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Altered microRNA expression associated with chromosomal changes contributes to cervical carcinogenesis

Oncogene volume 32, pages 106–116 (2013)Cite this article

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Abstract

Little is known about the alterations in microRNA (miRNA) expression patterns during the consecutive stages of cervical cancer development and their association with chromosomal instability. In this study, miRNA expression in normal cervical squamous epithelium, high-grade precancerous lesions (cervical intraepithelial neoplasia (CIN2–3)), squamous cell carcinomas (SCCs) and adenocarcinomas (AdCAs) was integrated with previously generated chromosomal profiles of the same samples. Significantly differential expression during the consecutive stages of cervical SCC development was observed for 106 miRNAs. Of these differentially expressed miRNAs, 27 showed early transiently altered expression in CIN2–3 lesions only, 46 miRNAs showed late altered expression in SCCs only and 33 showed continuously altered expression in both CIN2–3 and SCCs. Altered expression of five significantly differentially expressed miRNAs, hsa-miR-9 (1q23.2), hsa-miR-15b (3q25.32), hsa-miR-28-5p (3q27.3), hsa-miR-100 and hsa-miR-125b (both 11q24.1), was directly linked to frequent chromosomal alterations. Functional analyses were performed for hsa-miR-9, representing a potential oncogene with increased expression linked to a chromosomal gain of 1q. Hsa-miR-9 overexpression was found to increase cell viability, anchorage-independent growth and migration in vitro. Upon organic raft culturing, hsa-miR-9 hampered differentiation and induced proliferation in all strata of the epithelial layer. These findings support a potential oncogenic function of hsa-miR-9 in cervical cancer. In summary, differential expression of 106 miRNAs, partly associated with chromosomal alterations, was observed during cervical SCC development. Altered expression of hsa-miR-9 associated with a chromosomal gain of chromosome 1q was shown to be functionally relevant, underlining the importance of deregulated miRNA expression in cervical carcinogenesis.

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Acknowledgements

This work was supported by the V-ICI institute of the VU University Medical Center, Amsterdam, The Netherlands (grant number CCA20085-04) and the Dutch Cancer Society (KWF, grant number VU2010-4668). We are grateful to Marlon van der Plas, Suzanne Snellenberg, Nour Makazaji and Tim Schutte for excellent technical assistance.

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  1. C le Sage

    Present address: 7Current Address: The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, United Kingdom,

Authors and Affiliations

  1. Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands

    S M Wilting, P J F Snijders, W Verlaat, A Jaspers, G A Meijer, C J L M Meijer & R D M Steenbergen

  2. Department of Epidemiology & Biostatistics, VU University Medical Center, Amsterdam, The Netherlands

    M A van de Wiel & W N van Wieringen

  3. Department of Mathematics, VU University, Amsterdam, The Netherlands

    M A van de Wiel & W N van Wieringen

  4. Department of Obstetrics & Gynaecology, VU University Medical Center Amsterdam, Amsterdam, The Netherlands

    G G Kenter

  5. Division of Genetic Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA

    Y Yi

  6. Division of Gene Regulation, the Netherlands Cancer Institute, Amsterdam, The Netherlands

    C le Sage & R Agami

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Dr RDM Steenbergen, Professor Dr PJF Snijders and Professor Dr CJLM Meijer are stockholders of Self-screen BV, The Netherlands. All authors declare no conflict of interest.

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Wilting, S., Snijders, P., Verlaat, W. et al. Altered microRNA expression associated with chromosomal changes contributes to cervical carcinogenesis. Oncogene 32, 106–116 (2013). https://doi.org/10.1038/onc.2012.20

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