4.7 Article

Silencing of human papillomavirus (HPV) E6/E7 oncogene expression affects both the contents and the amounts of extracellular microvesicles released from HPV-positive cancer cells

期刊

INTERNATIONAL JOURNAL OF CANCER
卷 133, 期 7, 页码 1631-1642

出版社

WILEY
DOI: 10.1002/ijc.28164

关键词

tumor virology; cervical cancer; HPV; exosomes; Survivin; senescence

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资金

  1. Peter und Traudl Engelhorn-Stiftung

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The human papillomavirus (HPV) E6/E7 oncogenes play a crucial role in the HPV-induced carcinogenesis. In this study, the authors investigated whether silencing of endogenous HPV E6/E7 expression may influence the contents or amounts of extracellular microvesicles (eMVs) released from HPV-positive cancer cells. It was found that eMVs secreted from HeLa cells are enriched for Survivin protein. RNA interference studies revealed that maintenance of both intracellular and microvesicular Survivin amounts was strongly dependent on continuous E6/E7 expression. This indicates that intracellular HPV activities are translated into visible alterations of protein contents in eMVs. Besides Survivin, eMVs from HeLa cells contain additional members of the inhibitor of apoptosis protein (IAP) family (XIAP, c-IAP1 and Livin). In contrast, no evidence for the presence of the HPV E6 and E7 oncoproteins in eMVs was obtained. Moreover, it was found that silencing of HPV E6/E7 expression led to a significant increase of exosomesrepresenting eMVs of endocytic originreleased from HeLa cells. This effect was associated with the reinduction of p53, stimulation of the p53 target genes TSAP6 and CHMP4C that can enhance exosome production and induction of senescence. Taken together, these results show that silencing of HPV E6/E7 oncogene expression profoundly affects both the composition and amounts of eMVs secreted by HPV-positive cancer cells. This indicates that HPVs can induce molecular signatures in eMVs that may affect intercellular communication and could be explored for diagnostic purposes. What's new? Microvesicles derived from tumor cells produce macro-scale effects, from suppressing the body's antitumor immune response to expediting tumor invasiveness. In this work, it is shown for the first time that extracellular microvesicle (eMV) contents of specific proteins are profoundly altered by human papillomavirus (HPV) E6/E7 oncogene silencing in HPV-positive HeLa cells. E6/E7 inhibition was associated with enhanced HeLa cell release of exosomes, which are microvesicles of endocytic origin. The findings indicate that intracellular activities of HPVs translate into molecular alterations in eMVs, with possible implications for tumorigenesis and tumor diagnosis.

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