Circular RNA MCTP2 inhibits cisplatin resistance in gastric cancer by miR-99a-5p-mediated induction of MTMR3 expression.
Circular RNA MCTP2 inhibits cisplatin resistance in gastric cancer by miR-99a-5p-mediated induction of MTMR3 expression.
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环状RNA MCTP2通过miR-99a-5p介导的MTMR3表达诱导抑制胃癌顺铂耐药
DOI：
10.1186/s13046-020-01758-w
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发表时间：
2020-11-17
期刊：
影响因子：
--
通讯作者：
Xu Z
中科院分区：
文献类型：
--
作者：
Sun G;Li Z;He Z;Wang W;Wang S;Zhang X;Cao J;Xu P;Wang H;Huang X;Xia Y;Lv J;Xuan Z;Jiang T;Fang L;Yang J;Zhang D;Xu H;Xu Z
顺铂（CDDP）是胃癌（GC）的一线化疗药物。胃癌患者预后不良的部分原因是CDDP耐药的发生。环状rna （circRNAs）是非编码rna的一个亚类，其功能是microRNA （miRNA）海绵。环状rna在GC中CDDP耐药中的作用尚未得到评估。RNA测序用于鉴定cddp耐药和cddp敏感的GC细胞之间差异表达的环状RNA。采用qRT-PCR检测GC组织中circMCTP2的表达。在体外和体内研究了circMCTP2对CDDP耐药的影响。通过拉下试验和荧光素酶报告基因试验来确认circMCTP2、miR-99a-5p和肌小管蛋白相关蛋白3 （MTMR3）之间的相互作用。western blotting检测MTMR3蛋白表达水平。用共聚焦显微镜和透射电镜（TEM）观察自噬情况。与cddp敏感的GC细胞和组织相比，CircMCTP2在cddp抗性GC细胞和组织中下调。高水平的circMCTP2被发现是胃癌患者预后的有利因素。CircMCTP2抑制CDDP耐药GC细胞的增殖，同时促进CDDP治疗后的细胞凋亡。CircMCTP2也被发现可以减少cddp抗性GC细胞的自噬。证实MiR-99a-5p被circMCTP2擦拭过。抑制miR-99a-5p可使GC细胞对CDDP敏感。MTMR3被证实是miR-99a-5p的直接靶点。MTMR3的敲低逆转了circMCTP2对cddp耐药GC细胞增殖、凋亡和自噬的影响。在裸鼠异种移植模型中也证实了CircMCTP2在体内抑制CDDP耐药性。CircMCTP2通过海绵化miR-99a-5p上调MTMR3使GC对CDDP增敏。过表达CircMCTP2可能是对抗GC中CDDP耐药的一种新的治疗策略。在线版本包含补充材料，可在10.1186/s13046-020-01758-w获得。
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. 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). 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. 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. The online version contains supplementary material available at 10.1186/s13046-020-01758-w.
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