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.