Nanoparticle-based delivery of siDCAMKL-1 increases <it>microRNA-144 </it>and inhibits colorectal cancer tumor growth via a Notch-1 dependent mechanism
<p>Abstract</p> <p>Background</p> <p>The development of effective drug delivery systems capable of transporting small interfering RNA (siRNA) has been elusive. We have previously reported that colorectal cancer tumor xenograft growth was arrested following treatment wit...
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| Format: | Article |
| Language: | English |
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BMC
2011-09-01
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| Series: | Journal of Nanobiotechnology |
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| Online Access: | http://www.jnanobiotechnology.com/content/9/1/40 |
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| author | Ponnurangam Sivapriya Qu Dongfeng Mondalek Fadee G May Randal Sureban Sripathi M Pantazis Panayotis Anant Shrikant Ramanujam Rama P Houchen Courtney W |
| author_facet | Ponnurangam Sivapriya Qu Dongfeng Mondalek Fadee G May Randal Sureban Sripathi M Pantazis Panayotis Anant Shrikant Ramanujam Rama P Houchen Courtney W |
| author_sort | Ponnurangam Sivapriya |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>The development of effective drug delivery systems capable of transporting small interfering RNA (siRNA) has been elusive. We have previously reported that colorectal cancer tumor xenograft growth was arrested following treatment with liposomal preparation of siDCAMKL-1. In this report, we have utilized Nanoparticle (NP) technology to deliver DCAMKL-1 specific siRNA to knockdown potential key cancer regulators. In this study, mRNA/miRNA were analyzed using real-time RT-PCR and protein by western blot/immunohistochemistry. siDCAMKL-1 was encapsulated in Poly(lactide-<it>co</it>-glycolide)-based NPs (NP-siDCAMKL-1); Tumor xenografts were generated in nude mice, treated with NP-siDCAMKL-1 and DAPT (γ-secretase inhibitor) alone and in combination. To measure <it>let-7a </it>and <it>miR-144 </it>expression <it>in vitro</it>, HCT116 cells were transfected with plasmids encoding the firefly luciferase gene with <it>let-7a </it>and <it>miR-144 </it>miRNA binding sites in the 3'UTR.</p> <p>Results</p> <p>Administration of NP-siDCAMKL-1 into HCT116 xenografts resulted in tumor growth arrest, downregulation of proto-oncogene c-Myc and Notch-1 via <it>let-7a </it>and <it>miR-144 </it>miRNA-dependent mechanisms, respectively. A corresponding reduction in <it>let-7a </it>and <it>miR-144 </it>specific luciferase activity was observed <it>in vitro</it>. Moreover, an upregulation of EMT inhibitor <it>miR-200a </it>and downregulation of the EMT-associated transcription factors ZEB1, ZEB2, Snail and Slug were observed <it>in vivo</it>. Lastly, DAPT-mediated inhibition of Notch-1 resulted in HCT116 tumor growth arrest and down regulation of Notch-1 via a <it>miR-144 </it>dependent mechanism.</p> <p>Conclusions</p> <p>These findings demonstrate that nanoparticle-based delivery of siRNAs directed at critical targets such as DCAMKL-1 may provide a novel approach to treat cancer through the regulation of endogenous miRNAs.</p> |
| first_indexed | 2024-04-14T01:27:38Z |
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| issn | 1477-3155 |
| language | English |
| last_indexed | 2024-04-14T01:27:38Z |
| publishDate | 2011-09-01 |
