title: Peroxisome proliferator-activated receptor γ activation inhibits liver growth through miR-122-mediated downregulation of cMyc.
abstract: Although NR1C3 agonists inhibit cell growth, the molecular mechanism of their action has not been thoroughly characterized to date. A recent study demonstrated that NR1C3 can regulate miR-122 by binding to its promoter. Given that miR-122 can indirectly regulate cMyc-mediated promitogenic signaling by targeting E2f1, we hypothesized that NR1C3 activation inhibits hepatocyte proliferation through miR-122-mediated cMyc downregulation. In the present study, we examined if liver hyperplasia induced by a strong chemical mitogen for the liver, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), which is an agonist of NR1I3, can be repressed by NR1C3 activation through miR-122 upregulation. Acute TCPOBOP treatment caused a significant increase in liver-to-body weight ratio. The liver mass increase was accompanied with miR-122 downregulation. ChIP assays demonstrated that TCPOBOP-activated NR1I3 accumulated on the DR1 site in the pri-miR-122 promoter; and the NR1I3 accumulation is accompanied by a decrease in miR-122 and an increase in E2f1 and its transcription target cMyc. Rosiglitazone (Ros) treatment, which is an agonist of NR1C3, caused an opposite effect on liver-to-body weight ratio. When Ros was given with TCPOBOP, it attenuated the inhibitory effect of TCPOBOP on miR-122. Moreover, Ros treatment inhibited the NR1I3 binding with the DR1 site in the pri-miR-122 promoter. Furthermore, the increase of miR-122 produced by Ros was correlated with the downregulation of its targets, E2f1 and cMyc. Thus, our finding demonstrated that the liver growth inhibitory effect of NR1C3 activation was at least partly related to the decrease of cMyc though the activation of miR-122 and the downregulation of E2f1.
authors.affiliation: The Institute of Molecular Biology and Biophysics, Timakova str., 2/12, Novosibirsk 630117, Russia.
authors.forename: Andrei A
authors.initials: AA
authors.lastname: Yarushkin
authors.affiliation: The Institute of Molecular Biology and Biophysics, Timakova str., 2/12, Novosibirsk 630117, Russia.
authors.forename: Yuliya A
authors.initials: YA
authors.lastname: Kazantseva
authors.affiliation: The Institute of Molecular Biology and Biophysics, Timakova str., 2/12, Novosibirsk 630117, Russia.
authors.forename: Vyacheslav S
authors.initials: VS
authors.lastname: Kobelev
authors.affiliation: The Institute of Molecular Biology and Biophysics, Timakova str., 2/12, Novosibirsk 630117, Russia; Novosibirsk State University, Pirogova str., 1, Novosibirsk 630090, Russia.
authors.forename: Yuliya A
authors.initials: YA
authors.lastname: Pustylnyak
authors.affiliation: The Institute of Molecular Biology and Biophysics, Timakova str., 2/12, Novosibirsk 630117, Russia; Novosibirsk State University, Pirogova str., 1, Novosibirsk 630090, Russia. Electronic address: pustylnyak@post.nsu.ru.
authors.forename: Vladimir O
authors.initials: VO
authors.lastname: Pustylnyak
mesh_terms: D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D000090702:Constitutive Androstane Receptor; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects; D008099:Liver / Q000166:cytology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D008934:Mitogens / Q000494:pharmacology; D047495:PPAR gamma / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D011725:Pyridines / Q000494:pharmacology*
chemical_list: D000090702:Constitutive Androstane Receptor; D035683:MicroRNAs; C544354:Mirn122 microRNA, mouse; D008934:Mitogens; C489428:Myc protein, mouse; C000716328:Nr1i3 protein, mouse; D047495:PPAR gamma; D016271:Proto-Oncogene Proteins c-myc; D011725:Pyridines; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene
keywords: CMyc; Liver; MiR-122; NR1C3; NR1I3; Rosiglitazone (PubChem CID: 77999); TCPOBOP (PubChem CID: 5382)