miR-665 inhibits epithelial-to-mesenchymal transition in bladder cancer via the SMAD3/SNAIL axis

Cell Cycle. 2021 Jul;20(13):1242-1252. doi: 10.1080/15384101.2021.1929677. Epub 2021 Jul 1.

Abstract

Emerging research indicates that miRNAs can regulate cancer progression by influencing molecular pathways. Here, we studied miR-665, part of the DLK1-DIO3 miRNA cluster, which is downregulated by upstream methylation in bladder cancer. MiR-665 overexpression significantly downregulated the expression of SMAD3, phospho-SMAD3, and SNAIL, reversed epithelial-mesenchymal transition progression, and inhibited the migration of bladder cancer cells. To predict potential targets of miR-665, we used online databases and subsequently determined that miR-665 binds directly to the 3' untranslated region of SMAD3. Moreover, silencing of SMAD3 with small interfering RNAs phenocopied the effect of miR-665 overexpression, and overexpression of SMAD3 restored miR-665-overexpression-induced metastasis. This study revealed the role of the miR-665/SMAD3/SNAIL axis in bladder cancer, as well as the potential of miR-665 as a promising therapeutic target.

Keywords: bladder cancer; epithelial-mesenchymal transition; miR-665; migration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Binding Sites
  • Cell Line, Tumor
  • Cell Movement
  • Databases, Genetic
  • Epithelial-Mesenchymal Transition*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Neoplasm Invasiveness
  • Phosphorylation
  • Signal Transduction
  • Smad3 Protein / genetics
  • Smad3 Protein / metabolism*
  • Snail Family Transcription Factors / genetics
  • Snail Family Transcription Factors / metabolism*
  • Urinary Bladder Neoplasms / genetics
  • Urinary Bladder Neoplasms / metabolism*
  • Urinary Bladder Neoplasms / pathology

Substances

  • 3' Untranslated Regions
  • MIRN665 microRNA, human
  • MicroRNAs
  • SMAD3 protein, human
  • SNAI1 protein, human
  • Smad3 Protein
  • Snail Family Transcription Factors

Grants and funding

This work was supported by the China Postdoctoral Science Foundation [2018M632489]; National Natural Science Foundation of China [81802564]; National Natural Science Foundation of China [81874203]; National Natural Science Foundation of China [81902612]; National Natural Science Foundation of China [81772744]; National Natural Science Foundation of China [81972374]; Zhejiang Provincial Natural Science Foundation of China [LY20H160022]; Zhejiang Province Medical and Health Scientific Research Project [2019RC033]; Zhejiang Provincial Natural Science Foundation of China [LY20H160030].