MicroRNA-138 suppresses ovarian cancer cell invasion and metastasis by targeting SOX4 and HIF-1α

Int J Cancer. 2013 Aug 15;133(4):867-78. doi: 10.1002/ijc.28086. Epub 2013 Mar 9.


Metastasis is the major factor affecting patient survival in ovarian cancer. However, its molecular mechanisms remain unclear. Our study used isogenic pairs of low- and high-invasive ovarian cancer cell lines to demonstrate the downregulation of miRNA-138 in the highly invasive cells, and its functioning as an inhibitor of cell migration and invasion. An orthotopic xenograft mouse model further demonstrated that the expression of miRNA-138 inhibited ovarian cancer metastasis to other organs. Results indicated that miR-138 directly targeted SRY-related high mobility group box 4 (SOX4) and hypoxia-inducible factor-1α (HIF-1α), and overexpression of SOX4 and HIF-1α effectively reversed the miR-138-mediated suppression of cell invasion. Epidermal growth factor receptor acted as the downstream molecule of SOX4 by way of direct transcriptional control, whereas Slug was the downstream molecule of HIF-1α by way of proteasome-mediated degradation. Analysis of human ovarian tumors further revealed downregulation of miR-138 and upregulation of SOX4 in late-stage tumors. Patients with miR-138(low)/SOX(high) signature are predominant in late stage and tend to have malignant phenotypes including lymph nodes metastasis, larger ascites volume and higher tumor grade. Our study demonstrates the role and clinical relevance of miR-138 in ovarian cancer cell invasion and metastasis, providing a potential therapeutic strategy for suppression of ovarian cancer metastasis by targeting SOX4 and HIF-1α pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Base Sequence
  • Blotting, Western
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • DNA Primers
  • ErbB Receptors / physiology
  • Female
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / physiology*
  • Mice
  • MicroRNAs / physiology*
  • Neoplasm Invasiveness / genetics*
  • Neoplasm Metastasis / genetics*
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / pathology
  • Real-Time Polymerase Chain Reaction
  • SOXC Transcription Factors / physiology*
  • Snail Family Transcription Factors
  • Transcription Factors / physiology
  • Transplantation, Heterologous


  • 3' Untranslated Regions
  • DNA Primers
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • MIRN138 microRNA, human
  • MicroRNAs
  • SNAI1 protein, human
  • SOX4 protein, human
  • SOXC Transcription Factors
  • Snai2 protein, mouse
  • Snail Family Transcription Factors
  • Transcription Factors
  • ErbB Receptors