miR-448 inhibits the epithelial-mesenchymal transition in breast cancer cells by directly targeting the E-cadherin repressor ZEB1/2

Exp Biol Med (Maywood). 2018 Mar;243(5):473-480. doi: 10.1177/1535370218754848. Epub 2018 Jan 25.

Abstract

Recently, accumulating evidence provides that dysregulation of microRNAs (miRNAs) is considered to play vital roles in tumor progression. Based on microRNA arrays, we found that microRNA-448 (miR-448) was significantly downregulated in breast cancer tissue specimens. In our study, we were in an effort to clarify the function, the direct target gene, and the molecular mechanisms of miR-448 in breast cancer. By quantitative RT-PCR, we analyzed the expression of miR-448 in 16 patients with BC. Overexpression of miR-448 was established by transfecting miR-448-mimics into MDA-MB-231 and MCF-7 cells, methyl thiazolyl- tetrazolium and colony formation assays were performed to evaluate its effects on cell proliferation. We also performed cell migration and invasion assays in breast cells overexpressing miRNA-448. All the results indicated that overexpression of miR-448 in breast cancer cells markedly suppressed cell proliferation, migration, and invasion. Through the quantitative RT-PCR and Western Blots, we also evaluated epithelial-mesenchymal transition. We found that overexpression of miR-448 also downregulated the expression of vimentin, a well-known mesenchymal marker. Meanwhile, the epithelial marker E-cadherin was unregulated, suggesting that miR-448 inhibited epithelial-mesenchymal transition . Bioinformatics assay coupled with Western Blot and luciferase assays revealed that miR-448 directly binds to the 3'UTR of E-cadherin repressor ZEB1/2, resulting in suppression of epithelial-mesenchymal transition in breast cancer cells. Impact statement In our study, we revealed that miR-448 played a vital role in breast cancer development and we also uncovered the mechanisms of it. Following is the short description of the main findings: miR-448 is downregulated in BC. miR-448 regulates cell proliferation, migration, and invasion in BC. miR-448 specifically regulates ZEB1/2 through binding to the 3'UTR in BC cells. miR-448 inhibits cell migration, invasion, and EMT by targeting to the 3'UTR of ZEB1/2.

Keywords: Cancer; cell; disease; microRNA; molecular; oncogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology*
  • Cadherins / biosynthesis*
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • Down-Regulation
  • Epithelial-Mesenchymal Transition / genetics
  • Epithelial-Mesenchymal Transition / physiology*
  • Female
  • Humans
  • MCF-7 Cells
  • MicroRNAs / biosynthesis
  • MicroRNAs / genetics*
  • Neoplasm Invasiveness / genetics
  • Vimentin / biosynthesis
  • Zinc Finger E-box Binding Homeobox 2 / genetics*
  • Zinc Finger E-box-Binding Homeobox 1 / genetics*

Substances

  • Cadherins
  • MIRN448 microRNA, human
  • MicroRNAs
  • Vimentin
  • ZEB1 protein, human
  • ZEB2 protein, human
  • Zinc Finger E-box Binding Homeobox 2
  • Zinc Finger E-box-Binding Homeobox 1