Integrated genomic analysis of colorectal cancer progression reveals activation of EGFR through demethylation of the EREG promoter
Autor: | Omar Kabbarah, Thomas Sandmann, C Rumpel, Mark R. Lackner, Garret Hampton, Elicia Penuel, Richard Bourgon, Lukas C. Amler, Yulei Wang, Eloisa Fuentes, Christopher A. Moskaluk, Ling Fu, Josep Tabernero, Kwame Okrah, Andrea Pirzkall, Kimberly Walter, Shan Lu, Xueping Qu, Henry F. Frierson |
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Jazyk: | angličtina |
Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Cancer Research Biology Decitabine Epiregulin 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Cell Line Tumor Genetics Humans Epidermal growth factor receptor Phosphorylation Autocrine signalling Promoter Regions Genetic Molecular Biology EGFR inhibitors DNA Methylation Molecular biology digestive system diseases Gene expression profiling ErbB Receptors 030104 developmental biology 030220 oncology & carcinogenesis DNA methylation Cancer cell Cancer research biology.protein Azacitidine Disease Progression Original Article Colorectal Neoplasms |
Zdroj: | Oncogene |
ISSN: | 1476-5594 0950-9232 |
Popis: | Key molecular drivers that underlie transformation of colonic epithelium into colorectal adenocarcinoma (CRC) are well described. However, the mechanisms through which clinically targeted pathways are activated during CRC progression have yet to be elucidated. Here, we used an integrative genomics approach to examine CRC progression. We used laser capture microdissection to isolate colonic crypt cells, differentiated surface epithelium, adenomas, carcinomas and metastases, and used gene expression profiling to identify pathways that were differentially expressed between the different cell types. We identified a number of potentially important transcriptional changes in developmental and oncogenic pathways, and noted a marked upregulation of EREG in primary and metastatic cancer cells. We confirmed this pattern of gene expression by in situ hybridization and observed staining consistent with autocrine expression in the tumor cells. Upregulation of EREG during the adenoma-carcinoma transition was associated with demethylation of two key sites within its promoter, and this was accompanied by an increase in the levels of epidermal growth factor receptor (EGFR) phosphorylation, as assessed by reverse-phase protein analysis. In CRC cell lines, we demonstrated that EREG demethylation led to its transcriptional upregulation, higher levels of EGFR phosphorylation, and sensitization to EGFR inhibitors. Low levels of EREG methylation in patients who received cetuximab as part of a phase II study were associated with high expression of the ligand and a favorable response to therapy. Conversely, high levels of promoter methylation and low levels of EREG expression were observed in tumors that progressed after treatment. We also noted an inverse correlation between EREG methylation and expression levels in several other cancers, including those of the head and neck, lung and bladder. Therefore, we propose that upregulation of EREG expression through promoter demethylation might be an important means of activating the EGFR pathway during the genesis of CRC and potentially other cancers. |
Databáze: | OpenAIRE |
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