Genomic loss and epigenetic silencing of very-low-density lipoprotein receptor involved in gastric carcinogenesis

Abstract

Homozygous loss in the genomic sequence, a mechanism for inactivating tumor-suppressor genes (TSGs) in cancer, has been used as a tag for the identification of novel TSGs, and array-based comparative genomic hybridization (array-CGH) has a great potential for high-throughput identification of this change. We identified a homozygous loss of the very-low-density lipoprotein receptor (VLDLR) gene (9p24.2) from genome-wide screening for copynumber alterations in 32 gastric cancer (GC) cell lines using array-CGH. Although previous reports demonstrated mRNA or protein expression of VLDLR in various cancers including GC, the association between genomic losses or epigenetic silencing of this gene and carcinogenesis has never been reported before. Homozygous deletion of VLDLR was also seen in primary GCs, albeit infrequently, and about half of GC cell lines showed lost or reduced VLDLR expression. The VLDLR expression was restored in gene-silenced GC cells after treatment with 5-aza 2 0 -deoxycytidine. According to methylation analyses, hypermethylation of the VLDLR promoter region, which all of GC lines without its expression showed, occurred in some primary GCs. Restoration of VLDLR type I expression in GC cells reduced colony formation. These results suggest that not only the expression of VLDLR but also genetic or epigenetic silencing of this gene may contribute to tumor formation and be involved in gastric carcinogenesis.

Genetic analysis of multifocal superficial urothelial cancers by array-based comparative genomic hybridisation

“…Quantitative measurement of DNA copy numbers across the genome has revealed various oncogenes (Tanami et al, 2005) or tumour suppressor genes (Takada et al, 2005(Takada et al, , 2006) that had not been detected by earlier techniques. In addition, the higher resolution of array-CGH has allowed precise mapping of the boundaries of the gained and lost regions, thereby helping to elucidate the clonal relationship between multifocal tumours (Shelley Hwang et al, 2004;Wa et al, 2005).…”

PRTFDC1, a possible tumor-suppressor gene, is frequently silenced in oral squamous-cell carcinomas by aberrant promoter hypermethylation

“…Array-based CGH (array-CGH) technique allows high-throughput and quantitative analyses of copy-number changes at high-resolution throughout the genome, providing many advantages, including the identification of homozygous loss, over conventional methods (Snijders et al, 2001;Inazawa et al, 2004), although the resolution fully depends on the type of array. Indeed, our previous array-CGH studies using inhouse bacterial artificial chromosome-(BAC-)/P1-derived artificial chromosome-(PAC-) based arrays (BAC/ PAC-arrays) have successfully mapped complete genetic losses, allowing the rapid identification of candidate TSGs inactivated mainly by genetic and/or epigenetic mechanisms (Sonoda et al, 2004;Izumi et al, 2005;Takada et al, 2005bTakada et al, , 2006Imoto et al, 2006).…”

Epigenetic silencing of RELN in gastric cancer

“…Although the exact mechanism by which RELN contributes to tumorigenicity remains to be elucidated, the data presented in this study, together with the recent finding that the VLDLR gene, whose product functions as the receptor for RELN, is also epigenetically silenced in GC (9), clearly suggest that disruption of the RELN pathway is involved in gastric carcinogenesis.…”

“…The recent observation that the VLDLR gene is frequently silenced by promoter hypermethylation in GC suggested that disruption of the RELN pathway may be involved in gastric carcinogenesis (9). The RELN gene harbors a long CpG-rich promoter region (10) and expression of RELN is regulated by the methylation status of the promoter (11).…”