title: Downregulation of stanniocalcin 1 is responsible for sorafenib-induced cardiotoxicity.
abstract: Sorafenib is associated with adverse cardiac effects, including left ventricular dysfunction. However, the precise mechanism remains unclear. Here, we aimed to establish the genes responsible for this cardiotoxicity using zebrafish and human cardiomyocytes. Fluorescent cardiac imaging using pigmentless zebrafish with green fluorescent protein hearts revealed that the ventricular dimensions of the longitudinal axis with sorafenib were significantly shorter than those of the control group. Transcriptome analysis of their hearts revealed that stanniocalcin 1 (stc1) was downregulated by sorafenib. stc1 knockdown in zebrafish revealed that reduction of stc1 decreased the longitudinal dimensions of zebrafish ventricles, similar to that which occurs during sorafenib treatment. STC1 downregulation and cytotoxicity were also seen in human cardiomyocytes exposed to sorafenib. To clarify the molecular function of stc1 in sorafenib-induced cardiotoxicity, we focused on oxidative stress in cardiomyocytes treated with sorafenib. Reactive oxygen species (ROS) production significantly increased in both species of human cardiomyocytes and zebrafish exposed to sorafenib and STC1 knockdown compared with the controls. Finally, we found that forced expression of stc1 normalized impairment, decreasing the longitudinal dimensions in zebrafish treated with sorafenib. Our study demonstrated that STC1 plays a protective role against ventricular dysfunction and ROS overproduction, which are induced by sorafenib treatment. We discovered for the first time that STC1 downregulation is responsible for sorafenib-induced cardiotoxicity through activated ROS generation.
authors.affiliation: *Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Department of Clinical Anesthesiology, Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie 514-8507, Japan, Mie University Medical Zebrafish Research Center, Mie 514-8507, Japan, Department of Bioinformatics, Mie University Life Science Research Center, Mie 514-8507, Japan and Department of Omics Medicine, Mie University Industrial Technology Innovation, Mie 514-8507, Japan *Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Department of Clinical Anesthesiology, Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie 514-8507, Japan, Mie University Medical Zebrafish Research Center, Mie 514-8507, Japan, Department of Bioinformatics, Mie University Life Science Research Center, Mie 514-8507, Japan and Department of Omics Medicine, Mie University Industrial Technology Innovation, Mie 514-8507, Japan.
authors.forename: Miko
authors.initials: M
authors.lastname: Kawabata
authors.affiliation: *Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Department of Clinical Anesthesiology, Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie 514-8507, Japan, Mie University Medical Zebrafish Research Center, Mie 514-8507, Japan, Department of Bioinformatics, Mie University Life Science Research Center, Mie 514-8507, Japan and Department of Omics Medicine, Mie University Industrial Technology Innovation, Mie 514-8507, Japan *Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Department of Clinical Anesthesiology, Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie 514-8507, Japan, Mie University Medical Zebrafish Research Center, Mie 514-8507, Japan, Department of Bioinformatics, Mie University Life Science Research Center, Mie 514-8507, Japan and Department of Omics Medicine, Mie University Industrial Technology Innovation, Mie 514-8507, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Umemoto
authors.affiliation: *Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Department of Clinical Anesthesiology, Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie 514-8507, Japan, Mie University Medical Zebrafish Research Center, Mie 514-8507, Japan, Department of Bioinformatics, Mie University Life Science Research Center, Mie 514-8507, Japan and Department of Omics Medicine, Mie University Industrial Technology Innovation, Mie 514-8507, Japan *Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Department of Clinical Anesthesiology, Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie 514-8507, Japan, Mie University Medical Zebrafish Research Center, Mie 514-8507, Japan, Department of Bioinformatics, Mie University Life Science Research Center, Mie 514-8507, Japan and Department of Omics Medicine, Mie University Industrial Technology Innovation, Mie 514-8507, Japan *Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Department of Clinical Anesthesiology, Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie 514-8507, Japan, Mie University Medical Zebrafish Research Center, Mie 514-8507, Japan, Department of Bioinformatics, Mie University Life Science Research Center, Mie 514-8507, Japan and Department of Omics Medicine, Mie University Industrial Technology Innovation, Mie 514-8507, Japan *Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Department of Clinical Anesthesiology, Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie 514-8507, Japan, Mie University Medical Zebrafish Research Center, Mie 514-8507, Japan, Department of Bioinformatics, Mie University Life Science Research Center, Mie 514-8507, Japan and Department of Omics Medicine, Mie University Industrial Technology Innovation, Mie 514-
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Shimada
