Epigenetic regulation of Amphiregulin and Epiregulin in colorectal cancer.

Abstract

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.

• Authors: Felix Bormann, Sebastian Stinzing, Sascha Tierling, Markus Morkel, Maria Rivera Markelova, Jörn Walter, Wilko Weichert, Florian Roßner, Natalia Kuhn, Juliane Perner, Johanna Dietz, Sylvia Ispasanie, Manfred Dietel, Reinhold Schäfer, Volker Heinemann, Christine Sers
• Journal: International journal of cancer (Int J Cancer) Vol. 144 Issue 3 Pg. 569-581 (02 01 2019) ISSN: 1097-0215 [Electronic] United States
• PMID: 30252132 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 UICC.

Chemical References

• AREG protein, human
• Amphiregulin
• EREG protein, human
• Epiregulin
• KRAS protein, human
• RNA, Messenger
• EGFR protein, human
• ErbB Receptors
• Proto-Oncogene Proteins p21(ras)

Topics

• Amphiregulin (biosynthesis, genetics)
• Caco-2 Cells
• Cell Line, Tumor
• Colorectal Neoplasms (genetics, metabolism, pathology)
• DNA Methylation
• Epigenesis, Genetic
• Epiregulin (genetics)
• Epithelial Cells (metabolism, pathology)
• ErbB Receptors (genetics, metabolism)
• Gene Expression
• HCT116 Cells
• Humans
• Promoter Regions, Genetic
• Proto-Oncogene Proteins p21(ras) (genetics, metabolism)
• RNA, Messenger (biosynthesis, genetics)
• Retrospective Studies
• Stromal Cells (metabolism, pathology)