Aberrant Methylation Impairs Low Density Lipoprotein Receptor-Related Protein 1B Tumor Suppressor Function in Gastric Cancer

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.