Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
Invest New Drugs. 2012 Aug;30(4):1404-12. doi: 10.1007/s10637-011-9710-9. Epub 2011 Jul 1.
P-cadherin is frequently up-regulated in solid tumors such as gastric, colon, lung, pancreatic and breast cancers. Although P-cadherin promotes cadherin-mediated cell adhesion, the gastric cancer-linked regulation of P-cadherin has not been extensively investigated. In this study, we found epigenetic regulation of P-cadherin in human gastric cancer cells that was induced by treatment with DNA demethylating drug and histone deacetylase inhibitor. Silencing P-cadherin by using siRNA induces apoptosis in gastric cells and blocks expression of Tie-2, an angiogenic receptor tyrosine kinase. In contrast, ectopically expressed P-cadherin by generating P-cadherin stable cell line enhances Tie-2 expression and cell mobility. We also demonstrated that inhibition of P-cadherin by PF-03732010, a fully humanized anti-P-cadherin IgG1 monoclonal antibody, suppressed cell migration in vitro and tumor growth in BALB/c nude mice bearing SNU620 gastric cancer xenograft. The data reported here are the first to reveal that the inhibition of P-cadherin decreases tumor cell migration and blocks a tumorigenesis by down-regulation of Tie-2 in gastric cancer. This demonstrates the potential for P-cadherin to be used as a target for treatment of gastric cancer.
P-钙黏蛋白在胃癌、结肠癌、肺癌、胰腺癌和乳腺癌等实体瘤中常被上调。尽管 P-钙黏蛋白促进钙黏蛋白介导的细胞黏附，但与胃癌相关的 P-钙黏蛋白调节尚未得到广泛研究。在这项研究中，我们发现人胃癌细胞中存在 P-钙黏蛋白的表观遗传调控，这种调控是由 DNA 去甲基化药物和组蛋白去乙酰化抑制剂治疗诱导的。使用 siRNA 沉默 P-钙黏蛋白会诱导胃癌细胞凋亡，并阻断血管生成受体酪氨酸激酶 Tie-2 的表达。相比之下，通过生成 P-钙黏蛋白稳定细胞系过表达 P-钙黏蛋白会增强 Tie-2 的表达和细胞迁移能力。我们还证明，PF-03732010（一种完全人源化的抗 P-钙黏蛋白 IgG1 单克隆抗体）抑制 P-钙黏蛋白可抑制体外细胞迁移和荷瘤 BALB/c 裸鼠中 SNU620 胃癌异种移植物的肿瘤生长。这里报告的数据首次揭示了抑制 P-钙黏蛋白可通过下调胃癌中的 Tie-2 来减少肿瘤细胞迁移并阻断肿瘤发生。这表明 P-钙黏蛋白有可能成为治疗胃癌的靶点。
