DSC3 的表达受 p53 调控，而 DSC3 基因的甲基化是人类结直肠癌的一个预后标志物。
DSC3 expression is regulated by p53, and methylation of DSC3 DNA is a prognostic marker in human colorectal cancer.
机构信息
Institute of Pathology, University Hospital Jena, Ziegelmühlenweg 1, Jena 07743, Germany.
出版信息
Br J Cancer. 2011 Mar 15;104(6):1013-9. doi: 10.1038/bjc.2011.28. Epub 2011 Mar 1.
BACKGROUND
Desmocollin 3 (DSC3), a member of the cadherin superfamily and integral component of desmosomes, is involved in carcinogenesis. However, the role of DSC3 in colorectal cancer (CRC) has not yet been established.
METHODS
Desmocollin 3 expression in CRC cell lines was analysed by RT-PCR and western blotting. Methylation status of DSC3 was examined by demethylation tests, methylation-specific PCR, and bisulphite sequencing (BS). The regulatory role of p53 was investigated by transfection.
RESULTS
Desmocollin 3 was downregulated in CRC cells at mRNA and protein levels. Desmocollin 3 expression was restored in five out of seven cell lines after 5-aza-2'-deoxycytidine (DAC) treatment. A heterogeneous methylation pattern was detected by BS in promoter region and exon 1 of DSC3. Methylation of DSC3 genomic sequences was found in 41% (41 out of 99) of primary CRC, being associated with poor prognosis (P=0.002). Transfection of p53 alone or in combination of DAC increased the DSC3 expression. Similarly, treatment with p53 inducer adriamycin alone or in combination with DAC enhanced DSC3 expression.
CONCLUSIONS
DNA methylation contributes to downregulation of DSC3 in CRC cell lines. Methylation status of DSC3 DNA is a prognostic marker for CRC. P53 appears to have an important role in regulating DSC3 expression.
背景
桥粒胶蛋白 3（DSC3）是钙黏蛋白超家族的成员，也是桥粒的组成部分，参与了致癌过程。然而，DSC3 在结直肠癌（CRC）中的作用尚未确定。
方法
通过 RT-PCR 和 Western blot 分析 CRC 细胞系中的 DSC3 表达。通过去甲基化试验、甲基特异性 PCR 和亚硫酸氢盐测序（BS）检查 DSC3 的甲基化状态。通过转染研究 p53 的调节作用。
结果
DSC3 在 CRC 细胞中的 mRNA 和蛋白水平均下调。在 7 个细胞系中的 5 个中，经 5-氮杂-2′-脱氧胞苷（DAC）处理后，DSC3 的表达得到恢复。BS 检测到 DSC3 启动子区域和外显子 1 存在异质性甲基化模式。在 41%（99 例中的 41 例）的原发性 CRC 中发现了 DSC3 基因组序列的甲基化，与预后不良相关（P=0.002）。单独转染 p53 或与 DAC 联合转染可增加 DSC3 的表达。同样，单独使用 p53 诱导剂阿霉素或与 DAC 联合处理可增强 DSC3 的表达。
结论
DNA 甲基化导致 CRC 细胞系中 DSC3 的下调。DSC3 DNA 的甲基化状态是 CRC 的预后标志物。p53 似乎在调节 DSC3 表达方面具有重要作用。
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