title: MiR-154 directly suppresses DKK2 to activate Wnt signaling pathway and enhance activation of cardiac fibroblasts.
abstract: Excessive proliferation of cardiac fibroblasts (CFs) and their transdifferentiation into myofibroblasts leads to expression of α-smooth muscle actin (α-SMA), as well as excessive synthesis and secretion of collagens. This process represents an important pathological basis for myocardial fibrosis (MF). MicroRNA (miR)-154 and the Wnt signaling pathway play key roles in the above process, although their specific interactions are poorly understood. After transfecting CFs with miR-154 mimics or inhibitors, miR-154 was found to inhibit the expression of Dickkopf-related protein 2 (DKK2), while miR-154 inhibitors upregulated DKK2 expression in a Western blot analysis. In a subsequent dual-luciferase activity assay, direct binding of miR-154 to DKK2 was detected. Further experiments demonstrated that transfection of DKK2 siRNA or miR-154 resulted in increased levels of β-catenin, α-SMA, and collagens I and III. Moreover, these changes were observed in association with increases in CF proliferation and migration, and reduced apoptosis. Conversely, transfection of miR-154 inhibitors or DKK2 overexpression vector resulted in lower expression levels of β-catenin, α-SMA, and collagens I and III, suppressed cell proliferation and migration, and enhanced apoptosis. Furthermore, in each assay, when the DKK2 overexpression vector and miR-154 mimics were co-transfected, the functions of each component were counteracted by the other. Therefore, in CFs, targeting of DKK2 by miR-154 leads to upregulation of β-catenin expression and activation of the classical Wnt signaling pathway and CFs. These results suggest new targets for the clinical treatment of MF and ischemic heart disease.
authors.affiliation: Shandong University School of Medicine, Jinan, 250012, Shandong, China.|Department of Geratology, Yantai Yuhuangding Hospital, Yantai, 264000, Shandong, China.
authors.forename: Li-Ye
authors.initials: LY
authors.lastname: Sun
authors.affiliation: Shandong University School of Medicine, Jinan, 250012, Shandong, China.|Department of Cardiology, Weihai Central Hospital, Weihai, 264423, Shandong, China.
authors.forename: Zi-Dong
authors.initials: ZD
authors.lastname: Bie
authors.affiliation: Department of Cardiology, Yantai Yuhuangding Hospital, 20# Yuhuangding East Road, Zhifu District, Yantai, 264000, Shandong, China.
authors.forename: Chuan-Huan
authors.initials: CH
authors.lastname: Zhang
authors.affiliation: Department of Geratology, Yantai Yuhuangding Hospital, Yantai, 264000, Shandong, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Cardiology, Yantai Yuhuangding Hospital, 20# Yuhuangding East Road, Zhifu District, Yantai, 264000, Shandong, China.
authors.forename: Liu-Dong
authors.initials: LD
authors.lastname: Li
authors.affiliation: Department of Cardiology, Yantai Yuhuangding Hospital, 20# Yuhuangding East Road, Zhifu District, Yantai, 264000, Shandong, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
mesh_terms: D000328:Adult; D017209:Apoptosis; D001483:Base Sequence; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology*; D060449:Wnt Signaling Pathway / Q000235:genetics*
chemical_list: C498622:DKK2 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C561122:MIRN154 microRNA, human; D035683:MicroRNAs
keywords: DKK2; cardiac fibroblasts; miR-154; myocardial infarction