Frequent silencing of DBC1 is by genetic or epigenetic mechanisms in non-small cell lung cancers
Frequent silencing of DBC1 is by genetic or epigenetic mechanisms in non-small cell lung cancers
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DOI：
10.1093/hmg/ddi092
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发表时间：
2005-04-15
影响因子：
3.5
通讯作者：
Imoto, I
中科院分区：
文献类型：
--
作者：
Izumi, H;Inoue, J;Imoto, I
使用定制的比较基因组杂交（CGH）阵列，在来自非小细胞肺癌（NSCLC）的27个细胞系中进行DNA拷贝数畸变的全基因组筛选，在一个细胞系中鉴定了膀胱癌1基因（DBC 1）缺失的纯合缺失。在检查的53例原发性NSCLC肿瘤中，也观察到位于9q33.1的DBC 1纯合缺失。此外，其他26个细胞系中的21个显示出完全丧失了DBC 1表达，尽管正常肺组织表达该基因，并且用5-氮杂-2 '-脱氧胞苷处理恢复了DBC 1的表达。在尿路上皮癌中，已经报道了DBC 1外显子1周围CpG岛部分的超甲基化，但在该疾病中甲基化和表达状态之间的潜在关联从未得到澄清。在我们的实验中，相同CpG岛的不同部分在体外显示出启动子活性，并且在我们的细胞系和NSCLC原发性肿瘤中经常甲基化，其中甲基化状态与基因表达呈负相关。在我们的原发性NSCLC病例中，男性、老年患者和吸烟者的DBC 1启动子甲基化发生率分别高于女性、年轻患者和非吸烟者，但与肿瘤分期或组织学无关。在缺乏其表达的NSCLC细胞系中外源性过表达DBC 1抑制细胞生长。我们的研究结果提供了第一个证据表明，DBC 1是一个可能的肿瘤抑制NSCLC的基因沉默，通过纯合缺失或甲基化的启动子区域可能与这种疾病的进展。
Genome-wide screening of DNA copy number aberrations in 27 cell lines derived from non-small cell lung cancers (NSCLCs), using a custom-made comparative genomic hybridization (CGH)-array, identified a homozygous deletion of the deleted in bladder cancer 1 gene (DBC1) in one cell line. Homozygous deletion of DBC1, located at 9q33.1, was also observed in two of 53 primary NSCLC tumors examined. Moreover, 21 of the other 26 cell lines showed complete loss of DBC1 expression, although normal lung tissues express this gene, and treatment with 5-aza-2'-deoxycytidine restored expression of DBC1. Hypermethylation in part of a CpG island around the exon 1 of DBC1 has been reported in urothelial cancers, but the potential association between methylation and expression status was never clarified in that disease. In our experiments, a different part of the same CpG island showed promoter activity in vitro and was frequently methylated in our cell lines and primary tumors of NSCLC, where methylation status correlated inversely with gene expression. Among our primary NSCLC cases, methylation of the DBC1 promoter occurred more frequently in men, elderly patients and smokers than in women, younger patients and nonsmokers respectively, but it was not correlated with tumor stage or histology. Exogenous overexpression of DBC1 in NSCLC cell lines lacking its expression inhibited cell growth. Our results provide the first evidence that DBC1 is a likely tumor suppressor for NSCLC; silencing of the gene through homozygous deletion or methylation of its promoter region may be associated with progression of this disease.