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KMID : 0381120160380020217
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Genes and Genomics
2016 Volume.38 No. 2 p.217 ~ p.223
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miRNA-105 and -128 function as rheostats modulating MMP-2 activities by downregulation of TIMP-2 and upregulation of MT1-MMP
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Kim Jin-Hee
Li Li-Hua
Cai Hua
Nguyen Vu H.
Min Jung-Joon
Shin Boo-Ahn
Choi Seok-Yong
Koh Yang-Seok
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Abstract
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Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that remodel and degrade the extracellular matrix. Of various MMPs, MMP-2 plays an important role in tumor metastasis. Recently, microRNAs with pro- or anti-metastatic effects were collectively referred to as metastamiRs. We screened 215 human miRNA mimics for modulators of MMP-2 activities in HT-1080 cells, and found that miR-105 and miR-128 promote MMP-2 activities. Bioinformatics analysis predicted that miR-105 and miR-128 both bind to the 3′ untranslated region (UTR) of TIMP-2, an inhibitor of MMP-2 activities. This prediction was verified by reduced luciferase activity in HT-1080 cells co-transfected with miR-105 or miR-128 mimics and plasmids encoding luciferase fused to 3′ UTR of TIMP2. In addition, Western blotting showed that transfection of HT-1080 cells with miR-105 or miR-128 suppressed TIMP-2 levels and enhanced levels of MT1-MMP, an activator of MMP-2 activities. The mechanism by which miR-128 upregulates MT1-MMP was determined to be downregulation of PRKD1, an inhibitor of MT1-MMP, at least in part. Cell invasion assays using Matrigel demonstrated that HT-1080 cells transfected with miR-105 or miR-128 are more invasive as compared to control cells. Taken together, these findings show that miR-105 and miR-128 are metastamir promoting MMP-2 activities via simultaneously downregulating TIMP-2 and upregulating MT1-MMP, and may provide a platform for the development of therapeutics against metastasis.
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KEYWORD
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microRNA, Metastasis, Matrix metalloproteinase, MMP-2, MT1-MMP, TIMP-2, Protein kinase D
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