MicroRNA-214-3p enhances erastin-induced ferroptosis by targeting ATF4 in hepatoma cells
MicroRNA-214-3p enhances erastin-induced ferroptosis by targeting ATF4 in hepatoma cells
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MicroRNA-214-3p 通过靶向肝癌细胞中的 ATF4 增强erastin-诱导的铁死亡
DOI：
10.1002/jcp.29496
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发表时间：
2020-01-21
影响因子：
5.6
通讯作者：
Sun, Yuling
中科院分区：
文献类型：
--
作者：
Bai, Tao;Liang, Ruopeng;Sun, Yuling
原发性肝癌是与癌症相关的死亡的第二大常见原因。铁下垂，一种公认的调节性细胞死亡形式，最近得到了关注。MicroRNA-214-3p(miR-214)在肝癌发生中起调控作用。然而，miR-214在细胞性铁下垂中的作用尚不清楚。本研究旨在阐明miR-214对肝癌铁性下垂的调节作用。在体外，用铁下垂诱导剂erastin处理HepG2和Hep3B癌细胞，然后证实erastin抑制细胞活力。此外，前miR-214过表达导致HepG2和Hep3B细胞对erastin更敏感，而抗miR-214海绵的作用则相反。此外，前miR-214过表达增加了暴露于erastin的癌细胞中丙二醛和活性氧的水平，上调了Fe2+的浓度，并降低了谷胱甘肽的水平。此外，erastin增强了HepG2和Hep3B细胞中转录因子4(ATF4)的激活，而前miR-214过表达抑制了ATF4的表达。荧光素酶报告数据证实ATF4是miR-214的直接靶标。转染ATF4过表达质粒的癌细胞对miR-214诱导的铁链死亡的易感性降低。在体内，erastin显著减小移植瘤的大小和重量，miR-214增强erastin促进铁性下垂的作用，并降低ATF4的表达。综上所述，我们的研究表明miR-214对肝癌细胞铁性下垂的促进作用至少归因于其对ATF4的抑制作用，这可能为治疗肝癌的铁性下垂提供一个新的靶点。
Primary liver cancer is the second most frequent cause of cancer-related deaths. Ferroptosis, a recognized form of regulated cell death, recently gains attention. MicroRNA-214-3p (miR-214) plays a regulatory role in hepatocarcinogenesis. However, the role of miR-214 in cellular ferroptosis is unclear. This study aimed at elucidating whether miR-214 could regulate ferroptosis of liver cancer. In vitro, HepG2 and Hep3B cancer cells were treated with erastin, a ferroptosis inducer, and then erastin was demonstrated to suppress the cell viability. Moreover, pre-miR-214 overexpression caused that HepG2 and Hep3B cells were more susceptible to erastin, whereas anti-miR-214 sponge showed the opposite effect. Additionally, pre-miR-214 overexpression increased the malondialdehyde and reactive oxygen species levels, upregulated Fe2+ concentration, and decreased glutathione levels in cancer cells exposed to erastin. Further, erastin enhanced the activation of transcription factor 4 (ATF4) in HepG2 and Hep3B cells, and pre-miR-214 overexpression inhibited ATF4 expression. The luciferase reporter data validated ATF4 as a direct target of miR-214. Cancer cells transfected with ATF4 overexpression plasmid rendered lower susceptible to miR-214-induced ferroptotic death. In vivo, erastin significantly reduced the size and weight of xenografted tumors, and miR-214 elevated the ferroptosis-promoting effects of erastin and decreased ATF4 expression. In summary, our study demonstrates that the ferroptosis-promoting effects of miR-214 in hepatoma cells are attributed at least to its inhibitory effects on ATF4, which may provide a new target for therapy of hepatoma regarding ferroptosis.