authors.affiliation: *Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Department of Clinical Anesthesiology, Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie 514-8507, Japan, Mie University Medical Zebrafish Research Center, Mie 514-8507, Japan, Department of Bioinformatics, Mie University Life Science Research Center, Mie 514-8507, Japan and Department of Omics Medicine, Mie University Industrial Technology Innovation, Mie 514-8507, Japan *Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Department of Clinical Anesthesiology, Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie 514-8507, Japan, Mie University Medical Zebrafish Research Center, Mie 514-8507, Japan, Department of Bioinformatics, Mie University Life Science Research Center, Mie 514-8507, Japan and Department of Omics Medicine, Mie University Industrial Technology Innovation, Mie 514-8507, Japan *Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Department of Clinical Anesthesiology, Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie 514-8507, Japan, Mie University Medical Zebrafish Research Center, Mie 514-8507, Japan, Department of Bioinformatics, Mie University Life Science Research Center, Mie 514-8507, Japan and Department of Omics Medicine, Mie University Industrial Technology Innovation, Mie 514-8507, Japan *Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Department of Clinical Anesthesiology, Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie 514-8507, Japan, Mie University Medical Zebrafish Research Center, Mie 514-8507, Japan, Department of Bioinformatics, Mie University Life Science Research Center, Mie 514-8507, Japan and Department of Omics Medicine, Mie University Industrial Technology Innovation, Mie 514-
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Nishimura
authors.affiliation: *Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Department of Clinical Anesthesiology, Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie 514-8507, Japan, Mie University Medical Zebrafish Research Center, Mie 514-8507, Japan, Department of Bioinformatics, Mie University Life Science Research Center, Mie 514-8507, Japan and Department of Omics Medicine, Mie University Industrial Technology Innovation, Mie 514-8507, Japan.
authors.forename: Beibei
authors.initials: B
authors.lastname: Zhang
authors.affiliation: *Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Department of Clinical Anesthesiology, Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie 514-8507, Japan, Mie University Medical Zebrafish Research Center, Mie 514-8507, Japan, Department of Bioinformatics, Mie University Life Science Research Center, Mie 514-8507, Japan and Department of Omics Medicine, Mie University Industrial Technology Innovation, Mie 514-8507, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Kuroyanagi
authors.affiliation: *Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Department of Clinical Anesthesiology, Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie 514-8507, Japan, Mie University Medical Zebrafish Research Center, Mie 514-8507, Japan, Department of Bioinformatics, Mie University Life Science Research Center, Mie 514-8507, Japan and Department of Omics Medicine, Mie University Industrial Technology Innovation, Mie 514-8507, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Miyabe
authors.affiliation: *Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Department of Clinical Anesthesiology, Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie 514-8507, Japan, Mie University Medical Zebrafish Research Center, Mie 514-8507, Japan, Department of Bioinformatics, Mie University Life Science Research Center, Mie 514-8507, Japan and Department of Omics Medicine, Mie University Industrial Technology Innovation, Mie 514-8507, Japan *Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Department of Clinical Anesthesiology, Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie 514-8507, Japan, Mie University Medical Zebrafish Research Center, Mie 514-8507, Japan, Department of Bioinformatics, Mie University Life Science Research Center, Mie 514-8507, Japan and Department of Omics Medicine, Mie University Industrial Technology Innovation, Mie 514-8507, Japan *Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Department of Clinical Anesthesiology, Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie 514-8507, Japan, Mie University Medical Zebrafish Research Center, Mie 514-8507, Japan, Department of Bioinformatics, Mie University Life Science Research Center, Mie 514-8507, Japan and Department of Omics Medicine, Mie University Industrial Technology Innovation, Mie 514-8507, Japan *Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Department of Clinical Anesthesiology, Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie 514-8507, Japan, Mie University Medical Zebrafish Research Center, Mie 514-8507, Japan, Department of Bioinformatics, Mie University Life Science Research Center, Mie 514-8507, Japan and Department of Omics Medicine, Mie University Industrial Technology Innovation, Mie 514-
authors.forename: Toshio
authors.initials: T
authors.lastname: Tanaka
mesh_terms: D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D066126:Cardiotoxicity; D015536:Down-Regulation; D006023:Glycoproteins / Q000235:genetics*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D009536:Niacinamide / Q000009:adverse effects / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000009:adverse effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077157:Sorafenib; D018754:Ventricular Dysfunction / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish
chemical_list: D000970:Antineoplastic Agents; D006023:Glycoproteins; D010671:Phenylurea Compounds; D017382:Reactive Oxygen Species; D009536:Niacinamide; C051795:teleocalcin; D000077157:Sorafenib
keywords: cardiotoxicity; reactive oxygen species; sorafenib; stanniocalcin 1; zebrafish