MicroRNA miR-210 modulates cellular response to hypoxia through the MYC antagonist MNT
MicroRNA miR-210 modulates cellular response to hypoxia through the MYC antagonist MNT
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DOI：
10.4161/cc.8.17.9387
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发表时间：
2009-09-01
期刊：
影响因子：
4.3
通讯作者：
Grandori, Carla
中科院分区：
文献类型：
--
作者：
Zhang, Zhan;Sun, Hong;Grandori, Carla
低氧诱导因子（hypoxia-inducible factor，HIF）信号通路是低氧环境下细胞生存所必需的，并在肿瘤细胞内环境稳定中起重要作用。我们研究了miR-210的功能，miR-210是缺氧上调的最突出的microRNA，也是HIF的直接转录靶点。miR-210表达在多种癌症类型中升高，并与乳腺癌和黑色素瘤肿瘤的转移相关。miR-210在癌细胞系中的过表达绕过了缺氧诱导的细胞周期停滞，并部分逆转了缺氧基因表达特征。我们将已知的MYC拮抗剂MNT鉴定为miR-210靶标。MNT mRNA在3' UTR中含有多个miR-210结合位点，并且其敲低表型复制的miR-210过表达。此外，MYC的缺失消除了miR-210介导的对缺氧诱导的细胞周期停滞的覆盖。将miR-210和MYC过表达与MNT敲除特征进行比较也表明，miR-210触发了“MYC样”转录反应。因此，miR-210通过靶向MYC-MAX网络的关键转录阻遏物来影响肿瘤细胞中的缺氧反应。
The hypoxia-inducible factor (HIF) pathway is essential for cell survival under low oxygen and plays an important role in tumor cell homeostasis. We investigated the function of miR-210, the most prominent microRNA upregulated by hypoxia and a direct transcriptional target of HIFs. miR-210 expression was elevated in multiple cancer types and correlated with metastasis of breast and melanoma tumors. miR-210 overexpression in cancer cell lines bypassed hypoxia-induced cell cycle arrest and partially reversed the hypoxic gene expression signature. We identified MNT, a known MYC antagonist, as a miR-210 target. MNT mRNA contains multiple miR-210 binding sites in the 3' UTR and its knockdown phenocopied miR-210 overexpression. Furthermore, loss of MYC abolished miR-210-mediated override of hypoxia-induced cell cycle arrest. Comparison of miR-210 and MYC overexpression with MNT knockdown signatures also indicated that miR-210 triggered a "MYC-like" transcriptional response. Thus, miR-210 influences the hypoxia response in tumor cells through targeting a key transcriptional repressor of the MYC-MAX network.