MIR-1265 regulates cellular proliferation and apoptosis by targeting calcium binding protein 39 in gastric cancer and, thereby, impairing oncogenic autophagy
MIR-1265 regulates cellular proliferation and apoptosis by targeting calcium binding protein 39 in gastric cancer and, thereby, impairing oncogenic autophagy
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MIR-1265 通过靶向胃癌中的钙结合蛋白 39 来调节细胞增殖和凋亡，从而损害致癌自噬
DOI：
10.1016/j.canlet.2019.02.026
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发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
Xu, Zekuan
中科院分区：
文献类型：
--
作者：
Xu, Zhipeng;Li, Zheng;Xu, Zekuan
越来越多的证据表明microRNAs（miRNAs）通过调控下游靶基因和多种信号通路在多种肿瘤中发挥重要作用。在此，我们使用癌症基因组图谱（TCGA）数据库证实了miR-1265在胃癌（GC）中的表达，并评估了临床标本和细胞系中miR-1265的表达水平。我们发现miR-1265的表达与肿瘤大小呈负相关。进一步的功能分析显示，miR-1265抑制细胞增殖和自噬，同时诱导GC细胞凋亡。使用荧光素酶报告基因测定来鉴定miR-1265靶向基因，钙结合蛋白39（CAB 39），其是AMPK-mTOR信号传导途径中的必需上游调节剂。CAB 39表达的上调或下调分别逆转了miR-1265过表达或抑制的作用。值得注意的是，自噬相关基因12（ATG 12）的敲低损害了miR-1265抑制或CAB 39过表达在GC中的作用。miR-1265还抑制体内GC细胞和人胃类器官的生长。总之，我们的研究结果表明，miR-1265通过减少CAB 39表达和调节AMPK-mTOR信号通路来抑制GC进展和致癌性自噬。因此，miR-1265可能代表GC的潜在治疗靶点。
Increasing evidence indicates that microRNAs (miRNAs) play an important role in various tumors by regulating downstream target genes and diverse signaling pathways. Herein, we confirmed miR-1265 expression in gastric cancer (GC) using the Cancer Genome Atlas (TCGA) database and assessed the level of miR-1265 expression in clinical specimens and cell lines. We found that miR-1265 expression was negatively correlated with tumor size. Further functional analysis revealed that miR-1265 suppresses cellular proliferation and autophagy while inducing apoptosis in GC cells. A luciferase reporter assay was used to identify an miR-1265 targeted gene, calcium binding protein 39 (CAB39), which is an essential upstream regulator in the AMPK-mTOR signaling pathway. Upregulation or downregulation of CAB39 expression reversed the effects of miR-1265 overexpression or inhibition, respectively. Notably, the knockdown of autophagy-related gene 12 (ATG12) impaired the effects of miR-1265 inhibition or CAB39 overexpression in GC. MiR-1265 also suppressed the growth of GC cells in vivo and that of human gastric organoids. Altogether, our results show that miR-1265 suppresses GC progression and oncogenic autophagy by reducing CAB39 expression and regulating the AMPK-mTOR signaling pathway. Therefore, miR-1265 may represent a potential therapeutic target for GC.