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Epigenetic regulation of Amphiregulin and Epiregulin in colorectal cancer
Author(s) -
Bormann Felix,
Stinzing Sebastian,
Tierling Sascha,
Morkel Markus,
Markelova Maria Rivera,
Walter Jörn,
Weichert Wilko,
Roßner Florian,
Kuhn Natalia,
Perner Juliane,
Dietz Johanna,
Ispasanie Sylvia,
Dietel Manfred,
Schäfer Reinhold,
Heinemann Volker,
Sers Christine
Publication year - 2018
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.31892
Subject(s) - amphiregulin , epiregulin , colorectal cancer , epigenetics , oncology , medicine , cancer research , cancer , biology , genetics , gene , epidermal growth factor receptor
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.