MicroRNA-519c suppresses hypoxia-inducible factor-1alpha expression and tumor angiogenesis.
Hypoxia-inducible factor-1alpha (HIF-1alpha) 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-1alpha, acting through direct binding to the HIF-1alpha 3' untranslated region and leading to reduced tumor angiogenesis. Overexpression of miR-519c resulted in a significant decrease of HIF-1alpha protein levels and reduced the tube formation of human umbilical vein endothelial cells; similarly, antagomir inhibition of miR-519c increased the level of HIF-1alpha protein and enhanced angiogenic activity, suggesting an important role of miR-519c in HIF-1alpha-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-1alpha levels, followed by suppressed tumor angiogenesis, growth, and metastasis. In addition, we found that hepatocyte growth factor (HGF), a known HIF-1alpha inducer, reduced the miR-519c levels through an Akt-dependent pathway. This regulation was posttranscriptional 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.
Cha
Shih-Ting
ST
Laboratory of Molecular and Cellular Toxicology, Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Chen
Pai-Sheng
PS
Johansson
Gunnar
G
Chu
Chia-Yu
CY
Wang
Ming-Yang
MY
Jeng
Yung-Ming
YM
Yu
Sung-Liang
SL
Chen
Jin-Shing
JS
Chang
King-Jen
KJ
Jee
Shiou-Hwa
SH
Tan
Ching-Ting
CT
Lin
Ming-Tsan
MT
Kuo
Min-Liang
ML
D020413:3' Untranslated Regions; D000230:Adenocarcinoma / Q000098:blood supply / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D008175:Lung Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012323:RNA Processing, Post-Transcriptional
D020413:3' Untranslated Regions; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C546194:MIRN519 microRNA, human; D035683:MicroRNAs