MicroRNA-7 inhibits tumor metastasis and reverses epithelial-mesenchymal transition through AKT/ERK1/2 inactivation by targeting EGFR in epithelial ovarian cancer

PLoS One. 2014 May 9;9(5):e96718. doi: 10.1371/journal.pone.0096718. eCollection 2014.

Abstract

Epidermal growth factor receptor (EGFR) overexpression and activation result in increased proliferation and migration of solid tumors including ovarian cancer. In recent years, mounting evidence indicates that EGFR is a direct and functional target of miR-7. In this study, we found that miR-7 expression was significantly downregulated in highly metastatic epithelial ovarian cancer (EOC) cell lines and metastatic tissues, whereas the expression of, EGFR correlated positively with metastasis in both EOC patients and cell lines. Overexpression of miR-7 markedly suppressed the capacities of cell invasion and migration and resulted in morphological changes from a mesenchymal phenotype to an epithelial-like phenotype in EOC. In addition, overexpression of miR-7 upregulated CK-18 and β-catenin expression and downregulated Vimentin expression, accompanied with EGFR inhibition and AKT/ERK1/2 inactivation. Similar to miR-7 transfection, silencing of EGFR with this siRNA in EOC cells also upregulated CK-18 and β-catenin expression and downregulated Vimentin expression, and decreased phosphorylation of both Akt and ERK1/2, confirming that EGFR is a target of miR-7 in reversing EMT. The pharmacological inhibition of PI3K-AKT and ERK1/2 both significantly enhanced CK-18 and β-catenin expression and suppressed vimentin expression, indicating that AKT and ERK1/2 pathways are required for miR-7 mediating EMT. Finally, the expression of miR-7 and EGFR in primary EOC with matched metastasis tissues was explored. It was showed that miR-7 is inversely correlated with EGFR. Taken together, our results suggested that miR-7 inhibited tumor metastasis and reversed EMT through AKT and ERK1/2 pathway inactivation by reducing EGFR expression in EOC cell lines. Thus, miR-7 might be a potential prognostic marker and therapeutic target for ovarian cancer metastasis intervention.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Ovarian Epithelial
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Down-Regulation
  • Enzyme Activation
  • Epithelial-Mesenchymal Transition*
  • ErbB Receptors / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genes, Reporter / genetics
  • Humans
  • MAP Kinase Signaling System
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasms, Glandular and Epithelial / pathology*
  • Ovarian Neoplasms / pathology*
  • Proto-Oncogene Proteins c-akt / metabolism*

Substances

  • MIRN7 microRNA, human
  • MicroRNAs
  • EGFR protein, human
  • ErbB Receptors
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 3

Grants and funding

This work was supported by grants from National Natural Science Foundation of China (Grant No. 81072138), Medical-engineering cross project of Shanghai Jiao Tong University (YG2010MS24). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.