MicroRNA-138 suppresses ovarian cancer cell invasion and metastasis by targeting SOX4 and HIF-1
MicroRNA-138 suppresses ovarian cancer cell invasion and metastasis by targeting SOX4 and HIF-1
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DOI：
10.1002/ijc.28086
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发表时间：
2013-08-15
影响因子：
6.4
通讯作者：
Wang, Lu-Hai
中科院分区：
文献类型：
--
作者：
Yeh, Yu-Ming;Chuang, Chi-Mu;Wang, Lu-Hai
转移是影响卵巢癌患者生存的主要因素。然而，其分子机制尚不清楚。我们的研究使用低侵袭性和高侵袭性卵巢癌细胞系等基因对来证明miRNA-138在高侵袭性细胞中的下调，以及其作为细胞迁移和侵袭抑制剂的功能。原位异种移植小鼠模型进一步证明miRNA-138的表达抑制卵巢癌向其他器官的转移。结果表明，miR-138直接靶向sry相关的高迁移率组盒4 （SOX4）和缺氧诱导因子-1 (HIF-1)，过表达SOX4和HIF-1可有效逆转miR-138介导的细胞侵袭抑制。表皮生长因子受体通过直接转录调控作为SOX4的下游分子，而Slug通过蛋白酶体介导降解作为HIF-1的下游分子。对人卵巢肿瘤的分析进一步发现miR-138在晚期肿瘤中下调，SOX4上调。miR-138low/SOXhigh特征的患者在晚期多见，且易出现淋巴结转移、腹水体积较大、肿瘤分级较高等恶性表型。我们的研究证明了miR-138在卵巢癌细胞侵袭和转移中的作用和临床相关性，为通过靶向SOX4和HIF-1途径抑制卵巢癌转移提供了一种潜在的治疗策略。
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-1 (HIF-1), and overexpression of SOX4 and HIF-1 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-1 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-138low/SOXhigh 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-1 pathways.