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Differential TGFβ pathway targeting by miR-122 in humans and mice affects liver cancer metastasis

Author

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  • Shenyi Yin

    (State Key Laboratory of Natural and Biomimetic Drugs, College of Engineering, Peking University)

  • Yu Fan

    (State Key Laboratory of Natural and Biomimetic Drugs, College of Engineering, Peking University)

  • Hanshuo Zhang

    (State Key Laboratory of Natural and Biomimetic Drugs, College of Engineering, Peking University)

  • Zhihua Zhao

    (State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Molecular Medicine, Peking University)

  • Yang Hao

    (State Key Laboratory of Natural and Biomimetic Drugs, College of Engineering, Peking University)

  • Juan Li

    (State Key Laboratory of Natural and Biomimetic Drugs, College of Engineering, Peking University)

  • Changhong Sun

    (State Key Laboratory of Natural and Biomimetic Drugs, College of Engineering, Peking University)

  • Junyu Yang

    (State Key Laboratory of Natural and Biomimetic Drugs, College of Engineering, Peking University)

  • Zhenjun Yang

    (School of Pharmaceutical Sciences, Peking University)

  • Xiao Yang

    (State Key Laboratory of Proteomics, Genetic Laboratory of Development and Diseases, Institute of Biotechnology)

  • Jian Lu

    (College of Life Science, Peking University)

  • Jianzhong Jeff Xi

    (State Key Laboratory of Natural and Biomimetic Drugs, College of Engineering, Peking University
    State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Molecular Medicine, Peking University)

Abstract

Downregulation of a predominantly hepatocyte-specific miR-122 is associated with human liver cancer metastasis, whereas miR-122-deficient mice display normal liver function. Here we show a functional conservation of miR-122 in the TGFβ pathway: miR-122 target site is present in the mouse but not human TGFβR1, whereas a noncanonical target site is present in the TGFβ1 5′UTR in humans and other primates. Experimental switch of the miR-122 target between the receptor TGFβR1 and the ligand TGFβ1 changes the metastatic properties of mouse and human liver cancer cells. High expression of TGFβ1 in human primary liver tumours is associated with poor survival. We identify over 50 other miRNAs orthogonally targeting ligand/receptor pairs in humans and mice, suggesting that these are evolutionarily common events. These results reveal an evolutionary mechanism for miRNA-mediated gene regulation underlying species-specific physiological or pathological phenotype and provide a potentially valuable strategy for treating liver-associated diseases.

Suggested Citation

  • Shenyi Yin & Yu Fan & Hanshuo Zhang & Zhihua Zhao & Yang Hao & Juan Li & Changhong Sun & Junyu Yang & Zhenjun Yang & Xiao Yang & Jian Lu & Jianzhong Jeff Xi, 2016. "Differential TGFβ pathway targeting by miR-122 in humans and mice affects liver cancer metastasis," Nature Communications, Nature, vol. 7(1), pages 1-13, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11012
    DOI: 10.1038/ncomms11012
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