Premium
MicroRNA‐138 suppresses ovarian cancer cell invasion and metastasis by targeting SOX4 and HIF‐1α
Author(s) -
Yeh YuMing,
Chuang ChiMu,
Chao KuanChong,
Wang LuHai
Publication year - 2013
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.28086
Subject(s) - metastasis , ovarian cancer , downregulation and upregulation , cancer research , biology , sox4 , microrna , cancer , gene expression , gene , biochemistry , genetics , promoter
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.