Epigenetic regulation of Amphiregulin and Epiregulin in colorectal cancer
Epigenetic regulation of Amphiregulin and Epiregulin in colorectal cancer
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DOI：
10.1002/ijc.31892
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发表时间：
2019-02-01
影响因子：
6.4
通讯作者：
Sers, Christine
中科院分区：
文献类型：
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作者：
Bormann, Felix;Stinzing, Sebastian;Sers, Christine
表皮生长因子配体双调蛋白（AREG）和表皮调节蛋白（EREG）的表达与结直肠癌EGFR靶向治疗的反应呈正相关。使用靶向454 FLX-亚硫酸氢盐测序和AREG/EREG启动子和基因内CpG的SIRPH分析，在细胞系中鉴定了与AREG和EREG基因表达呈强负相关的基因体甲基化位点。在用5-氮杂-2 '-脱氧胞苷处理结直肠癌细胞后，在特定基因内CpG处甲基化降低，伴随AREG和EREG基因表达的上调。在人类结直肠癌样本中也发现了相同的AREG基因体甲基化，并且与KRAS和NRAS突变无关。与基质组织和正常上皮相比，肿瘤上皮区室中的甲基化特异性降低。AREG外显子2区域的启动子/增强子功能的研究揭示了反向方向的潜在启动子功能。使用来自接受抗EGFR抑制剂治疗的结直肠癌患者的样本，回顾性比较AREG基因体甲基化与AREG基因表达的预测能力，并进行完整的临床随访，结果显示AREG表达上级AREG基因甲基化。AREG和EREG基因经历复杂的调控，涉及基因内甲基化和启动子依赖性控制。
Expression of the epidermal growth factor ligands amphiregulin (AREG) and epiregulin (EREG) is positively correlated with a response to EGFR-targeted therapies in colorectal cancer. Gene-body methylation sites, which show a strong inverse correlation with AREG and EREG gene expression, were identified in cell lines using targeted 454 FLX-bisulfite sequencing and SIRPH analyses for AREG/EREG promoters and intragenic CpGs. Upon treatment of colorectal cancer cells with 5-aza-2 '-desoxycytidine, methylation decreases at specific intragenic CpGs accompanied by upregulation of AREG and EREG gene expression. The same AREG gene-body methylation was also found in human colorectal cancer samples and is independent of KRAS and NRAS mutations. Methylation is specifically decreased in the tumor epithelial compartment as compared to stromal tissue and normal epithelium. Investigation of a promoter/enhancer function of the AREG exon 2 region revealed a potential promoter function in reverse orientation. Retrospective comparison of the predictive power of AREG gene-body methylation versus AREG gene expression using samples from colorectal cancer patients treated with anti-EGFR inhibitors with complete clinical follow-up revealed that AREG expression is superior to AREG gene methylation. AREG and EREG genes undergo a complex regulation involving both intragenic methylation and promoter-dependent control.