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

      Cell Cycle
      Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, genetics, metabolism, Basic Helix-Loop-Helix Transcription Factors, Binding Sites, Cell Cycle, Cell Hypoxia, Cell Line, Tumor, Cluster Analysis, Gene Knockdown Techniques, Humans, Hypoxia-Inducible Factor 1, MicroRNAs, Models, Biological, Proto-Oncogene Proteins c-myc, antagonists & inhibitors, RNA, Small Interfering, Repressor Proteins, Up-Regulation

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          Abstract

          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.

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