title: Differential TGFβ pathway targeting by miR-122 in humans and mice affects liver cancer metastasis.
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.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Biomedical Engineering, College of Engineering, Peking University, Beijing 100871, China.
authors.forename: Shenyi
authors.initials: S
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Biomedical Engineering, College of Engineering, Peking University, Beijing 100871, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Fan
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Biomedical Engineering, College of Engineering, Peking University, Beijing 100871, China.
authors.forename: Hanshuo
authors.initials: H
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Biomedical Engineering, College of Engineering, Peking University, Beijing 100871, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Hao
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Biomedical Engineering, College of Engineering, Peking University, Beijing 100871, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Biomedical Engineering, College of Engineering, Peking University, Beijing 100871, China.
authors.forename: Changhong
authors.initials: C
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Biomedical Engineering, College of Engineering, Peking University, Beijing 100871, China.
authors.forename: Junyu
authors.initials: J
authors.lastname: Yang
authors.affiliation: School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Zhenjun
authors.initials: Z
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Proteomics, Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing 100071, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
authors.affiliation: College of Life Science, Peking University, Beijing 100871, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Biomedical Engineering, College of Engineering, Peking University, Beijing 100871, China.|State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Jianzhong Jeff
authors.initials: JJ
authors.lastname: Xi
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D064591:Allografts; D000818:Animals; D020029:Base Pairing / Q000235:genetics; D001483:Base Sequence; D002460:Cell Line; D017124:Conserved Sequence / Q000235:genetics; D019143:Evolution, Molecular; D016678:Genome; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000556:secondary*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013045:Species Specificity; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020121:5' Untranslated Regions; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; C544354:Mirn122 microRNA, mouse; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I