Novel mechanism for the angiogenesis in hepatocellular carcinoma

脱-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，增殖增加1.5倍。KDR抑制剂消除了这些作用。序列分析表明，外显子2跳跃剪接变异体γ-谷氨酰羧化酶（Δ2-GGCX）在DCP阳性的肝癌细胞中表达。DCP阳性HCC细胞表达69%的Δ2-GGCX，而DCP阴性HCC细胞表达8%的Δ2-GGCX。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WT-GGCX和Δ2-GGCX的Hep 3B细胞皮下注射到裸鼠中。Δ2-GGCX-Hep 3B形成的血管生成肿瘤比WT-GGCX-Hep 3B大4.2倍。HCC组织样本显示DCP产生与通过CD 31指数确定的血管生成之间呈正相关。血供丰富的肝癌血清DCP水平明显高于血供不足的肝癌。总的来说，DCP表达与HCC中的肿瘤血管生成相关。

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.