异常甲基化削弱了胃癌中低密度脂蛋白受体相关蛋白 1B 的肿瘤抑制功能。

Aberrant methylation impairs low density lipoprotein receptor-related protein 1B tumor suppressor function in gastric cancer.

机构信息

Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.

出版信息

Genes Chromosomes Cancer. 2010 May;49(5):412-24. doi: 10.1002/gcc.20752.

DOI:10.1002/gcc.20752

PMID:20095042

Abstract

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 1B (LRP1B) as a novel epigenetic target in gastric cancer. LRP1B was hypermethylated in four gastric cancer cell lines, and low LRP1B 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 LRP1B in these cell lines, indicating that DNA methylation is involved in regulating LRP1B expression. In 45 out of 74 (61%) clinical samples, LRP1B was highly methylated; LRP1B 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 mLRP1B4 in gastric cancer cell lines suppressed cell growth, colony formation and tumor formation in nude mice. These results collectively indicate that LRP1B is a functional tumor suppressor gene in gastric cancer and that is regulated by DNA methylation.

摘要

DNA 甲基化在肿瘤进展中起着重要作用。在这项研究中，我们使用 CpG 微阵列和差异甲基化杂交方法，确定低密度脂蛋白受体相关蛋白 1B（LRP1B）是胃癌中的一个新的表观遗传靶标。在四种胃癌细胞系中，LRP1B 发生高甲基化，并且在胃癌细胞系中，低 LRP1B mRNA 表达与高甲基化水平相关。添加 DNA 甲基化抑制剂（5-Aza-dC）可恢复这些细胞系中 LRP1B 的 mRNA 表达，表明 DNA 甲基化参与调节 LRP1B 的表达。在 74 个临床样本中的 45 个中，LRP1B 高度甲基化；在 19 个胃癌组织中有 15 个（79%，P<0.001）中，LRP1B mRNA 表达明显低于相应的相邻正常组织。此外，在胃癌细胞系中异位表达 mLRP1B4 可抑制细胞生长、集落形成和裸鼠肿瘤形成。这些结果共同表明，LRP1B 是胃癌中的一个功能性肿瘤抑制基因，受 DNA 甲基化调控。