MicroRNA-302 represses epithelial-mesenchymal transition and cisplatin resistance by regulating ATAD2 in ovarian carcinoma

Exp Cell Res. 2020 Nov 1;396(1):112241. doi: 10.1016/j.yexcr.2020.112241. Epub 2020 Aug 21.


Epithelial-mesenchymal transition (EMT) is an important contributor to drug resistance in ovarian cancer. The aims of this study were to explore the potential role of the miR-302 cluster in modulating EMT and cisplatin resistance in ovarian cancer. We used qRT-PCR and western blotting to show that miR-302 expression was lower in chemoresistant than in chemosensitive cells, and miR-302 was upregulated in chemosensitive, but not chemoresistant ovarian cancer cells in response to cisplatin treatment. We identified ATAD2 as a target of miR-302 and showed that ectopic expression of miR-302 increased cisplatin sensitivity and inhibited EMT and the invasiveness of cisplatin-resistant cells in vitro by targeting ATAD2. Knockdown of ATAD2 restored cisplatin sensitivity and reversed EMT/metastasis in cisplatin-resistant cells, as shown by western blotting and invasion/migration assays. The effect of miR-302 overexpression on EMT and invasiveness was mediated by the modulation of β-catenin nuclear expression. Immunofluorescence analysis showed that ATAD2 overexpression reversed the miR-302-induced downregulation of nuclear β-catenin in cisplatin resistant cells. A xenograft tumor model was used to show that miR-302 increases the antitumor effect of cisplatin in vivo. Taken together, these results identify a potential regulatory axis involving miR-302 and ATAD2 with a role in chemoresistance, indicating that activation of miR-302 or inactivation of ATAD2 could serve as a novel approach to reverse cisplatin resistance in ovarian cancer.

Keywords: ATAD2; Cisplatin resistance; Ovarian cancer; miR-302.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATPases Associated with Diverse Cellular Activities / genetics*
  • ATPases Associated with Diverse Cellular Activities / metabolism
  • Animals
  • Antagomirs / genetics
  • Antagomirs / metabolism
  • Antineoplastic Agents / pharmacology*
  • Carcinoma, Ovarian Epithelial / drug therapy
  • Carcinoma, Ovarian Epithelial / genetics*
  • Carcinoma, Ovarian Epithelial / metabolism
  • Carcinoma, Ovarian Epithelial / pathology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cisplatin / pharmacology*
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Drug Resistance, Neoplasm / genetics*
  • Epithelial-Mesenchymal Transition / drug effects
  • Epithelial-Mesenchymal Transition / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / agonists
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Oligoribonucleotides / genetics
  • Oligoribonucleotides / metabolism
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Signal Transduction
  • Tumor Burden
  • Xenograft Model Antitumor Assays


  • Antagomirs
  • Antineoplastic Agents
  • DNA-Binding Proteins
  • MIRN302A microRNA, human
  • MicroRNAs
  • Oligoribonucleotides
  • ATAD2 protein, human
  • ATPases Associated with Diverse Cellular Activities
  • Cisplatin