Slug-upregulated miR-221 promotes breast cancer progression through suppressing E-cadherin expression

Sci Rep. 2016 May 13;6:25798. doi: 10.1038/srep25798.

Abstract

It is generally regarded that E-cadherin is downregulated during tumorigenesis via Snail/Slug-mediated E-cadherin transcriptional reduction. However, this transcriptional suppressive mechanism cannot explain the failure of producing E-cadherin protein in metastatic breast cancer cells after overexpressing E-cadherin mRNA. Here we reveal a novel mechanism that E-cadherin is post-transcriptionally regulated by Slug-promoted miR-221, which serves as an additional blocker for E-cadherin expression in metastatic tumor cells. Profiling the predicted E-cadherin-targeting miRNAs in breast cancer tissues and cells showed that miR-221 was abundantly expressed in breast tumor and metastatic MDA-MB-231 cells and its level was significantly higher in breast tumor or MDA-MB-231 cells than in distal non-tumor tissue and low-metastatic MCF-7 cells, respectively. MiR-221, which level inversely correlated with E-cadherin level in breast cancer cells, targeted E-cadherin mRNA open reading frame (ORF) and suppressed E-cadherin protein expression. Depleting or increasing miR-221 level in breast cancer cells induced or decreased E-cadherin protein level, leading to suppressing or promoting tumor cell progression, respectively. Moreover, miR-221 was specifically upregulated by Slug but not Snail. TGF-β treatment enhanced Slug activity and thus increased miR-221 level in MCF-7 cells. In summary, our results provide the first evidence that Slug-upregulated miR-221 promotes breast cancer progression via reducing E-cadherin expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antigens, CD
  • Base Sequence
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology*
  • Cadherins / chemistry
  • Cadherins / genetics*
  • Cadherins / metabolism
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Disease Models, Animal
  • Disease Progression*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / secondary
  • Mice, SCID
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Models, Biological
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Snail Family Transcription Factors / metabolism*
  • Up-Regulation / genetics*

Substances

  • Antigens, CD
  • CDH1 protein, human
  • Cadherins
  • MIRN221 microRNA, human
  • MicroRNAs
  • RNA, Messenger
  • Snail Family Transcription Factors