Aberrant Methylation Impairs Low Density Lipoprotein Receptor-Related Protein 1B Tumor Suppressor Function in Gastric Cancer
Aberrant Methylation Impairs Low Density Lipoprotein Receptor-Related Protein 1B Tumor Suppressor Function in Gastric Cancer
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DOI：
10.1002/gcc.20752
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发表时间：
2010-05-01
影响因子：
3.7
通讯作者：
Chang, Yu-Sun
中科院分区：
文献类型：
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作者：
Lu, Yen-Jung;Wu, Chi-Sheng;Chang, Yu-Sun
DNA甲基化在肿瘤进展中起重要作用。在这项研究中，我们使用CpG微阵列和差异甲基化杂交的方法来确定低密度脂蛋白受体相关蛋白IB（LRPIB）作为一个新的胃癌表观遗传靶点。LRP 1B在4种胃癌细胞系中高甲基化，并且LRP 1B mRNA低表达与胃癌细胞系中的高甲基化水平相关。添加DNA甲基化抑制剂（5-Aza-dC）恢复了这些细胞系中LRPIB的mRNA表达，表明DNA甲基化参与调节LRPIB表达。在74例临床标本中，45例（61%）LRP I B基因高度甲基化，19例胃癌组织中，15例（79%）LRP I B mRNA表达显著低于相应癌旁正常组织（P < 0.001）。此外，mLRP I B4在胃癌细胞系中的异位表达抑制细胞生长、集落形成和裸鼠成瘤。这些结果共同表明，LRPIB是胃癌中的功能性肿瘤抑制基因，并且受DNA甲基化调控。(C)2010 Wiley-Liss，Inc.
DNA methylation plays a significant role in tumor progression. In this study, we used CpG microarray and differential methylation hybridization approaches to identify low density lipoprotein receptor-related protein IB (LRPIB) as a novel epigenetic target in gastric cancer. LRPIB was hypermethylated in four gastric cancer cell lines, and low LRP 1B mRNA expression was associated with high methylation levels in gastric cancer cell lines. Addition of a DNA methylation inhibitor (5-Aza-dC) restored the mRNA expression of LRPIB in these cell lines, indicating that DNA methylation is involved in regulating LRPIB expression. In 45 out of 74 (61%) clinical samples, LRP I B was highly methylated; LRPIB mRNA expression was significantly lower in 15 out of 19 (79%, P < 0.001) gastric tumor tissues than in corresponding adjacent normal tissues. In addition, ectopic expression of mLRP I B4 in gastric cancer cell lines suppressed cell growth, colony formation and tumor formation in nude mice. These results collectively indicate that LRPIB is a functional tumor suppressor gene in gastric cancer and that is regulated by DNA methylation. (C) 2010 Wiley-Liss, Inc.