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 (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.

Genetic and Methylation-Induced Loss of miR-181a2/181b2 within chr9q33.3 Facilitates Tumor Growth of Cervical Cancer through the PIK3R3/Akt/FoxO Signaling Pathway

“…But according to the GEO public database (GSE19611, GSE20592, GSE30656), there is no significant deregulation of miR-181a2/181b2 expression in other smaller cervical cancer cohorts. It is worth noting that the expression of miR-181a/181b is also reported to be controversial in breast and colon cancers (18,21,36). These conclusions were based on the low patient number.…”

“…Emerging evidence showed that miR-181a2/181b2 might function as either oncogenes or tumor suppressors in different cancer types. miR-181a2/181b2 were recently known as suppressors of EMT and tumor metastasis in colon cancer and NSCLC (18,20,21). In contrast, miR-181a2/181b2 appeared to promote the metastasis of breast cancer and HCC (22,37).…”

“…miR-181a-2 (miR-181a2) and miR-181b-2 (miR-181b2) locate in the lost chr9q31-33 region and belong to the miR-181 family. The four highly conserved mature miRNA members, miR-181a, 181b, 181c, and 181d, are independently derived from six precursors located on three different chromosomes: miR-181a-1 and miR-181b-1 on chromosome 1p32.1, miR-181a-2 and miR181b-2 on chromosome 9q33.3, and miR-181c and miR-181d on chromosome 19p13.12 (18,19). The recent emerging data suggest that the miR-181 family is deregulated in several tumors and plays a central role in cancer progression (18,(20)(21)(22).…”

The Dual Regulatory Role of MiR-181a in Breast Cancer

“…In human breast cancer cell lines, miR-181a expression is significantly lower in aggressive cancer cells such as TNBC adenocarcinoma MDA-MB-231 and breast cancer stem SK-3rd cells as compared to less aggressive breast cancer cell lines such as MCF-7 (ER+/PR+/HER2-; one of the most low-invasive breast cancer cells) and SK-BR3 (ER-/HER2+) [33]. Downregulation of miR-181a is also observed in multidrug-resistant MCF-7 cells compared with its parental cell line [19], and in mitoxantrone-resistant MCF-7 cells [34].…”

MicroRNA-181a-5p Impedes IL-17-Induced Nonsmall Cell Lung Cancer Proliferation and Migration through Targeting VCAM-1

“…In gastric and lung cancer cell lines, miR-181 sensitized cancer cells to vincristine or cisplatin induced apoptosis by targeting BCL2 expression [19]. Furthermore, in breast and colon cancer cells, miR-181a-5p, one member of miR-181 family can regress cancer cell migration and invasion through regulating MMP-14 expression in cancers [20]. In in NSCLC tissues and cell lines, the expression of miR-181 was found to be downregulated [21].…”