Targeting melanoma growth and metastasis with systemic delivery of liposome-incorporated protease-activated receptor-1 small interfering RNA.
Enviado por Pablo Vivas-Mejia el
Título | Targeting melanoma growth and metastasis with systemic delivery of liposome-incorporated protease-activated receptor-1 small interfering RNA. |
Publication Type | Journal Article |
Year of Publication | 2008 |
Autores | Villares, GJ, Zigler, M, Wang, H, Melnikova, VO, Wu, H, Friedman, R, Leslie, MC, Vivas-Mejia, P, Lopez-Berestein, G, Sood, AK, Bar-Eli, M |
Journal | Cancer Res |
Volume | 68 |
Issue | 21 |
Pagination | 9078-86 |
Date Published | 2008 Nov 1 |
ISSN | 1538-7445 |
Palabras clave | Animals, Base Sequence, Cell Division, Cell Line, Tumor, Female, Humans, Immunohistochemistry, Liposomes, Melanoma, Mice, Mice, Nude, Neoplasm Metastasis, Receptor, PAR-1, Reverse Transcriptase Polymerase Chain Reaction, RNA, Small Interfering |
Abstract | The thrombin receptor [protease-activated receptor-1 (PAR-1)] is overexpressed in highly metastatic melanoma cell lines and in patients with metastatic lesions. Activation of PAR-1 leads to cell signaling and up-regulation of genes involved in adhesion, invasion, and angiogenesis. Herein, we stably silence PAR-1 through the use of lentiviral short hairpin RNA and found significant decreases in both tumor growth (P < 0.01) and metastasis (P < 0.001) of highly metastatic melanoma cell lines in vivo. The use of viruses for therapy is not ideal as it can induce toxic immune responses and possible gene alterations following viral integration. Therefore, we also used systemic delivery of PAR-1 small interfering RNA (siRNA) incorporated into neutral liposomes [1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC)] to decrease melanoma growth and metastasis in vivo. Significant decreases in tumor growth, weight, and metastatic lung colonies (P < 0.001 for all) were found in mice treated with PAR-1 siRNA-DOPC. The in vivo effects of PAR-1 on invasion and angiogenesis were analyzed via immunohistochemistry. Concomitant decreases in vascular endothelial growth factor, interleukin-8, and matrix metalloproteinase-2 expression levels, as well as decreased blood vessel density (CD31), were found in tumor samples from PAR-1 siRNA-treated mice, suggesting that PAR-1 is a regulator of melanoma cell growth and metastasis by affecting angiogenic and invasive factors. We propose that siRNA incorporated into DOPC nanoparticles could be delivered systemically and used as a new modality for melanoma treatment. |
DOI | 10.1158/0008-5472.CAN-08-2397 |
Alternate Journal | Cancer Res. |
PubMed ID | 18974154 |
PubMed Central ID | PMC2597081 |
Grant List | R01 CA076098 / CA / NCI NIH HHS / United States R01 CA076098-09A1 / CA / NCI NIH HHS / United States R01CA76098 / CA / NCI NIH HHS / United States |