Dependence of Intracellular and Exosomal microRNAs on Viral E6/E7 Oncogene Expression in HPV-positive Tumor Cells

Honegger, Anja; Schilling, Daniela; Bastian, Sandra; Sponagel, Jasmin; Kuryshev, Vladimir; Sültmann, Holger; Scheffner, Martin; Hoppe-Seyler, Karin; Hoppe-Seyler, Felix

Dependence of Intracellular and Exosomal microRNAs on Viral E6/E7 Oncogene Expression in HPV-positive Tumor Cells

Dateien

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Datum

2015

Autor:innen

Honegger, Anja

Schilling, Daniela

Bastian, Sandra

Sponagel, Jasmin

Kuryshev, Vladimir

Sültmann, Holger

Scheffner, Martin

Hoppe-Seyler, Karin

Hoppe-Seyler, Felix

Open Access-Veröffentlichung

Open Access Gold

Sammlungen

Biologie

Publikationstyp

Zeitschriftenartikel

Publikationsstatus

Published

Erschienen in

PLoS Pathogens. 2015, 11(3), e1004712. ISSN 1553-7366. eISSN 1553-7374. Available under: doi: 10.1371/journal.ppat.1004712

Zusammenfassung

Specific types of human papillomaviruses (HPVs) cause cervical cancer. Cervical cancers exhibit aberrant cellular microRNA (miRNA) expression patterns. By genome-wide analyses, we investigate whether the intracellular and exosomal miRNA compositions of HPV-positive cancer cells are dependent on endogenous E6/E7 oncogene expression. Deep sequencing studies combined with qRT-PCR analyses show that E6/E7 silencing significantly affects ten of the 52 most abundant intracellular miRNAs in HPV18-positive HeLa cells, downregulating miR-17-5p, miR-186-5p, miR-378a-3p, miR-378f, miR-629-5p and miR-7-5p, and upregulating miR-143-3p, miR-23a-3p, miR-23b-3p and miR-27b-3p. The effects of E6/E7 silencing on miRNA levels are mainly not dependent on p53 and similarly observed in HPV16-positive SiHa cells. The E6/E7-regulated miRNAs are enriched for species involved in the control of cell proliferation, senescence and apoptosis, suggesting that they contribute to the growth of HPV-positive cancer cells. Consistently, we show that sustained E6/E7 expression is required to maintain the intracellular levels of members of the miR-17~92 cluster, which reduce expression of the anti-proliferative p21 gene in HPV-positive cancer cells. In exosomes secreted by HeLa cells, a distinct seven-miRNA-signature was identified among the most abundant miRNAs, with significant downregulation of let-7d-5p, miR-20a-5p, miR-378a-3p, miR-423-3p, miR-7-5p, miR-92a-3p and upregulation of miR-21-5p, upon E6/E7 silencing. Several of the E6/E7-dependent exosomal miRNAs have also been linked to the control of cell proliferation and apoptosis. This study represents the first global analysis of intracellular and exosomal miRNAs and shows that viral oncogene expression affects the abundance of multiple miRNAs likely contributing to the E6/E7-dependent growth of HPV-positive cancer cells.

Fachgebiet (DDC)

570 Biowissenschaften, Biologie

Schlagwörter

MicroRNAs, RNA sequencing, HeLa cells, Small interfering RNAs, Cervical cancer, Transfection, RNA extraction, Human papillomavirus infection

Zitieren

ISO 690

HONEGGER, Anja, Daniela SCHILLING, Sandra BASTIAN, Jasmin SPONAGEL, Vladimir KURYSHEV, Holger SÜLTMANN, Martin SCHEFFNER, Karin HOPPE-SEYLER, Felix HOPPE-SEYLER, 2015. Dependence of Intracellular and Exosomal microRNAs on Viral E6/E7 Oncogene Expression in HPV-positive Tumor Cells. In: PLoS Pathogens. 2015, 11(3), e1004712. ISSN 1553-7366. eISSN 1553-7374. Available under: doi: 10.1371/journal.ppat.1004712

BibTex

@article{Honegger2015Depen-31250,
  year={2015},
  doi={10.1371/journal.ppat.1004712},
  title={Dependence of Intracellular and Exosomal microRNAs on Viral E6/E7 Oncogene Expression in HPV-positive Tumor Cells},
  number={3},
  volume={11},
  issn={1553-7366},
  journal={PLoS Pathogens},
  author={Honegger, Anja and Schilling, Daniela and Bastian, Sandra and Sponagel, Jasmin and Kuryshev, Vladimir and Sültmann, Holger and Scheffner, Martin and Hoppe-Seyler, Karin and Hoppe-Seyler, Felix},
  note={Article Number: e1004712}
}

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Universitätsbibliographie

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