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| spelling | doaj.art-dad574d17ee1498b95fe55e0fbb1f99c2022-12-22T02:20:20ZengBMCJournal of Nanobiotechnology1477-31552011-09-01914010.1186/1477-3155-9-40Nanoparticle-based delivery of siDCAMKL-1 increases <it>microRNA-144 </it>and inhibits colorectal cancer tumor growth via a Notch-1 dependent mechanismPonnurangam SivapriyaQu DongfengMondalek Fadee GMay RandalSureban Sripathi MPantazis PanayotisAnant ShrikantRamanujam Rama PHouchen Courtney W<p>Abstract</p> <p>Background</p> <p>The development of effective drug delivery systems capable of transporting small interfering RNA (siRNA) has been elusive. We have previously reported that colorectal cancer tumor xenograft growth was arrested following treatment with liposomal preparation of siDCAMKL-1. In this report, we have utilized Nanoparticle (NP) technology to deliver DCAMKL-1 specific siRNA to knockdown potential key cancer regulators. In this study, mRNA/miRNA were analyzed using real-time RT-PCR and protein by western blot/immunohistochemistry. siDCAMKL-1 was encapsulated in Poly(lactide-<it>co</it>-glycolide)-based NPs (NP-siDCAMKL-1); Tumor xenografts were generated in nude mice, treated with NP-siDCAMKL-1 and DAPT (γ-secretase inhibitor) alone and in combination. To measure <it>let-7a </it>and <it>miR-144 </it>expression <it>in vitro</it>, HCT116 cells were transfected with plasmids encoding the firefly luciferase gene with <it>let-7a </it>and <it>miR-144 </it>miRNA binding sites in the 3'UTR.</p> <p>Results</p> <p>Administration of NP-siDCAMKL-1 into HCT116 xenografts resulted in tumor growth arrest, downregulation of proto-oncogene c-Myc and Notch-1 via <it>let-7a </it>and <it>miR-144 </it>miRNA-dependent mechanisms, respectively. A corresponding reduction in <it>let-7a </it>and <it>miR-144 </it>specific luciferase activity was observed <it>in vitro</it>. Moreover, an upregulation of EMT inhibitor <it>miR-200a </it>and downregulation of the EMT-associated transcription factors ZEB1, ZEB2, Snail and Slug were observed <it>in vivo</it>. Lastly, DAPT-mediated inhibition of Notch-1 resulted in HCT116 tumor growth arrest and down regulation of Notch-1 via a <it>miR-144 </it>dependent mechanism.</p> <p>Conclusions</p> <p>These findings demonstrate that nanoparticle-based delivery of siRNAs directed at critical targets such as DCAMKL-1 may provide a novel approach to treat cancer through the regulation of endogenous miRNAs.</p>http://www.jnanobiotechnology.com/content/9/1/40DCAMKL-1<it>miR-144</it>microRNAsiRNAnotch signalingnanoparticlesHCT116tumor xenograftcancer stem cells |
| spellingShingle | Ponnurangam Sivapriya Qu Dongfeng Mondalek Fadee G May Randal Sureban Sripathi M Pantazis Panayotis Anant Shrikant Ramanujam Rama P Houchen Courtney W Nanoparticle-based delivery of siDCAMKL-1 increases <it>microRNA-144 </it>and inhibits colorectal cancer tumor growth via a Notch-1 dependent mechanism Journal of Nanobiotechnology DCAMKL-1 <it>miR-144</it> microRNA siRNA notch signaling nanoparticles HCT116 tumor xenograft cancer stem cells |
| title | Nanoparticle-based delivery of siDCAMKL-1 increases <it>microRNA-144 </it>and inhibits colorectal cancer tumor growth via a Notch-1 dependent mechanism |
| title_full | Nanoparticle-based delivery of siDCAMKL-1 increases <it>microRNA-144 </it>and inhibits colorectal cancer tumor growth via a Notch-1 dependent mechanism |
| title_fullStr | Nanoparticle-based delivery of siDCAMKL-1 increases <it>microRNA-144 </it>and inhibits colorectal cancer tumor growth via a Notch-1 dependent mechanism |
| title_full_unstemmed | Nanoparticle-based delivery of siDCAMKL-1 increases <it>microRNA-144 </it>and inhibits colorectal cancer tumor growth via a Notch-1 dependent mechanism |
| title_short | Nanoparticle-based delivery of siDCAMKL-1 increases <it>microRNA-144 </it>and inhibits colorectal cancer tumor growth via a Notch-1 dependent mechanism |
| title_sort | nanoparticle based delivery of sidcamkl 1 increases it microrna 144 it and inhibits colorectal cancer tumor growth via a notch 1 dependent mechanism |
| topic | DCAMKL-1 <it>miR-144</it> microRNA siRNA notch signaling nanoparticles HCT116 tumor xenograft cancer stem cells |
| url | http://www.jnanobiotechnology.com/content/9/1/40 |
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