Hypoxia blocks ferroptosis of hepatocellular carcinoma via suppression of METTL14 triggered YTHDF2-dependent silencing of SLC7A11.
Hypoxia blocks ferroptosis of hepatocellular carcinoma via suppression of METTL14 triggered YTHDF2-dependent silencing of SLC7A11.
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缺氧通过抑制 METTL14 触发 YTHDF2 依赖性 SLC7A11 沉默来阻止肝细胞癌铁死亡
DOI：
10.1111/jcmm.16957
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发表时间：
2021-11
影响因子：
5.3
通讯作者：
Shu M
中科院分区：
文献类型：
--
作者：
Fan Z;Yang G;Zhang W;Liu Q;Liu G;Liu P;Xu L;Wang J;Yan Z;Han H;Liu R;Shu M
残留肝细胞癌(HCC)细胞耐受介入性栓塞术所引发的低氧环境，获得了更多的恶性潜能，但其机制尚未阐明。N6-甲基腺苷(M6A)的生物活性在多种生理过程中起着至关重要的作用。然而，它在低氧条件下的作用在很大程度上仍未被探索。RT-qPCR法和Western印迹法检测METTL14在低氧肝癌细胞中的表达。采用丙二醛测定法和电子显微镜照相技术评价铁性下垂。通过生物信息学分析，对SLC7A11和METTL14进行了相关性分析。用流式细胞仪检测SLC7A11对ROS产生的影响。细胞计数Kit-8法检测细胞增殖能力。低氧以HIF-1α依赖的方式抑制METTL14，有效地抑制肝癌细胞的铁性下垂。机制调查证实SLC7A11是METTL14的直接目标。体外和体内实验表明，METTL14诱导SLC7A11基因5‘端非编码区m6A修饰，进而通过依赖YTHDF2的途径降解。重要的是，SLC7A11的异位表达强烈阻断了METTL14诱导的缺氧性肝癌的肿瘤抑制作用。我们的研究侧重于肝癌细胞中缺氧调节的铁性下垂，并确定HIF-1α/METTL14/YTHDF2/SLC7A11轴是肝癌介入栓塞治疗的潜在治疗靶点。
Residue hepatocellular carcinoma (HCC) cells enduring hypoxic environment triggered by interventional embolization obtain more malignant potential with little clarified mechanism. The N6‐methyladenosine (m6A) biological activity plays essential roles in diverse physiological processes. However, its role under hypoxic condition remains largely unexplored. RT‐qPCR and Western blot were used to evaluate METTL14 expression in hypoxic HCC cells. MDA assay and electronic microscopy photography were used to evaluate ferroptosis. The correlation between SLC7A11 and METTL14 was conducted by bioinformatical analysis. Flow cytometry was used to verify the effect of SLC7A11 on ROS production. Cell counting kit‐8 assay was performed to detect cells proliferation ability. Hypoxia triggered suppression of METTL14 in a HIF‐1α–dependent manner potently abrogated ferroptosis of HCC cells. Mechanistic investigation identified SLC7A11 was a direct target of METTL14. Both in vitro and in vivo assay demonstrated that METTL14 induced m6A modification at 5’UTR of SLC7A11 mRNA, which in turn underwent degradation relied on the YTHDF2‐dependent pathway. Importantly, ectopic expression of SLC7A11 strongly blocked METTL14‐induced tumour‐suppressive effect in hypoxic HCC. Our investigations lay the emphasis on the hypoxia‐regulated ferroptosis in HCC cells and identify the HIF‐1α /METTL14/YTHDF2/SLC7A11 axis as a potential therapeutic target for the HCC interventional embolization treatment.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
4.6
作者：
Lee HW;Park BS;Joo JH;Patidar SK;Choi HJ;Jin E;Han MS
通讯作者：
Han MS
影响因子：
4.7
作者：
Gilreath C;Boerma M;Qin Z;Hudson MK;Wang S
通讯作者：
Wang S
R-Spondin3 促进绒毛膜癌 JEG-3 细胞的肿瘤生长。
影响因子：
5.5
作者：
Chen, Zhilong;Zhang, Juzuo;Yang, Qing
通讯作者：
Yang, Qing
影响因子：
64.8
作者：
Jiang, Le;Kon, Ning;Li, Tongyuan;Wang, Shang-Jui;Su, Tao;Hibshoosh, Hanina;Baer, Richard;Gu, Wei
通讯作者：
Gu, Wei