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The negative feedback between miR-143 and DNMT3A regulates cisplatin resistance in ovarian cancer

Xi Han1,2, Dan Liu3, Yuanyuan Zhou3

  • 1Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.

Cell Biology International
|October 22, 2020
PubMed

Insights

MicroRNA-143 (miR-143) reverses cisplatin resistance in ovarian cancer by downregulating DNMT3A, an epigenetic modifier. This finding reveals a negative feedback loop crucial for overcoming chemotherapy resistance.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Oncology

Background:

  • Ovarian cancer often develops resistance to cisplatin chemotherapy.
  • MicroRNAs (miRNAs) are increasingly recognized for their roles in cancer progression and drug resistance.

Purpose of the Study:

  • To elucidate the mechanism by which miR-143 influences cisplatin resistance in ovarian cancer.
  • To investigate the regulatory relationship between miR-143 and DNMT3A in the context of chemoresistance.

Main Methods:

  • Establishment of a cisplatin-resistant ovarian cancer cell line (A2780/CDDP).
  • Quantitative real-time polymerase chain reaction (qRT-PCR) to assess miR-143 and DNMT3A expression.
  • Western blot analysis and luciferase reporter assays to confirm direct targeting.
  • Methylation-specific polymerase chain reaction to evaluate promoter methylation levels.

Main Results:

  • miR-143 was significantly downregulated in cisplatin-resistant cells.
  • Overexpression of miR-143 resensitized cells to cisplatin, while inhibition increased resistance.
  • DNMT3A was identified as a direct target of miR-143 and was upregulated in resistant cells.
  • DNMT3A mediated hypermethylation of the miR-143 precursor, leading to its downregulation.
  • miR-143 inhibited tumor growth in vivo.

Conclusions:

  • A negative feedback loop exists between miR-143 and DNMT3A, acting as a key epigenetic regulator of cisplatin resistance in ovarian cancer.
  • Targeting the miR-143/DNMT3A axis offers a potential therapeutic strategy to overcome chemoresistance.
Keywords:
cisplatin resistancemethylationmicroRNAovarian cancer

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