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


Oncogenic human papillomaviruses (HPVs) are major human carcinogens of broad biomedical importance. The growth of HPV-positive cervical cancer cells is critically dependent on sustained E6/E7 oncogene expression from endogenous viral DNA sequences. We here addressed the question of whether this process is linked to specific, E6/E7-dependent alterations of the cellular micro(mi)RNA network. By comprehensive deep sequencing analyses we show that endogenous E6/E7 expression significantly affects the concentrations of abundant intracellular miRNAs in HPV-positive cervical cancer cells, which are linked to the control of cell proliferation, senescence and apoptosis. These include members of the miR-17~92 cluster, which are expressed at increased levels by sustained E6/E7 expression and repress the anti-proliferative p21 gene in HPV-positive cancer cells. Moreover, we identified an E6/E7-dependent seven-miRNA-signature in exosomes secreted from HPV-positive cancer cells. These small vesicles are involved in intercellular communication and may serve as novel diagnostic markers. Taken together, our results show that continuous E6/E7 expression in HPV-positive cancer cells is linked to significant alterations in the amounts of intracellular and exosomal miRNAs with growth-promoting, anti-senescent and anti-apoptotic potential.


Vyšlo v časopise: Dependence of Intracellular and Exosomal microRNAs on Viral Oncogene Expression in HPV-positive Tumor Cells. PLoS Pathog 11(3): e32767. doi:10.1371/journal.ppat.1004712
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004712

Souhrn

Oncogenic human papillomaviruses (HPVs) are major human carcinogens of broad biomedical importance. The growth of HPV-positive cervical cancer cells is critically dependent on sustained E6/E7 oncogene expression from endogenous viral DNA sequences. We here addressed the question of whether this process is linked to specific, E6/E7-dependent alterations of the cellular micro(mi)RNA network. By comprehensive deep sequencing analyses we show that endogenous E6/E7 expression significantly affects the concentrations of abundant intracellular miRNAs in HPV-positive cervical cancer cells, which are linked to the control of cell proliferation, senescence and apoptosis. These include members of the miR-17~92 cluster, which are expressed at increased levels by sustained E6/E7 expression and repress the anti-proliferative p21 gene in HPV-positive cancer cells. Moreover, we identified an E6/E7-dependent seven-miRNA-signature in exosomes secreted from HPV-positive cancer cells. These small vesicles are involved in intercellular communication and may serve as novel diagnostic markers. Taken together, our results show that continuous E6/E7 expression in HPV-positive cancer cells is linked to significant alterations in the amounts of intracellular and exosomal miRNAs with growth-promoting, anti-senescent and anti-apoptotic potential.


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Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

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PLOS Pathogens


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