Endoglin (CD105) Silencing Mediated by shRNA Under the Control of Endothelin-1 Promoter for Targeted Gene Therapy of Melanoma.
Endoglin (CD105), a transforming growth factor (TGF)-β coreceptor, and endothelin-1, a vasoconstrictor peptide, are both overexpressed in tumor endothelial and melanoma cells. Their targeting is therefore a promising therapeutic approach for melanoma tumors. The aim of our study was to construct a eukaryotic expression plasmid encoding the shRNA molecules against CD105 under the control of endothelin-1 promoter and to evaluate its therapeutic potential both in vitro in murine B16F10-luc melanoma and SVEC4-10 endothelial cells and in vivo in mice bearing highly metastatic B16F10-luc tumors. Plasmid encoding shRNA against CD105 under the control of the constitutive U6 promoter was used as a control. We demonstrated the antiproliferative and antiangiogenic effects of both plasmids in SVEC4-10 cells, as well as a moderate antitumor and pronounced antimetastatic effect in B16F10-luc tumors in vivo. Our results provide evidence that targeting melanoma with shRNA molecules against CD105 under the control of endothelin-1 promoter is a feasible and effective treatment, especially for the reduction of metastatic spread.
Faculty of Health Sciences, University of Primorska, Isola, Slovenia.
Natasa
N
Tesic
Department of Experimental Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
Urska
U
Kamensek
Department of Experimental Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
Gregor
G
Sersa
Department of Experimental Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
Simona
S
Kranjc
Department of Experimental Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
Monika
M
Stimac
Department of Experimental Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
Ursa
U
Lampreht
Université Catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Woluwe-Saint-Lambert, Belgium.
Veronique
V
Preat
Université Catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Woluwe-Saint-Lambert, Belgium.
Gaelle
G
Vandermeulen
Department of Biochemistry and Molecular and Structural Biology, Jozef Stefan Institute, Ljubljana, Slovenia.
Miha
M
Butinar
Department of Biochemistry and Molecular and Structural Biology, Jozef Stefan Institute, Ljubljana, Slovenia.
Boris
B
Turk
1] Faculty of Health Sciences, University of Primorska, Isola, Slovenia [2] Department of Experimental Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
Maja
M
Cemazar