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

Shenyi Yin, Yu Fan, Hanshuo Zhang, Zhihua Zhao, Yang Hao, Juan Li, Changhong Sun, Junyu Yang, Zhenjun Yang, Xiao Yang, Jian Lu and Jianzhong Jeff Xi ()
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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

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11012

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