miR-138-5p suppresses autophagy in pancreatic cancer by targeting SIRT1.
miR-138-5p suppresses autophagy in pancreatic cancer by targeting SIRT1.
复制标题
miR-138-5p 通过靶向 SIRT1 抑制胰腺癌中的自噬。
DOI：
10.18632/oncotarget.14360
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发表时间：
2017-02-14
期刊：
影响因子：
--
通讯作者：
Jiang J
中科院分区：
文献类型：
--
作者：
Tian S;Guo X;Yu C;Sun C;Jiang J
microRNA在胰腺癌中发生的异常自噬中的作用仍然存在争议。因为缺氧是已知的诱导自噬，我们筛选差异表达的microRNA使用的miRNA微阵列与胰腺癌细胞培养在常氧和缺氧条件下。我们发现miR-138- 5 p是缺氧刺激细胞中下调最多的miRNA之一，并且miR-138- 5 p的过表达显著降低了自噬标记物的表达。此外，免疫印迹和免疫荧光分析以及电子显微镜显示，miR-138- 5 p抑制胰腺癌细胞中的自噬，并独立于典型的自噬信号通路阻断血清饥饿诱导的自噬通量。miR-138- 5 p对ATG 3、ATG 5或ATG 7这三个主要的自噬相关基因没有影响。相反，miR-138- 5 p特异性靶向SIRT 1 3′非翻译区，并通过降低SIRT 1的水平来抑制自噬，SIRT 1使FoxO 1乙酰化并通过FoxO 1/Rab 7调节自噬。SIRT 1或Rab 7敲低阻断SIRT 1/FoxO 1/Rab 7轴并抑制miR-138- 5 p的自噬抑制。最后，我们发现miR-138- 5 p在体内抑制自噬和肿瘤生长。这些结果表明，miR-138- 5 p通过靶向SIRT 1抑制胰腺癌中的自噬。
The role of microRNA in the aberrant autophagy that occurs in pancreatic cancer remains controversial. Because hypoxia is known to induce autophagy, we screened for differentially expressed microRNAs using a miRNA microarray with pancreatic cancer cells cultured under normoxic and hypoxic conditions. We found that miR-138-5p was among the most downregulated miRNA in hypoxia-stimulated cells, and that overexpression of miR-138-5p substantially reduced expression of autophagy markers. In addition, western blot and immunofluorescence analyses and electron microscopy revealed that miR-138-5p inhibited autophagy in pancreatic cancer cells and blocked serum starvation-induced autophagic flux independently of the typical autophagic signaling pathway. miR-138-5p had no effect on ATG3, ATG5, or ATG7, three primary autophagy-associated genes. Instead, miR-138-5p specifically targeted the SIRT1 3′ untranslated region and suppressed autophagy by reducing the level of SIRT1, which acetylates FoxO1 and regulates autophagy via FoxO1/Rab7. SIRT1 or Rab7 knockdown blocked the SIRT1/FoxO1/Rab7 axis and suppressed autophagic inhibition by miR-138-5p. Finally, we found that miR-138-5p inhibited autophagy and tumor growth in vivo. These results indicate that miR-138-5p suppresses autophagy in pancreatic cancer by targeting SIRT1.