Expression of MUC5AC, an early marker of pancreatobiliary cancer, is regulated by DNA methylation in the distal promoter region in cancer cells
Expression of MUC5AC, an early marker of pancreatobiliary cancer, is regulated by DNA methylation in the distal promoter region in cancer cells
复制标题
DOI：
10.1007/s00534-010-0278-0
复制
发表时间：
2010-11-01
影响因子：
3
通讯作者：
Yonezawa, Suguru
中科院分区：
文献类型：
--
作者：
Yamada, Norishige;Nishida, Yukari;Yonezawa, Suguru
在许多类型的胰胆管肿瘤（包括前驱病变）中观察到MUC 5AC（一种胃型分泌粘蛋白）的高从头表达。在这项研究中，我们发现DNA甲基化模式与10种癌细胞系（乳腺癌、肺癌、胰腺癌和结肠癌）中MUC 5AC的表达密切相关。使用MassARRAY分析，利用核酸的碱基特异性切割，对MUC 5AC启动子从-3855到+321的CpG甲基化状态进行了定位。还在MUC 5AC阳性细胞和不表达或低表达MUC 5AC的细胞中进行ChIP测定和微小RNA（miRNA）微阵列表达谱分析。MDA-MB-453）高度甲基化，而MUC 5AC阳性细胞（例如，MCF-7）具有低甲基化水平。组蛋白H3赖氨酸9（H3-K9）的修饰状态也与MUC 5AC的表达密切相关。结果表明，MUC 5AC的表达受MUC 5AC启动子远端CpG甲基化和组蛋白H3-K9修饰的调控，而与miRNA无关。了解MUC 5AC的表观遗传调控可能对胰胆系统致癌风险的诊断具有重要意义。
High de novo expression of MUC5AC (a gastric-type secreted mucin) is observed in many types of pancreatobiliary neoplasms, including precursor lesions. In this study, we show that the DNA methylation pattern is intimately correlated with MUC5AC expression in ten cancer cell lines (breast, lung, pancreas, and colon).The CpG methylation status of the MUC5AC promoter from -3855 to +321 was mapped using MassARRAY analysis, which utilizes base-specific cleavage of nucleic acids. ChIP assays and micro-RNA (miRNA) microarray expression profiling were also carried out in both MUC5AC-positive cells and in those with no or low MUC5AC expression.In the distal region from -3718 to -3670 of the promoter, MUC5AC-negative cancer cells (e.g., MDA-MB-453) were highly methylated, whereas MUC5AC-positive cells (e.g., MCF-7) had low methylation levels. The modification status of histone H3 lysine 9 (H3-K9) was also closely related to MUC5AC expression. Expression levels of miRNAs in the cancer cells were not correlated with MUC5AC expression.Our results indicate that MUC5AC is regulated by CpG methylation and histone H3-K9 modification of the MUC5AC promoter distal region, but not by miRNAs. An understanding of the epigenetic regulation of MUC5AC may be of importance for the diagnosis of carcinogenic risk in the pancreatobiliary system.