Signals from the Metastatic Niche Regulate Early and Advanced Ovarian Cancer Metastasis through miR-4454 Downregulation

Mol Cancer Res. 2020 Aug;18(8):1202-1217. doi: 10.1158/1541-7786.MCR-19-1162. Epub 2020 Apr 29.


Treatment of ovarian cancer is limited by extensive metastasis and yet it remains poorly understood. We have studied the critical step of metastatic colonization in the context of the productive interactions with the metastatic microenvironment with a goal of identifying key regulators. By combining miRNA expression analysis using an organotypic 3D culture model of early ovarian cancer metastasis with that of matched primary and metastatic tumors from 42 patients with ovarian cancer, we identified miR-4454 as a key regulator of both early colonization and advanced metastasis in patients with ovarian cancer. miR-4454 was downregulated in the metastasizing ovarian cancer cells through paracrine signals from microenvironmental fibroblasts, which promoted migration, invasion, proliferation, and clonogenic growth in ovarian cancer cells as well as their ability to penetrate through the outer layers of the omentum. Stable overexpression of miR-4454 decreased metastasis in ovarian cancer xenografts. Its mechanism of action was through the upregulation of its targets, secreted protein acidic and cysteine rich (SPARC) and BCL2 associated athanogene 5 (BAG5), which activated focal adhesion kinase (FAK) signaling, promoted mutant p53 gain of function by its stabilization, and inhibited apoptosis. Because microenvironment-induced downregulation of miR-4454 is essential for early and advanced metastasis, targeting it could be a promising therapeutic approach. IMPLICATIONS: This study identifies a miRNA, miR-4454, which is downregulated by signals from the microenvironment and promotes early and advanced ovarian cancer metastasis through its effects on FAK activation, mutant p53 stabilization, and apoptosis inhibition.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Animals
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Down-Regulation*
  • Female
  • Focal Adhesion Kinase 1 / genetics
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice
  • MicroRNAs / genetics*
  • Mutation
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Osteonectin / genetics*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / pathology*
  • Protein Stability
  • Tumor Microenvironment
  • Tumor Suppressor Protein p53 / chemistry
  • Tumor Suppressor Protein p53 / genetics


  • Adaptor Proteins, Signal Transducing
  • BAG5 protein, human
  • MIRN4454 microRNA, human
  • MicroRNAs
  • Osteonectin
  • SPARC protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Focal Adhesion Kinase 1
  • PTK2 protein, human