miR-181a-5p Inhibits Cancer Cell Migration and Angiogenesis via Downregulation of Matrix Metalloproteinase-14.

Abstract

Upregulation of matrix metalloproteinase MMP-14 (MT1-MMP) is associated with poor prognosis in cancer patients, but it is unclear how MMP-14 becomes elevated in tumors. Here, we show that miR-181a-5p is downregulated in aggressive human breast and colon cancers where its levels correlate inversely with MMP-14 expression. In clinical specimens, enhanced expression of MMP-14 was observed in cancer cells located at the invasive front of tumors where miR-181a-5p was downregulated relative to adjacent normal cells. Bioinformatics analyses defined a potential miR-181a-5p response element within the 3'-untranslated region of MMP-14 that was validated in reporter gene experiments. Ectopic miR-181a-5p reduced MMP-14 expression, whereas miR-181a-5p attenuation elevated MMP-14 expression. In support of a critical relationship between these two genes, miR-181a-5p-mediated reduction of MMP-14 levels was sufficient to decrease cancer cell migration, invasion, and activation of pro-MMP-2. Furthermore, this reduction in MMP-14 levels was sufficient to reduce in vivo invasion and angiogenesis in chick chorioallantoic membrane assays. Taken together, our results establish the regulation of MMP-14 in cancers by miR-181a-5p through a posttranscriptional mechanism, and they further suggest strategies to elevate miR-181a-5p to prevent cancer metastasis.

• Authors: Yiyi Li, Cem Kuscu, Anna Banach, Qian Zhang, Ashleigh Pulkoski-Gross, Deborah Kim, Jingxuan Liu, Eric Roth, Ellen Li, Kenneth R Shroyer, Paula I Denoya, Xiaoxia Zhu, Longhua Chen, Jian Cao
• Journal: Cancer research (Cancer Res) Vol. 75 Issue 13 Pg. 2674-85 (Jul 01 2015) ISSN: 1538-7445 [Electronic] United States
• PMID: 25977338 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• 3' Untranslated Regions
• MIrn181 microRNA, human
• MicroRNAs
• MMP14 protein, human
• Matrix Metalloproteinase 14

Topics

• 3' Untranslated Regions
• Breast Neoplasms (blood supply, genetics, metabolism, pathology)
• Cell Movement (physiology)
• Colonic Neoplasms (blood supply, genetics, metabolism, pathology)
• Down-Regulation
• Female
• Humans
• Matrix Metalloproteinase 14 (biosynthesis, genetics)
• MicroRNAs (genetics, metabolism)
• Neovascularization, Pathologic (genetics, metabolism, pathology)
• Response Elements
• Transfection
• Up-Regulation