miR-20a inhibits hypoxia-induced autophagy by targeting ATG5/FIP200 in colorectal cancer
miR-20a inhibits hypoxia-induced autophagy by targeting ATG5/FIP200 in colorectal cancer
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DOI：
10.1002/mc.23006
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发表时间：
2019-07-01
影响因子：
4.6
通讯作者：
Yuan, Xianglin
中科院分区：
文献类型：
--
作者：
Che, Jing;Wang, Wenshan;Yuan, Xianglin
自噬是一种高度保守的溶酶体介导的保护性细胞过程，其中细胞质成分（包括受损的细胞器和长寿命蛋白质）被清除。许多研究表明，自噬在缺氧区域上调。然而，结直肠癌（CRC）中缺氧诱导自噬的精确分子机制仍不清楚。在本研究中，我们发现结肠癌细胞缺氧下miR-20a显着下调，并且miR-20a的过表达减轻了缺氧诱导的自噬。此外，miR-20a 通过靶向自噬的多个关键调节因子（包括 ATG5 和 FIP200）来抑制缺氧诱导的自噬流。此外，通过双荧光素酶测定，我们证明 miR-20a 直接靶向 ATG5 和 FIP200 的 3'-非翻译区，调节它们的信使 RNA 和蛋白质水平。此外，重新引入外源ATG5或FIP200可部分逆转缺氧条件下miR-20a介导的自噬抑制。在结肠癌组织的缺氧区域观察到miR-20a与其靶基因呈负相关。综上所述，我们的研究结果表明，结直肠癌中缺氧介导的自噬受到 miR-20a/ATG5/FI200 信号通路的调节。 miR-20a介导的自噬缺陷可能在结直肠肿瘤发生过程中缺氧诱导的自噬中发挥重要作用。
Autophagy is a highly conserved lysosome-mediated protective cellular process in which cytosolic components, including damaged organelles and long-lived proteins, are cleared. Many studies have shown that autophagy was upregulated in hypoxic regions. However, the precise molecular mechanism of hypoxia-induced autophagy in colorectal cancer (CRC) is still elusive. In this study, we found that miR-20a was significantly downregulated under hypoxia in colon cancer cells, and overexpression of miR-20a alleviated hypoxia-induced autophagy. Moreover, miR-20a inhibits the hypoxia-induced autophagic flux by targeting multiple key regulators of autophagy, including ATG5 and FIP200. Furthermore, by dual-luciferase assay we demonstrated that miR-20a directly targeted the 3 '-untranslated region of ATG5 and FIP200, regulating their messenger RNA and protein levels. In addition, reintroduction of exogenous ATG5 or FIP200 partially reversed miR-20a-mediated autophagy inhibition under hypoxia. A negative correlation between miR-20a and its target genes is observed in the hypoxic region of colon cancer tissues. Taken together, our findings suggest that hypoxia-mediated autophagy was regulated by miR-20a/ATG5/FI200 signaling pathway in CRC. miR-20a-mediated autophagy defect that might play an important role in hypoxia-induced autophagy during colorectal tumorigenesis.