dc.contributor.author | Khairuddin, Norliana | |
dc.contributor.author | Gantier, Michael P | |
dc.contributor.author | Blake, Stephen J | |
dc.contributor.author | Wu, Sherry Y | |
dc.contributor.author | Behlke, Mark A | |
dc.contributor.author | Williams, Bryan RG | |
dc.contributor.author | McMillan, Nigel AJ | |
dc.date.accessioned | 2017-10-10T03:46:38Z | |
dc.date.available | 2017-10-10T03:46:38Z | |
dc.date.issued | 2012 | |
dc.date.modified | 2013-06-11T04:21:55Z | |
dc.identifier.issn | 0818-9641 | |
dc.identifier.doi | 10.1038/icb.2011.19 | |
dc.identifier.uri | http://hdl.handle.net/10072/47103 | |
dc.description.abstract | Oncogene-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.peerreviewed | Yes | |
dc.description.publicationstatus | Yes | |
dc.language | English | |
dc.language.iso | eng | |
dc.publisher | Nature Publishing Group | |
dc.publisher.place | United Kingdom | |
dc.relation.ispartofstudentpublication | N | |
dc.relation.ispartofpagefrom | 187 | |
dc.relation.ispartofpageto | 196 | |
dc.relation.ispartofissue | 2 | |
dc.relation.ispartofjournal | Immunology and Cell Biology | |
dc.relation.ispartofvolume | 90 | |
dc.rights.retention | Y | |
dc.subject.fieldofresearch | Biochemistry and cell biology | |
dc.subject.fieldofresearch | Immunology | |
dc.subject.fieldofresearch | Oncology and carcinogenesis not elsewhere classified | |
dc.subject.fieldofresearchcode | 3101 | |
dc.subject.fieldofresearchcode | 3204 | |
dc.subject.fieldofresearchcode | 321199 | |
dc.title | siRNA-induced immunostimulation through TLR7 promotes antitumoral activity against HPV-driven tumors in vivo | |
dc.type | Journal article | |
dc.type.description | C1 - Articles | |
dc.type.code | C - Journal Articles | |
dc.description.version | Accepted 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.issued | 2012 | |
gro.hasfulltext | Full Text | |
gro.griffith.author | McMillan, Nigel | |