Convergent multi-miRNA targeting of ApoE grives LRP1/LRP8-dependent melanoma metastasis and angiogenesis Journal Article

   

Authors:	Pencheva, N.; Tran, H.; Buss, C.; Huh, D.; Drobnjak, M.; Busam, K.; Tavazoie, S. F.
Article Title:	Convergent multi-miRNA targeting of ApoE grives LRP1/LRP8-dependent melanoma metastasis and angiogenesis
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. © 2012 Elsevier Inc.
Keywords:	protein expression; unclassified drug; human cell; nonhuman; outcome assessment; animal cell; mouse; animals; mice; cells, cultured; gene targeting; melanoma; microrna; cell line, tumor; angiogenesis; neovascularization, pathologic; mice, inbred c57bl; cancer invasion; endothelium cell; endothelial cells; gene expression regulation, neoplastic; mice, nude; neoplasm metastasis; melanoma cell; micrornas; disease models, animal; antiangiogenic activity; drug delivery system; oligonucleotides; nucleic acid; low density lipoprotein receptor related protein; apolipoprotein e; heat shock protein; hsp40 heat-shock proteins; apolipoproteins e; melanoma metastasis; heat shock factor dnaja4; low density lipoprotein receptor related protein 8; ldl-receptor related proteins; low density lipoprotein receptor-related protein-1
Journal Title:	Cell
Volume:	151
Issue:	5
ISSN:	0092-8674
Publisher:	Cell Press
Date Published:	2012-11-21
Start Page:	1068
End Page:	1082
Language:	English
DOI:	10.1016/j.cell.2012.10.028
PROVIDER:	scopus
PUBMED:	23142051
PMCID:	PMC3753115
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84870052886&partnerID=40&md5=5697e8569f6e5722335b5e97218af4b9
Notes:	--- - "Export Date: 2 January 2013" - "CODEN: CELLB" - "Source: Scopus"

https://synapse.mskcc.org/synapse/works/has_related_data_chk/37397