Genomic loss and epigenetic silencing of very-low-density lipoprotein receptor involved in gastric carcinogenesis.
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 copy-number 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'-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.
Takada
H
H
Department of Molecular Cytogenetics, Medical Research Institute and Graduate School of Biomedical Science, Tokyo, Japan.
Imoto
I
I
Tsuda
H
H
Nakanishi
Y
Y
Sakakura
C
C
Mitsufuji
S
S
Hirohashi
S
S
Inazawa
J
J
D001706:Biopsy; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000601:surgery; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002899:Chromosomes, Human, Pair 9; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D017353:Gene Deletion; D020868:Gene Silencing; D006720:Homozygote; D006801:Humans; D009693:Nucleic Acid Hybridization / Q000379:methods; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011401:Promoter Regions, Genetic; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics* / Q000601:surgery; D014407:Tumor Cells, Cultured
D011973:Receptors, LDL; C036053:VLDL receptor