MicroRNA-421 inhibits breast cancer metastasis by targeting metastasis associated 1

Biomed Pharmacother. 2016 Oct;83:1398-1406. doi: 10.1016/j.biopha.2016.08.058. Epub 2016 Aug 29.

Abstract

Dysregulation of microRNAs is involved in the initiation and progression of several human cancers, including breast cancer, as strong evidence of miRNAs acting as oncogenes or tumour suppressor genes has been found. This study was performed to investigate the biological functions of microRNA-421 (miR-421) in breast cancer and the underlying mechanisms. The expression level of miR-421 was detected in 50 pairs of surgical specimens and human breast cancer cell lines. The results showed that miR-421 is downregulated in breast cancer tissues and metastatic cell lines. In addition, the decrease in miR-421 levels was significantly associated with lymph node metastasis, recurrence/metastasis, or pTNM stage. Functions of miR-421 in cell migration and invasion were assessed through its silencing and overexpression. The results showed that miR-421 knockdown promotes invasion and metastasis in MCF-7 cells and its overexpression suppresses invasion and metastasis in MDA-MB-231 cells. The specific target genes of miR-421 were predicted by TargetScan algorithm and determined by dual luciferase reporter assay, quantitative reverse transcriptase PCR, and western blot analysis. miR-421 could suppress luciferase activity of the reporter containing 3'-untranslated region of metastasis associated 1 (MTA1), a potent oncogene. miR-421 overexpression or knockdown had no effect on the mRNA expression of MTA1, but it could modulate MTA1 protein level. Furthermore, MTA1 knockdown receded the effect of miR-421 inhibitor on invasion and metastasis of MCF-7 cells, and its overexpression receded the effect of miR-421 on invasion and metastasis of MDA-MB-231 cells. Our findings clearly demonstrate that miR-421 suppresses breast cancer metastasis by directly inhibiting MTA1 expression. The present study provides a new insight into the tumour suppressor roles of miR-421 and suggests that miR-421/MTA1 pathway is a putative therapeutic target in breast cancer.

Keywords: Invasion; MCF-7; MDA-MB-231; Metastasis associated 1; MicroRNA-421; Migration.

MeSH terms

  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Breast Neoplasms / prevention & control
  • Female
  • HEK293 Cells
  • Histone Deacetylases / biosynthesis*
  • Humans
  • MCF-7 Cells
  • MicroRNAs / biosynthesis*
  • Neoplasm Metastasis / pathology
  • Neoplasm Metastasis / prevention & control
  • Repressor Proteins / antagonists & inhibitors*
  • Repressor Proteins / biosynthesis*
  • Trans-Activators
  • Tumor Cells, Cultured

Substances

  • MIRN421 microRNA, human
  • MicroRNAs
  • Mta1 protein, human
  • Repressor Proteins
  • Trans-Activators
  • Histone Deacetylases