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

Overview

MeSH Major

  • Apolipoproteins E
  • Melanoma
  • MicroRNAs
  • Neoplasm Metastasis
  • Neovascularization, Pathologic

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.

publication date

  • November 21, 2012

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3753115

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2012.10.028

PubMed ID

  • 23142051

Additional Document Info

start page

  • 1068

end page

  • 82

volume

  • 151

number

  • 5