Focal aberrations indicate EYA2 and hsa‐miR‐375 as oncogene and tumor suppressor in cervical carcinogenesis12. Issue 1 (14th September 2012)

• Record Type: Journal Article
• Authors: Bierkens, Mariska; Krijgsman, Oscar; Wilting, Saskia M.; Bosch, Leontien; Jaspers, Annelieke; Meijer, Gerrit A.; Meijer, Chris J. L. M.; Snijders, Peter J. F.; Ylstra, Bauke; Steenbergen, Renske D. M.
• Is Part Of: Genes, chromosomes & cancer. Volume 52:Issue 1(2013:Jan.)
• Page Start: 56
• Page End: 68
• Publication Date: 2012-09-14
• Subjects: Cancer -- Genetic aspects -- Periodicals; 616.994042
• DOI: 10.1002/gcc.22006
• Languages: English
• ISSNs: 1045-2257

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>Cervical cancer results from persistent infection with high‐risk human papillomavirus (hrHPV). Common genetic aberrations in cervical (pre)cancers encompass large genomic regions with numerous genes, hampering identification of driver genes. This study aimed to identify genes functionally involved in HPV‐mediated transformation by analysis of focal aberrations (<3 Mb) in high‐grade cervical intraepithelial neoplasia (hgCIN). Focal chromosomal aberrations were determined in high‐resolution array comparative genomic hybridization data of 60 hgCIN. Genes located within focal aberrations were validated using 2 external gene expression datasets or qRT‐PCR. Functional roles of candidate genes <italic>EYA2</italic> (20q13) and <italic>hsa‐miR‐375</italic> (2q35) were studied by siRNA‐mediated knock‐down and overexpression, respectively, in hrHPV‐containing cell lines. We identified 74 focal aberrations encoding 305 genes. Concurrent altered expression in hgCIN and/or cervical carcinomas compared with normal cervical samples was shown for <italic>ATP13A3, HES1, OPA1, HRASLS, EYA2, ZMYND8, APOBEC2</italic>, and <italic>NCR2</italic>. Gene silencing of <italic>EYA2</italic> significantly reduced viability, migratory capacity, and anchorage‐independent growth of HPV16‐transformed keratinocytes. For <italic>hsa‐miR‐375</italic>, a direct correlation between a (focal) loss and significantly reduced expression was found. Downregulation of <italic>hsa‐miR‐375</italic> expression was confirmed in an independent series of cervical tissues. Ectopic expression of <italic>hsa‐miR‐375</italic> in 2 cervical carcinoma cell lines reduced cellular viability. Our data provide a proof of concept that chromosomal aberrations are actively contributing to HPV‐induced carcinogenesis and identify <italic>EYA2</italic> and <italic>hsa‐miR‐375</italic> as oncogene and tumor suppressor gene, respectively. © 2012 Wiley Periodicals, Inc.</p> </abstract>