title: 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.affiliation: Department of Medicine/Cancer Prevention, Stony Brook University, Stony Brook, New York. Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Yiyi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Medicine/Cancer Prevention, Stony Brook University, Stony Brook, New York.
authors.forename: Cem
authors.initials: C
authors.lastname: Kuscu
authors.affiliation: Department of Medicine/Cancer Prevention, Stony Brook University, Stony Brook, New York.
authors.forename: Anna
authors.initials: A
authors.lastname: Banach
authors.affiliation: Department of Medicine/Cancer Prevention, Stony Brook University, Stony Brook, New York.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Medicine/Cancer Prevention, Stony Brook University, Stony Brook, New York.
authors.forename: Ashleigh
authors.initials: A
authors.lastname: Pulkoski-Gross
authors.affiliation: Department of Medicine/Cancer Prevention, Stony Brook University, Stony Brook, New York.
authors.forename: Deborah
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Pathology, Stony Brook University, Stony Brook, New York.
authors.forename: Jingxuan
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Medicine/Cancer Prevention, Stony Brook University, Stony Brook, New York.
authors.forename: Eric
authors.initials: E
authors.lastname: Roth
authors.affiliation: Department of Medicine/Division of Gastroenterology and Hepatology, Stony Brook University, Stony Brook, New York.
authors.forename: Ellen
authors.initials: E
authors.lastname: Li
authors.affiliation: Department of Pathology, Stony Brook University, Stony Brook, New York.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Shroyer
authors.affiliation: Department of Surgery, Stony Brook University, Stony Brook, New York.
authors.forename: Paula I
authors.initials: PI
authors.lastname: Denoya
authors.affiliation: Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China. jian.cao@sunysb.edu zhuxx01@126.com chenlonghuafl01@126.com.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China. jian.cao@sunysb.edu zhuxx01@126.com chenlonghuafl01@126.com.
authors.forename: Longhua
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Medicine/Cancer Prevention, Stony Brook University, Stony Brook, New York. jian.cao@sunysb.edu zhuxx01@126.com chenlonghuafl01@126.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Cao
mesh_terms: D020413:3' Untranslated Regions; D001943:Breast Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement / Q000502:physiology*; D003110:Colonic Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D005260:Female; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000096:biosynthesis* / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020218:Response Elements; D014162:Transfection; D015854:Up-Regulation
chemical_list: D020413:3' Untranslated Regions; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14