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

Guangli SunDepartment of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, ChinaZheng LiDepartment of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, ChinaZhongyuan HeDepartment of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, ChinaWeizhi WangDepartment of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, ChinaSen WangDepartment of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, ChinaXing ZhangDepartment of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, ChinaJiacheng CaoDepartment of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, ChinaPenghui XuDepartment of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, ChinaHaixiao WangDepartment of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, ChinaXiaoxu HuangDepartment of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, ChinaYiwen XiaDepartment of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, ChinaJialun LvDepartment of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, ChinaZhe XuanDepartment of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, ChinaTianlu JiangDepartment of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, ChinaLang FangDepartment of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, ChinaJing YangDepartment of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, ChinaDiancai ZhangDepartment of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, ChinaHao XuDepartment of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu province, ChinaZekuan XuCollaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu province, China. [email protected]

2020en

ABI

Аннотация

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.

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DOI: 10.1186/s13046-020-01758-w

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