Epigenetic regulation of the tumor suppressor gene, TCF21 on 6q23-q24 in lung and head and neck cancer
Epigenetic regulation of the tumor suppressor gene, TCF21 on 6q23-q24 in lung and head and neck cancer
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DOI：
10.1073/pnas.0510171102
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发表时间：
2006-01-24
影响因子：
11.1
通讯作者：
Plass, C
中科院分区：
文献类型：
--
作者：
Smith, LT;Lin, MT;Plass, C
肿瘤抑制基因的鉴定传统上依赖于它们在杂合性丢失的复发区域内的定位。根据克努森的两次打击假说，剩下的等位基因丢失了，要么是遗传上的，要么是最近发现的，通过表观遗传事件。迄今为止，回顾性分析已经确定启动子甲基化是癌细胞中沉默癌症相关基因的常见替代改变。在这里，我们报告了限制性标志基因组扫描，允许DNA甲基化分析沿着在染色体6 q23-q24的杂合性丢失的区域的应用。这种方法导致了肿瘤抑制基因TCF 21的鉴定，该基因在人类恶性肿瘤中经常丢失。我们证明TCF 21在正常的肺气道上皮细胞中表达，并且在所分析的大多数头颈部鳞状细胞癌和非小细胞肺癌中异常甲基化和沉默。已知TCF 21调节间充质细胞向上皮细胞的转化，这是一种在癌中缺乏的特性。我们进一步证明，TCF 21的外源性表达的细胞，沉默了内源性TCF 21基因座导致在体外和体内的肿瘤特性的减少。
The identification of tumor suppressor genes has classically depended on their localization within recurrent regions of loss of heterozygosity. According to Knudson's two-hit hypothesis, the remaining allele is lost, either genetically or, more recently identified, through epigenetic events. To date, retrospective analyses have determined promoter methylation as a common alternative alteration in cancer cells to silence cancer-related genes. Here we report an application of restriction landmark genomic scanning that allows for DNA methylation profiling along a region of recurrent loss of heterozygosity at chromosome 6q23-q24. This approach resulted in the identification of a tumor suppressor gene, TCF21, which is frequently lost in human malignancies. We demonstrate that TCF21 is expressed in normal lung airway epithelial cells and aberrantly methylated and silenced in the majority of head and neck squamous cell carcinomas and non-small-cell lung cancers analyzed. TCF21 is known to regulate mesenchymal cell transition into epithelial cells, a property that has been shown to be deficient in carcinomas. We further demonstrate that exogenous expression of TCF21 in cells that have silenced the endogenous TCF21 locus resulted in a reduction of tumor properties in vitro and in vivo.