Efficient in vivo microRNA targeting of liver metastasis

• Published in: Oncogene Vol. 30; no. 12; pp. 1481 - 1488
• Main Authors: Huynh, C, Segura, M F, Gaziel-Sovran, A, Menendez, S, Darvishian, F, Chiriboga, L, Levin, B, Meruelo, D, Osman, I, Zavadil, J, Marcusson, E G, Hernando, E
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.03.2011; Nature Publishing Group
• Subjects: 631/67/1813/1634; 631/67/322; 631/92/555; 692/698/2741/288; Animals; Apoptosis; Biological and medical sciences; Cancer therapies; Care and treatment; Cell Biology; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Dermatology; Diagnosis; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; Gene targeting; Genomics; Human Genetics; Humans; Internal Medicine; Liver; Liver cancer; Liver Neoplasms - secondary; Liver Neoplasms - therapy; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Medicine; Medicine & Public Health; Melanoma; Melanoma - secondary; Melanoma - therapy; Metastases; Metastasis; Mice; MicroRNA; MicroRNAs; MicroRNAs - antagonists & inhibitors; MicroRNAs - genetics; miRNA; Molecular and cellular biology; Oligonucleotides; Oligonucleotides, Antisense - genetics; Oligonucleotides, Antisense - therapeutic use; Oncology; Phosphorothioate; Properties; Ribonucleic acid; RNA; short-communication; Skin Neoplasms - pathology; Spleen; Transcription; Tumor Burden; Tumors; Tumors of the skin and soft tissue. Premalignant lesions; United States; miR-182; microRNA; melanoma; metastasis; liver; RNA interference; Targeting; Digestive system; Liver; Micro RNA; Hepatic disease; Malignant tumor; Carcinogenesis; Gene silencing; In vivo; Malignant melanoma; Digestive diseases; Liver metastasis; Cancer
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2010.523

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′ 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 miRNA-controlled 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.