Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea 305-806.
Carcinogenesis. 2010 Sep;31(9):1685-93. doi: 10.1093/carcin/bgq144. Epub 2010 Jul 12.
The Popeye domain-containing (POPDC) genes BVES, POPDC2 and POPDC3 encode proteins that regulate cell-cell adhesion and cell migration during development. Herein, we report the frequent downregulation of BVES and POPDC3 by promoter hypermethylation in gastric cancer. POPDC expression in 11 gastric cancer cell lines and 96 paired gastric tumor and normal adjacent tissues was analyzed with quantitative reverse transcription-polymerase chain reaction. The methylation status of BVES and POPDC3 was analyzed with methylated DNA immunoprecipitation sequencing, bisulfite sequencing and pyrosequencing. Expression of BVES and POPDC3 was downregulated in 73% of the gastric cancer cell lines and in 69% (BVES) and 87% (POPDC3) of the gastric cancer tissues. The BVES and POPDC3 promoter regions were hypermethylated in the gastric cancer cell lines in which they were silenced. Combined treatment with a DNA methylation inhibitor and a histone deacetylase inhibitor strongly induced BVES and POPDC3 expression. BVES and POPDC3 were hypermethylated in 69% (BVES) and 64% (POPDC3) of the gastric cancer tissues. We knocked down POPDC3 expression with short hairpin RNAs and examined the consequences on cell migration and invasion. Knockdown of POPDC3 in SNU-216 cells caused increased cell migration and invasion. Thus, epigenetic inactivation of BVES and POPDC3 occurs frequently in gastric tumors and may promote gastric cancer cell migration and invasion.
波菲氏蛋白结构域（POPDC）基因 BVES、POPDC2 和 POPDC3 编码的蛋白质在发育过程中调节细胞-细胞黏附和细胞迁移。在此，我们报道胃腺癌中频繁出现的 BVES 和 POPDC3 启动子超甲基化下调。采用定量逆转录-聚合酶链反应分析了 11 种胃癌细胞系和 96 对胃癌组织和正常相邻组织中的 POPDC 表达。采用甲基化 DNA 免疫沉淀测序、亚硫酸氢盐测序和焦磷酸测序分析 BVES 和 POPDC3 的甲基化状态。在 73%的胃癌细胞系和 69%（BVES）和 87%（POPDC3）的胃癌组织中下调了 BVES 和 POPDC3 的表达。沉默的胃癌细胞系中，BVES 和 POPDC3 启动子区域发生超甲基化。DNA 甲基化抑制剂和组蛋白去乙酰化酶抑制剂联合治疗强烈诱导了 BVES 和 POPDC3 的表达。在 69%（BVES）和 64%（POPDC3）的胃癌组织中发现了 BVES 和 POPDC3 的甲基化。我们用短发夹 RNA 敲低了 POPDC3 的表达，并研究了对细胞迁移和侵袭的影响。在 SNU-216 细胞中敲低 POPDC3 导致细胞迁移和侵袭增加。因此，BVES 和 POPDC3 的表观遗传失活在胃肿瘤中经常发生，可能促进胃癌细胞的迁移和侵袭。
