Department of Pathology, Hiroshima University, Graduate School of Biomedical Sciences, Minami-ku, Hiroshima 734-8551, Japan.
Oncol Rep. 2010 Aug;24(2):423-31. doi: 10.3892/or_00000875.
WIF-1 is a negative regulator of the Wnt-signaling pathway that may have important implications for tumorigenesis. Microarray analysis of whole genome expression in mesothelioma tissue revealed down-regulation of 491 genes and up-regulation of 167 genes involved mainly in Jak-STAT signaling (8 genes), MAPK signaling (16 genes) and Wnt signaling (13 genes) pathways. Of these, WIF-1 gene was down-regulated in mesothelioma 72-fold compared to normal tissue. We also analyzed WIF-1 and SFRPs promoter methylations in 46 mesothelioma tissues, 8 mesothelioma cell lines by methylation-specific polymerase chain reaction (MSP). WIF-1 promoter methylation was observed in 34 of 46 mesothelioma tissues (73.9%) and in all 8 mesothelioma cell lines. SFRP1, 2 and 4 promoter methylation was observed in 21 of 37 (56.8%), 26 of 42 (61.9%) and 17 of 36 (47.2%) mesothelioma tissues, respectively. Promoter methylation of any WIF-1 and/or SFRP genes was observed in 44 of 46 (95.6%) mesothelioma tissues. The treatment of mesothelioma cell lines with 5-aza-2'-deoxycytidine (5-aza-2dC) showed WIF-1 promoter methylation recovery followed by restoration of WIF-1 expression in 6 of 8 mesothelioma cell lines. The cytoplasmic expression of beta-catenin was observed in 38 of 43 cases of mesothelioma without any nuclear reactivity. The eight mesothelioma cell lines and 27 cases of mesothelioma examined showed no mutation in exon 3 of beta-catenin suggesting no alteration of canonical Wnt signaling pathway. Our data suggest that WIF-1 promoter methylation is a common event in mesothelioma.
WIF-1 是 Wnt 信号通路的负调节剂，它可能对肿瘤发生有重要影响。对间皮瘤组织的全基因组表达进行微阵列分析显示，491 个基因下调，167 个基因上调，这些基因主要涉及 Jak-STAT 信号（8 个基因）、MAPK 信号（16 个基因）和 Wnt 信号（13 个基因）途径。其中，WIF-1 基因在间皮瘤组织中比正常组织下调了 72 倍。我们还通过甲基化特异性聚合酶链反应（MSP）分析了 46 个间皮瘤组织、8 个间皮瘤细胞系中的 WIF-1 和 SFRPs 启动子甲基化。在 46 个间皮瘤组织中观察到 34 个（73.9%）WIF-1 启动子甲基化，在 8 个间皮瘤细胞系中均观察到甲基化。在 37 个间皮瘤组织中观察到 SFRP1、2 和 4 启动子甲基化分别为 21 个（56.8%）、26 个（61.9%）和 17 个（47.2%），在 42 个间皮瘤组织中观察到 SFRP1、2 和 4 启动子甲基化分别为 26 个（61.9%）、21 个（50.0%）和 17 个（40.5%），在 36 个间皮瘤组织中观察到 SFRP1、2 和 4 启动子甲基化分别为 17 个（47.2%）、21 个（56.8%）和 17 个（47.2%）。在 46 个间皮瘤组织中观察到任何 WIF-1 和/或 SFRP 基因的启动子甲基化，在 8 个间皮瘤细胞系中观察到 6 个（75.0%）。用 5-氮杂-2'-脱氧胞苷（5-aza-2dC）处理间皮瘤细胞系，6 个间皮瘤细胞系中有 6 个显示 WIF-1 启动子甲基化恢复，随后 WIF-1 表达恢复。在 43 例间皮瘤病例中观察到细胞质中 beta-catenin 的表达，而无核反应。在 8 个间皮瘤细胞系和 27 例间皮瘤病例中未观察到 beta-catenin 外显子 3 的突变，提示经典 Wnt 信号通路无改变。我们的数据表明，WIF-1 启动子甲基化是间皮瘤中的常见事件。
