Antiangiogenic property of pigment epithelium-derived factor in hepatocellular carcinoma
Antiangiogenic property of pigment epithelium-derived factor in hepatocellular carcinoma
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DOI：
10.1002/hep.20259
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发表时间：
2004-07-01
期刊：
影响因子：
13.5
通讯作者：
Eguchi, K
中科院分区：
文献类型：
--
作者：
Matsumoto, K;Ishikawa, H;Eguchi, K
色素上皮衍生因子(PEDF)是迄今为止发现的最有效的内源性抗血管生成试剂之一。它在肿瘤疾病中的抗血管生成潜力尚不清楚。在本研究中，我们研究了PEDF在肝细胞癌(一种典型的多血管肿瘤)中的抗血管生成特性。在肝癌细胞系中，PEDF的组成型信使RNA和蛋白的表达发生了变化。经Southern blotting检测，细胞株中编码PEDF基因的基因组DNA相同。在化学诱导的低氧条件下，分泌的PEDF蛋白受到抑制，而血管内皮生长因子蛋白则升高。当PEDF通过基因转移过表达时，所有肝癌细胞系的条件培养液中内皮细胞的增殖和迁移都受到抑制。然而，与健康志愿者和慢性肝炎患者相比，肝硬变或肝细胞癌合并肝硬变患者的血清PEDF浓度降低。内皮细胞增殖实验显示，肝癌患者血清PEDF具有抗血管生成活性。此外，在无瘤小鼠模型中，瘤内注射PEDF表达质粒可显著抑制预先建立的肿瘤生长。综上所述，PEDF在肝细胞癌的血管生成特性中起作用。随着慢性肝病的发展，血清PEDF浓度的降低可能有助于肝细胞癌的进展。此外，使用PEDF的基因治疗可能为肝癌提供一种有效的治疗方法。
Pigment epithelium-derived factor (PEDF) is one of the most powerful endogenous antiangiogenic reagents discovered to date. Its antiangiogenic potential in neoplastic disease remains unclear. In this study, we investigated antiangiogenic property of PEDF in hepatocellular carcinoma (HCC), a typical hypervascular tumor. In HCC cell lines, constitutive messenger RNA and protein expression of PEDF varied. Genomic DNA encoding the PEDF gene was the same in the cell lines examined by Southern blotting. In chemically induced hypoxic conditions, secreted PEDF protein was suppressed in contrast to elevation of vascular endothelial growth factor protein. When PEDF was overexpressed by gene transfer, proliferation and migration of endothelial cells were inhibited in conditioned media derived from all HCC cell lines. However, the serum concentration of PEDF, as measured by enzyme-linked immunosorbent assay, was decreased in patients with cirrhosis or HCC complicated by cirrhosis compared to healthy volunteers and patients with chronic hepatitis. According to the endothelial cell proliferation assay, the serum PEDF of patients with HCC had antiangiogenic activity. Moreover, intratumoral injection of a PEDF-expressing plasmid in athymic mouse models caused significant inhibition of preestablished tumor growth. In conclusion, PEDF plays a role in the angiogenic properties of HCC. Reduction of serum PEDF concentration associated with the development of chronic liver diseases may contribute to the progression of HCC. In addition, gene therapy using PEDF may provide an efficient treatment for HCC.