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dc.contributor.authorKhairuddin, Norliana
dc.contributor.authorGantier, Michael P
dc.contributor.authorBlake, Stephen J
dc.contributor.authorWu, Sherry Y
dc.contributor.authorBehlke, Mark A
dc.contributor.authorWilliams, Bryan RG
dc.contributor.authorMcMillan, Nigel AJ
dc.date.accessioned2017-10-10T03:46:38Z
dc.date.available2017-10-10T03:46:38Z
dc.date.issued2012
dc.date.modified2013-06-11T04:21:55Z
dc.identifier.issn0818-9641
dc.identifier.doi10.1038/icb.2011.19
dc.identifier.urihttp://hdl.handle.net/10072/47103
dc.description.abstractOncogene-specific downregulation mediated by RNA interference (RNAi) is a promising avenue for cancer therapy. In addition to specific gene silencing, in vivo RNAi treatment with short interfering RNAs (siRNAs) can initiate immune activation through innate immune receptors including Toll-like receptors, (TLRs) 7 and 8. Two recent studies have shown that activation of innate immunity by addition of tri-phosphate motifs to oncogene-specific siRNAs, or by co-treatment with CpG oligos, can potentiate siRNA antitumor effects. To date, there are no reports on applying such approach against human papillomavirus (HPV)-driven cancers. Here, we characterized the antitumor effects of non-modified siRNAs that can target a specific oncogene and/or recruit the innate immune system against HPV-driven tumors. Following the characterization of silencing efficacy and TLR7 immunostimulatory potential of 15 siRNAs targeting the HPV type 16 E6/E7 oncogenes, we identified a bifunctional siRNA sequence that displayed both potent gene silencing and active immunostimulation effect. In vivo systemic administration of this siRNA resulted in reduced growth of established TC-1 tumors in C57BL/6 mice. Ablation of TLR7 recruitment via 2'O-methyl modification of the oligo backbone reduced these antitumor effects. Further, a highly immunostimulatory, but non-HPV targeting siRNA was also able to exert antitumoral effects although for less prolonged time compared with the bifunctional siRNA. Collectively, our work demonstrates for the first time that siRNA-induced immunostimulation can have antitumoral effects against HPV-driven tumors in vivo, even independent of gene silencing efficacy.
dc.description.peerreviewedYes
dc.description.publicationstatusYes
dc.languageEnglish
dc.language.isoeng
dc.publisherNature Publishing Group
dc.publisher.placeUnited Kingdom
dc.relation.ispartofstudentpublicationN
dc.relation.ispartofpagefrom187
dc.relation.ispartofpageto196
dc.relation.ispartofissue2
dc.relation.ispartofjournalImmunology and Cell Biology
dc.relation.ispartofvolume90
dc.rights.retentionY
dc.subject.fieldofresearchBiochemistry and cell biology
dc.subject.fieldofresearchImmunology
dc.subject.fieldofresearchOncology and carcinogenesis not elsewhere classified
dc.subject.fieldofresearchcode3101
dc.subject.fieldofresearchcode3204
dc.subject.fieldofresearchcode321199
dc.titlesiRNA-induced immunostimulation through TLR7 promotes antitumoral activity against HPV-driven tumors in vivo
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
dc.description.versionAccepted Manuscript (AM)
gro.rights.copyright© 2012 Nature Publishing Group. This is the author-manuscript version of this paper. Reproduced in accordance with the copyright policy of the publisher. Please refer to the journal website for access to the definitive, published version.
gro.date.issued2012
gro.hasfulltextFull Text
gro.griffith.authorMcMillan, Nigel


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