (WT)-GGCX converted DCP-positive HCC cells into DCP-negative HCC cells. WT-GGCX and Δ2-GGCX expressing Hep3B cells were injected subcutaneously into nude mice. Δ2-GGCX-Hep3B formed more angiogenic tumors and 4.2-fold larger tumors than WT-GGCX-Hep3B. HCC tissue samples demonstrated a positive correlation between DCP production and angiogenesis determined by CD31 index. The serum DCP level of hypervascular HCC was significantly higher than that of hypovascular HCC. In toto, DCP expression is associated with tumor angiogenesis in HCC.