Efficient in vivo microRNA targeting of liver metastasis

Abstract

Targeting oncogenic microRNAs (miRNAs) is emerging as a promising strategy for cancer therapy. In this study, we provide proof of principle for the safety and efficacy of miRNA targeting against metastatic tumors. We tested the impact of targeting miR-182, a pro-metastatic miRNA frequently overexpressed in melanoma, the in vitro silencing of which represses invasion and induces apoptosis. Specifically, we assessed the effect of anti-miR-182 oligonucleotides synthesized with 2 0 sugar modifications and a phosphorothioate backbone in a mouse model of melanoma liver metastasis. Luciferase imaging showed that mice treated with anti-miR-182 had a lower burden of liver metastases compared with control. We confirmed that miR-182 levels were effectively downregulated in the tumors of anti-miR-treated mice compared with tumors of control-treated mice, both in the liver and in the spleen. This effect was accompanied by an upregulation of multiple miR-182 direct targets. Transcriptional profiling of tumors treated with anti-miR-182 or with control oligonucleotides revealed an enrichment of genes controlling survival, adhesion and migration modulated in response to anti-miR-182 treatment. These data indicate that in vivo administration of anti-miRs allows for efficient miRNA targeting and concomitant upregulation of miRNAcontrolled genes. Our results demonstrate that the use of anti-miR-182 is a promising therapeutic strategy for metastatic melanoma and provide a solid basis for testing similar strategies in human metastatic tumors.

Autocrine/Paracrine Human Growth Hormone-stimulated MicroRNA 96-182-183 Cluster Promotes Epithelial-Mesenchymal Transition and Invasion in Breast Cancer

“…Conversely, miR-20b was reported to modulate HIF-1 and VEGF expression in breast cancer, and miR-137 is down-regulated in colorectal cancer and suppresses cell invasion and metastasis, suggesting their tumor suppressor functions (44,45). The miR-96-182-183 cluster has been reported to modulate cancer invasion and metastasis in liver cancer (46), melanoma (47), prostate cancer (48), and breast cancer (49). Hundreds of putative targets of this cluster were identified by bioinformatics analysis (Fig.…”

miR-33a functions as a tumor suppressor in melanoma by targeting HIF-1α

“…34 MicroRNA interference technique can effectively inhibit the progress of melanoma invasion. 35 Therefore, targeting the miR-33a/HIF-1a signaling axis is likely to provide a new strategy for the clinical treatment of melanoma and inhibition of tumor invasion and metastasis.…”

Salivary miRNAome profiling uncovers epithelial and proliferative miRNAs with differential expression across dentition stages

“…74 The prospect to better understand such clinical challenges and the possibility of using miRNAs in novel treatment strategies stands as a good reason to advance this area of oral biology, especially considering recent advances in applying miRNA therapeutics to other diseases. 75,76 The results presented here also provide a useful background for forthcoming research on systemic diseases associated with development and linked to modulations in saliva composition.…”