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

Guangli Sun,Lang Fang,Penghui Xu,Zheng Li,Yiwen Xia,Jing Yang,Xiaoxu Huang,Zekuan Xu,Weizhi Wang,Zhe Xuan,Sen Wang,Tianlu Jiang,Diancai Zhang,Haixiao Wang,Hao Xu,Jialun Lv,Zhongyuan He,Jiacheng Cao,Xing Zhang

doi:10.1186/s13046-020-01758-w

Abstract

BackgroundCisplatin (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.MethodsRNA 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).ResultsCircMCTP2 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.ConclusionsCircMCTP2 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.

Highlights

Cisplatin (CDDP) is the first-line chemotherapy for gastric cancer (GC)
We report that circMCTP2 acts as a miR-99a-5p sponge and sensitizes GC cells to CDDP through the upregulation of Myotubularin-related protein 3 (MTMR3)
CircMCTP2 is downregulated in CDDP-resistant GC cells and tissues To generate the profile of differentially expressed circular RNAs in CDDP-sensitive and CDDP-resistant GC cells, we performed RNA-seq analysis of BGC823 (CDDP-sensitive), BGC823CDDP (CDDP-resistant), SGC7901 (CDDP-sensitive), and SGC7901CDDP (CDDP-resistant) cells

Summary

Introduction

The poor prognosis of GC patients is partially due to the development of CDDP resistance. The role of circRNAs in CDDP resistance in GC has not been evaluated. Compared with other areas of the world, GC is more common in East Asia, with 43% of GC patients in China alone [2]. Despite improved treatment for GC, the prognosis of advanced GC patients remains poor, with a low 5-year survival rate [3]. CDDP-based chemotherapy is the main treatment strategy for patients with advanced GC [4]. After several cycles of chemotherapy, 50% of the patients exhibit acquired drug resistance. The 5-year survival rate of these CDDP-resistant patients is only approximately 20% [5,6,7].

Methods

Results

Conclusion