Metastasis is the major factor affecting patient survival in ovarian cancer. However, its molecular mechanisms remain unclear. The present 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 SOX4 and HIF-1alpha, and overexpression of SOX4 and HIF-1alpha effectively reversed the miR-138-mediated suppression of cell invasion. Epidermal growth factor receptor (EGFR) acted as the downstream molecule of SOX4 by way of direct transcriptional control, whereas Slug was the downstream molecule of HIF-1alpha 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. This study demonstrate 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-1alpha pathways.
Date:
2013-08
Relation:
International Journal of Cancer. 2013 Aug;133(4):867-878.
