MicroRNA miR-210 modulates cellular response to hypoxia through the MYC antagonist MNT

作者：Zhan Zhang, Hong Sun, Hongyue Dai, Ryan Walsh, Maki Imakura, Janell M. Schelter, Julja Burchard, Xudong Dai, Aaron N. Chang, Robert L. Diaz, Joseph R. Marszalek, Steven R. Bartz, Michael Carleton, Michele A. Cleary, Peter S. Linsley, Carla Grandori · 发表于：Cell Cycle · 年份：2009 · DOI：10.4161/cc.8.17.9387 · 被引用次数：284 · 研究领域：MicroRNA in disease regulation、Cancer-related molecular mechanisms research、RNA modifications and cancer

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.