Title | Convergent multi-miRNA targeting of ApoE drives LRP1/LRP8-dependent melanoma metastasis and angiogenesis. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | Pencheva N, Tran H, Buss C, Huh D, Drobnjak M, Busam K, Tavazoie SF |
Journal | Cell |
Volume | 151 |
Issue | 5 |
Pagination | 1068-82 |
Date Published | 2012 Nov 21 |
ISSN | 1097-4172 |
Keywords | Animals, Apolipoproteins E, Cell Line, Tumor, Cells, Cultured, Disease Models, Animal, Endothelial Cells, Gene Expression Regulation, Neoplastic, HSP40 Heat-Shock Proteins, Humans, LDL-Receptor Related Proteins, Low Density Lipoprotein Receptor-Related Protein-1, Melanoma, Mice, Mice, Inbred C57BL, Mice, Nude, MicroRNAs, Neoplasm Metastasis, Neovascularization, Pathologic, Oligonucleotides |
Abstract | Through in vivo selection of human cancer cell populations, we uncover a convergent and cooperative miRNA network that drives melanoma metastasis. We identify miR-1908, miR-199a-5p, and miR-199a-3p as endogenous promoters of metastatic invasion, angiogenesis, and colonization in melanoma. These miRNAs convergently target apolipoprotein E (ApoE) and the heat shock factor DNAJA4. Cancer-secreted ApoE suppresses invasion and metastatic endothelial recruitment (MER) by engaging melanoma cell LRP1 and endothelial cell LRP8 receptors, respectively, while DNAJA4 promotes ApoE expression. Expression levels of these miRNAs and ApoE correlate with human metastatic progression outcomes. Treatment of cells with locked nucleic acids (LNAs) targeting these miRNAs inhibits metastasis to multiple organs, and therapeutic delivery of these LNAs strongly suppresses melanoma metastasis. We thus identify miRNAs with dual cell-intrinsic/cell-extrinsic roles in cancer, reveal convergent cooperativity in a metastatic miRNA network, identify ApoE as an anti-angiogenic and metastasis-suppressive factor, and uncover multiple prognostic miRNAs with synergistic combinatorial therapeutic potential in melanoma. |
DOI | 10.1016/j.cell.2012.10.028 |
Alternate Journal | Cell |
PubMed ID | 23142051 |
PubMed Central ID | PMC3753115 |
Grant List | KL2 RR024142 / RR / NCRR NIH HHS / United States 5KL2 RR024142-04 / RR / NCRR NIH HHS / United States |
Submitted by api_import on December 20, 2019 - 1:38pm