Identification of Endoglin as an epigenetically regulated tumour-suppressor gene in lung cancer
| Autor: | Francesco Mauri, Marco Merlano, Karen O’Leary, F. Cavicchioli, A Shia, Manfred Wischnewsky, Tim Crook, Peter Schmid, C. Lo Nigro, Alberto Comino, Kimberly Walter, Mark R. Lackner, V. Haley |
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| Rok vydání: | 2015 |
| Předmět: |
Cancer Research
Lung Neoplasms tumour suppressor Protein Array Analysis Down-Regulation Genome-wide association study Receptors Cell Surface Biology Genetics & Genomics Methylation Downregulation and upregulation Antigens CD hemic and lymphatic diseases Carcinoma Non-Small-Cell Lung Cell Line Tumor medicine otorhinolaryngologic diseases Gene silencing Humans Genes Tumor Suppressor Gene Silencing Tumour suppressor gene Lung cancer Promoter Regions Genetic Gene Endoglin EMT Sequence Analysis DNA respiratory system medicine.disease respiratory tract diseases lung cancer Oncology Cancer research Disease Progression epigenetic Genome-Wide Association Study |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 |
| Popis: | Background: The transforming growth factor-beta (TGF- β) pathway has been implicated in proliferation, migration and invasion of various cancers. Endoglin is a TGF-β accessory receptor that modulates signalling. We identified Endoglin as an epigenetically silenced tumour-suppressor gene in lung cancer by means of a genome-wide screening approach, then sought to characterise its effect on lung cancer progression. Methods: Methylation microarray and RNA sequencing were carried out on lung cancer cell lines. Epigenetic silencing of Endoglin was confirmed by methylation and expression analyses. An expression vector and a 20-gene expression panel were used to evaluate Endoglin function. Pyrosequencing was carried out on two independent cohorts comprising 112 and 202 NSCLC cases, respectively, and the impact of Endoglin methylation on overall survival (OS) was evaluated. Results: Methylation in the promoter region resulted in silencing of Endoglin, which could be reactivated by demethylation. Increased invasion coupled with altered EMT marker expression was observed in cell lines with an epithelial-like, but not those with a mesenchymal-like, profile when Endoglin was absent. Methylation was associated with decreased OS in stage I but not in stages II–III disease. Conclusions: We show that Endoglin is a common target of epigenetic silencing in lung cancer. We reveal a link between Endoglin silencing and EMT progression that might be associated with decreased survival in stage I disease. |
| Databáze: | OpenAIRE |
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