MicroRNA-519c Suppresses Hypoxia-Inducible Factor-1α Expression and Tumor Angiogenesis

被引:165
作者
Cha, Shih-Ting [1 ]
Chen, Pai-Sheng [1 ,7 ]
Johansson, Gunnar [1 ]
Chu, Chia-Yu [1 ,4 ]
Wang, Ming-Yang [1 ,3 ,7 ]
Jeng, Yung-Ming [5 ]
Yu, Sung-Liang [2 ]
Chen, Jin-Shing [3 ]
Chang, King-Jen [3 ,7 ]
Jee, Shiou-Hwa [4 ]
Tan, Ching-Ting [6 ]
Lin, Ming-Tsan [3 ]
Kuo, Min-Liang [1 ,5 ]
机构
[1] Natl Taiwan Univ, Lab Mol & Cellular Toxicol, Inst Toxicol, Taipei 100, Taiwan
[2] Natl Taiwan Univ, Dept Clin Lab Sci & Med Biotechnol, Coll Med, Taipei 100, Taiwan
[3] Natl Taiwan Univ Hosp, Dept Surg, Taipei 100, Taiwan
[4] Natl Taiwan Univ Hosp, Dept Dermatol, Taipei, Taiwan
[5] Natl Taiwan Univ Hosp, Dept Pathol, Taipei 100, Taiwan
[6] Natl Taiwan Univ Hosp, Dept Otolaryngol, Taipei, Taiwan
[7] Natl Taiwan Univ, Angiogenesis Res Ctr, Taipei 100, Taiwan
关键词
POSTTRANSCRIPTIONAL REGULATION; GROWTH-FACTOR; HIF-1; HIF-2-ALPHA; TARGET; CANCER; REGULATORS; HYPOXIA-INDUCIBLE-FACTOR-1-ALPHA; HIF-1-ALPHA; MECHANISMS;
D O I
10.1158/0008-5472.CAN-09-2448
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is widely considered to be one of the key regulators of tumor angiogenesis. The upstream regulation is complex and involves several growth factors, cytokines, and hypoxia. Herein, we have identified miR-519c as a hypoxia-independent regulator of HIF-1 alpha, acting through direct binding to the HIF-1 alpha 3' untranslated region and leading to reduced tumor angiogenesis. Overexpression of miR-519c resulted in a significant decrease of HIF-1 alpha protein levels and reduced the tube formation of human umbilical vein endothelial cells; similarly, antagomir inhibition of miR-519c increased the level of HIF-1 alpha protein and enhanced angiogenic activity, suggesting an important role of miR-519c in HIF-1 alpha-mediated angiogenesis. Consistent with the overexpression of miR-519c in cancer patients with better prognosis, mice injected with miR-519c-overexpressing cells exhibited dramatically reduced HIF-1 alpha levels, followed by suppressed tumor angiogenesis, growth, and metastasis. In addition, we found that hepatocyte growth factor (HGF), a known HIF-1 alpha inducer, reduced the miR-519c levels through an Akt-dependent pathway. This regulation was post-transcriptional and may be mediated by suppression of miR-519c maturation. Taken together, our findings provide the first evidence that miR-519c is a pivotal regulator of tumor angiogenesis and that microenvironmental HGF contributes to regulating miR-519c biogenesis in cancer cells. Cancer Res; 70(7); 2675-85. (C) 2010 AACR.
引用
收藏
页码:2675 / 2685
页数:11
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