Genomic loss and epigenetic silencing of very-low-density lipoprotein receptor involved in gastric carcinogenesis
Genomic loss and epigenetic silencing of very-low-density lipoprotein receptor involved in gastric carcinogenesis
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DOI：
10.1038/sj.onc.1209657
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发表时间：
2006-10-19
期刊：
影响因子：
8
通讯作者：
Inazawa, J.
中科院分区：
文献类型：
--
作者：
Takada, H.;Imoto, I.;Inazawa, J.
基因组序列中的纯合缺失是癌症中肿瘤抑制基因（TSGs）失活的一种机制，已被用作鉴定新型TSGs的标签，基于阵列的比较基因组杂交（array-CGH）具有高通量鉴定这种变化的巨大潜力。我们在32个胃癌（GC）细胞系中使用阵列CGH从全基因组筛查拷贝数改变中鉴定了极低密度脂蛋白受体（VLDLR）基因（9p24.2）的纯合丢失。尽管先前的报道表明VLDLR在包括GC在内的各种癌症中的mRNA或蛋白质表达，但该基因的基因组丢失或表观遗传沉默与癌发生之间的关联以前从未报道过。在原发性GC中也观察到VLDLR的纯合缺失，尽管不常见，并且约一半的GC细胞系显示VLDLR表达丧失或降低。用5-氮杂2 '-脱氧胞苷处理后，基因沉默的GC细胞中VLDLR表达恢复。甲基化分析表明，VLDLR启动子区在某些原发性胃癌中发生了高甲基化，而所有不表达VLDLR的胃癌细胞系均表现出高甲基化。GC细胞中VLDLR I型表达的恢复减少了集落形成。这些结果表明，不仅VLDLR的表达，而且该基因的遗传或表观遗传沉默可能有助于肿瘤的形成，并参与胃癌的发生。
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.