| Summary: | 博士 === 國立清華大學 === 分子醫學研究所 === 101 === 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 and miRNA-708 in the highly invasive cells, and their 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 miRNA-138 directly targeted SOX4 and HIF-1α, and overexpression of SOX4 and HIF-1α effectively reversed the miRNA-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-1α by way of proteasome-mediated degradation. Analysis of human ovarian tumors further revealed downregulation of miRNA-138 and upregulation of SOX4 in late stage tumors. Patients with miRNA-138low/ SOX4high signature are predominant in late stage and tend to have malignant phenotypes including lymph nodes metastasis, larger ascites volume and higher tumor grade. For miR-708, we found it suppressed ovarian cancer cells invasion and directly targets Rap1B. Glucorcoticoid receptor-alpha, a transcriptional factor activated by dexamethasone, might be the upstream regulator of miRNA-708. Our cell-based study revealed a novel role of miRNA-708 in the inhibition of ovarian cancer cell invasion by dexamethasone. Clinically, expression of miRNA-708 was downregulated while that of Rap1B was upregulated in malignant human ovarian cancers compared to normal tissues. This study demonstrates the functional role and clinical relevance of miRNA-138 and miRNA-708 in ovarian cancer cell invasion and metastasis, providing a potential therapeutic strategy and diagnosis markers for ovarian cancer.
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