Combined Inhibition of FOSL-1 and YAP Using siRNA-Lipoplexes Reduces the Growth of Pancreatic Tumor
Pancreatic cancer evades most of the current therapies and there is an urgent need for new treatments that could efficiently eliminate this aggressive tumor, such as the blocking of routes driving cell proliferation. In this work, we propose the use of small interfering RNA (siRNA) to inhibit the co...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-06-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/13/3102 |
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| author | Lara Diego-González Andrea Fernández-Carrera Ana Igea Amparo Martínez-Pérez M. Elisabete C. D. Real Oliveira Andreia C. Gomes Carmen Guerra Mariano Barbacid África González-Fernández Rosana Simón-Vázquez |
| author_facet | Lara Diego-González Andrea Fernández-Carrera Ana Igea Amparo Martínez-Pérez M. Elisabete C. D. Real Oliveira Andreia C. Gomes Carmen Guerra Mariano Barbacid África González-Fernández Rosana Simón-Vázquez |
| author_sort | Lara Diego-González |
| collection | DOAJ |
| description | Pancreatic cancer evades most of the current therapies and there is an urgent need for new treatments that could efficiently eliminate this aggressive tumor, such as the blocking of routes driving cell proliferation. In this work, we propose the use of small interfering RNA (siRNA) to inhibit the combined expression of FOSL-1 and YAP, two signaling proteins related with tumor cell proliferation and survival. To improve the efficacy of cell transfection, DODAB:MO (1:2) liposomes were used as siRNA nanocarriers, forming a complex denominated siRNA-lipoplexes. Liposomes and lipoplexes (carrying two siRNA for each targeted protein, or the combination of four siRNAs) were physico-chemically and biologically characterized. They showed very good biocompatibility and stability. The efficient targeting of FOSL-1 and YAP expression at both mRNA and protein levels was first proved in vitro using mouse pancreatic tumoral cell lines (KRAS<sup>G12V</sup> and p53 knockout), followed by in vivo studies using subcutaneous allografts on mice. The peri-tumoral injection of lipoplexes lead to a significant decrease in the tumor growth in both Athymic Nude-Foxn1<sup>nu</sup> and C57BL/6 mice, mainly in those receiving the combination of four siRNAs, targeting both YAP and FOSL-1. These results open a new perspective to overcome the fast tumor progression in pancreatic cancer. |
| first_indexed | 2024-03-09T22:03:36Z |
| format | Article |
| id | doaj.art-7a48a0a937684f4fa3fa47406022a328 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T22:03:36Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-7a48a0a937684f4fa3fa47406022a3282023-11-23T19:44:29ZengMDPI AGCancers2072-66942022-06-011413310210.3390/cancers14133102Combined Inhibition of FOSL-1 and YAP Using siRNA-Lipoplexes Reduces the Growth of Pancreatic TumorLara Diego-González0Andrea Fernández-Carrera1Ana Igea2Amparo Martínez-Pérez3M. Elisabete C. D. Real Oliveira4Andreia C. Gomes5Carmen Guerra6Mariano Barbacid7África González-Fernández8Rosana Simón-Vázquez9CINBIO, Universidade de Vigo, Immunology Group, 36310 Vigo, SpainCINBIO, Universidade de Vigo, Immunology Group, 36310 Vigo, SpainCINBIO, Universidade de Vigo, Immunology Group, 36310 Vigo, SpainCINBIO, Universidade de Vigo, Immunology Group, 36310 Vigo, SpainCFUM (Center of Physics), Department of Physics, University of Minho, Campus of Gualtar, 4710-057 Braga, PortugalCBMA (Centre of Molecular and Environmental Biology), Department of Biology, University of Minho, Campus of Gualtar, 4710-057 Braga, PortugalCNIO (Centro Nacional de Investigaciones Oncológicas), Experimental Oncology Group, 28029 Madrid, SpainCNIO (Centro Nacional de Investigaciones Oncológicas), Experimental Oncology Group, 28029 Madrid, SpainCINBIO, Universidade de Vigo, Immunology Group, 36310 Vigo, SpainCINBIO, Universidade de Vigo, Immunology Group, 36310 Vigo, SpainPancreatic cancer evades most of the current therapies and there is an urgent need for new treatments that could efficiently eliminate this aggressive tumor, such as the blocking of routes driving cell proliferation. In this work, we propose the use of small interfering RNA (siRNA) to inhibit the combined expression of FOSL-1 and YAP, two signaling proteins related with tumor cell proliferation and survival. To improve the efficacy of cell transfection, DODAB:MO (1:2) liposomes were used as siRNA nanocarriers, forming a complex denominated siRNA-lipoplexes. Liposomes and lipoplexes (carrying two siRNA for each targeted protein, or the combination of four siRNAs) were physico-chemically and biologically characterized. They showed very good biocompatibility and stability. The efficient targeting of FOSL-1 and YAP expression at both mRNA and protein levels was first proved in vitro using mouse pancreatic tumoral cell lines (KRAS<sup>G12V</sup> and p53 knockout), followed by in vivo studies using subcutaneous allografts on mice. The peri-tumoral injection of lipoplexes lead to a significant decrease in the tumor growth in both Athymic Nude-Foxn1<sup>nu</sup> and C57BL/6 mice, mainly in those receiving the combination of four siRNAs, targeting both YAP and FOSL-1. These results open a new perspective to overcome the fast tumor progression in pancreatic cancer.https://www.mdpi.com/2072-6694/14/13/3102pancreatic ductal adenocarcinomananomedicineliposomesgene silencingKRASHippo pathway |
| spellingShingle | Lara Diego-González Andrea Fernández-Carrera Ana Igea Amparo Martínez-Pérez M. Elisabete C. D. Real Oliveira Andreia C. Gomes Carmen Guerra Mariano Barbacid África González-Fernández Rosana Simón-Vázquez Combined Inhibition of FOSL-1 and YAP Using siRNA-Lipoplexes Reduces the Growth of Pancreatic Tumor Cancers pancreatic ductal adenocarcinoma nanomedicine liposomes gene silencing KRAS Hippo pathway |
| title | Combined Inhibition of FOSL-1 and YAP Using siRNA-Lipoplexes Reduces the Growth of Pancreatic Tumor |
| title_full | Combined Inhibition of FOSL-1 and YAP Using siRNA-Lipoplexes Reduces the Growth of Pancreatic Tumor |
| title_fullStr | Combined Inhibition of FOSL-1 and YAP Using siRNA-Lipoplexes Reduces the Growth of Pancreatic Tumor |
| title_full_unstemmed | Combined Inhibition of FOSL-1 and YAP Using siRNA-Lipoplexes Reduces the Growth of Pancreatic Tumor |
| title_short | Combined Inhibition of FOSL-1 and YAP Using siRNA-Lipoplexes Reduces the Growth of Pancreatic Tumor |
| title_sort | combined inhibition of fosl 1 and yap using sirna lipoplexes reduces the growth of pancreatic tumor |
| topic | pancreatic ductal adenocarcinoma nanomedicine liposomes gene silencing KRAS Hippo pathway |
| url | https://www.mdpi.com/2072-6694/14/13/3102 |
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