Branch of Cancer Genomics, Research Institute, National Cancer Center, Goyang Gyeonggi-do, South Korea.
Am J Pathol. 2012 Jul;181(1):43-52. doi: 10.1016/j.ajpath.2012.03.027. Epub 2012 May 18.
In an effort to identify novel genes related to the prognosis of gastric cancer, we performed gene expression profiling and found overexpressed levels of human interferon-induced transmembrane protein 1 (IFITM1). We validated the gastric cancer-specific up-regulation of IFITM1 and its association with cancer progression. We also studied its epigenetic regulation and tumorigenesis-related functions. Expression of IFITM1 was evaluated in various human gastric cancer cells and in 35 patient tumor tissues by quantitative RT-PCR and Western blot analyses. The results showed highly up-regulated IFITM1 in cancer cell lines and tissues. Furthermore, IHC studies were performed on 151 patient tissues, and a significant correlation was revealed between higher IFITM1 expression and Lauren's intestinal type (P = 0.007) and differentiated adenocarcinoma (P = 0.025). Quantitative studies of DNA methylation for 27 CpG sites in the regulatory region showed hypermethylation in cells expressing low levels of IFITM1. Methylation-dependent IFITM1 expression was confirmed further by in vitro demethylation using 5-aza-2'-deoxycytidine and luciferase assays. The functional analysis of IFITM1 by silencing of its expression with small-interfering RNA showed decreased migration and invasiveness of cancer cells, whereas its overexpression exhibited the opposite results. In this study, we demonstrated gastric cancer-specific overexpression of IFITM1 regulated by promoter methylation and the role of IFITM1 in cancer prognosis.
为了鉴定与胃癌预后相关的新基因，我们进行了基因表达谱分析，发现人类干扰素诱导跨膜蛋白 1（IFITM1）表达水平升高。我们验证了 IFITM1 在胃癌中的特异性上调及其与癌症进展的关联。我们还研究了其表观遗传调控和与肿瘤发生相关的功能。通过定量 RT-PCR 和 Western blot 分析，评估了 IFITM1 在各种人胃癌细胞和 35 例患者肿瘤组织中的表达。结果显示，癌细胞系和组织中 IFITM1 表达水平上调。此外，对 151 例患者组织进行了 IHC 研究，发现 IFITM1 表达较高与 Lauren 的肠型（P=0.007）和分化型腺癌（P=0.025）显著相关。对调控区 27 个 CpG 位点的 DNA 甲基化进行定量研究显示，IFITM1 低表达的细胞存在高甲基化。通过使用 5-氮杂-2'-脱氧胞苷进行体外去甲基化和荧光素酶测定，进一步证实了 IFITM1 的甲基化依赖性表达。通过用小干扰 RNA 沉默其表达进行 IFITM1 的功能分析显示，癌细胞的迁移和侵袭能力降低，而其过表达则产生相反的结果。在这项研究中，我们证明了 IFITM1 的胃癌特异性过表达受启动子甲基化调控，以及 IFITM1 在癌症预后中的作用。
