Circular RNA MCTP2 inhibits cisplatin resistance in gastric cancer by miR-99a-5p-mediated induction of MTMR3 expression

J Exp Clin Cancer Res. 2020 Nov 17;39(1):246. doi: 10.1186/s13046-020-01758-w.


Background: Cisplatin (CDDP) is the first-line chemotherapy for gastric cancer (GC). The poor prognosis of GC patients is partially due to the development of CDDP resistance. Circular RNAs (circRNAs) are a subclass of noncoding RNAs that function as microRNA (miRNA) sponges. The role of circRNAs in CDDP resistance in GC has not been evaluated.

Methods: RNA sequencing was used to identify the differentially expressed circRNAs between CDDP-resistant and CDDP-sensitive GC cells. qRT-PCR was used to detect the expression of circMCTP2 in GC tissues. The effects of circMCTP2 on CDDP resistance were investigated in vitro and in vivo. Pull-down assays and luciferase reporter assays were performed to confirm the interactions among circMCTP2, miR-99a-5p, and myotubularin-related protein 3 (MTMR3). The protein expression levels of MTMR3 were detected by western blotting. Autophagy was evaluated by confocal microscopy and transmission electron microscopy (TEM).

Results: CircMCTP2 was downregulated in CDDP-resistant GC cells and tissues compared to CDDP-sensitive GC cells and tissues. A high level of circMCTP2 was found to be a favorable factor for the prognosis of patients with GC. CircMCTP2 inhibited proliferation while promoting apoptosis of CDDP-resistant GC cells in response to CDDP treatment. CircMCTP2 was also found to reduce autophagy in CDDP-resistant GC cells. MiR-99a-5p was verified to be sponged by circMCTP2. Inhibition of miR-99a-5p could sensitize GC cells to CDDP. MTMR3 was confirmed to be a direct target of miR-99a-5p. Knockdown of MTMR3 reversed the effects of circMCTP2 on the proliferation, apoptosis and autophagy of CDDP-resistant GC cells. CircMCTP2 was also confirmed to inhibit CDDP resistance in vivo in a nude mouse xenograft model.

Conclusions: CircMCTP2 sensitizes GC to CDDP through the upregulation of MTMR3 by sponging miR-99a-5p. Overexpression of CircMCTP2 could be a new therapeutic strategy for counteracting CDDP resistance in GC.

Keywords: CircMCTP2; Cisplatin; GC; MTMR3; miR-99a-5p.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cisplatin / pharmacology*
  • Female
  • Humans
  • Membrane Proteins / genetics*
  • Mice
  • Mice, Nude
  • MicroRNAs / metabolism*
  • Middle Aged
  • Prognosis
  • Protein Tyrosine Phosphatases, Non-Receptor / metabolism*
  • RNA, Circular / metabolism*
  • Stomach Neoplasms / drug therapy*
  • Stomach Neoplasms / genetics*
  • Transfection


  • MCTP2 protein, human
  • MIRN99 microRNA, human
  • Membrane Proteins
  • MicroRNAs
  • RNA, Circular
  • MTMR3 protein, human
  • Protein Tyrosine Phosphatases, Non-Receptor
  • Cisplatin