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，使细胞迁移增加2.2倍，细胞增殖增加1.5倍。KDR抑制剂可消除上述作用。序列分析表明，在Δ阳性的肝细胞癌细胞中表达第二外显子跳跃剪接变异体γ-谷氨酰羧酶(DCP2GGCX)。DCP阳性的肝癌细胞表达69%的Δ2-GGCX，而DCP阴性的肝癌细胞表达8%的Δ2-GGCX。Δ-2-GGCX基因的导入将DCP阴性的肝癌细胞转化为DCP阳性的肝癌细胞。另一方面，野生型(WT)-GGCX的导入将DCP阳性的肝癌细胞转化为DCP阴性的肝癌细胞。将表达WT-GGCX和Δ-2-GGCX的肝癌细胞接种于裸鼠皮下。Δ-2-GGCX-Hep3B形成了更多的血管生成肿瘤，肿瘤体积是WT-GGCX-Hep3B的4.2倍。肝细胞癌组织标本中DCP的产生与CD31指数测定的血管生成呈正相关。多血供肝细胞癌患者血清DCP水平显著高于少血供肝细胞癌患者。在TOTO中，DCP的表达与肝癌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.