miR-181a-5p Inhibits Cancer Cell Migration and Angiogenesis via Downregulation of Matrix Metalloproteinase-14.
miR-181a-5p Inhibits Cancer Cell Migration and Angiogenesis via Downregulation of Matrix Metalloproteinase-14.
复制标题
DOI：
10.1158/0008-5472.can-14-2875
复制
发表时间：
2015-07-01
期刊：
影响因子：
11.2
通讯作者：
Cao J
中科院分区：
文献类型：
--
作者：
Li Y;Kuscu C;Banach A;Zhang Q;Pulkoski-Gross A;Kim D;Liu J;Roth E;Li E;Shroyer KR;Denoya PI;Zhu X;Chen L;Cao J
基质金属蛋白酶MMP-14 （MT1-MMP）的上调与癌症患者预后不良有关，但目前尚不清楚MMP-14如何在肿瘤中升高。在这里，我们发现miR-181a-5p在侵袭性人类乳腺癌和结肠癌中下调，其水平与MMP-14的表达呈负相关。在临床标本中，位于肿瘤侵袭前的癌细胞中观察到MMP-14的表达增强，miR-181a-5p相对于邻近的正常细胞下调。生物信息学分析在MMP-14的3'未翻译区（UTR）中定义了一个潜在的miR-181a-5p响应元件，并在报告基因实验中得到验证。异位miR-181a-5p降低了MMP-14的表达，而miR-181a-5p的衰减提高了MMP-14的表达。为了支持这两个基因之间的关键关系，mir -181a-5p介导的MMP-14水平的降低足以减少癌细胞的迁移、侵袭和pro-MMP-2的激活。此外，在鸡绒毛膜尿囊膜实验中，这种MMP-14水平的降低足以减少体内入侵和血管生成。综上所述，我们的研究结果确定了miR-181a-5p通过转录后机制对癌症中MMP-14的调控，并进一步提出了提高miR-181a-5p以防止癌症转移的策略。
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 (UTR) 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. Further, 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 post-transcriptional mechanism, and they further suggest strategies to elevate miR-181a-5p to prevent cancer metastasis.