title: Sorafenib exerts an anti-keloid activity by antagonizing TGF-β/Smad and MAPK/ERK signaling pathways.
abstract: Keloid disease is characterized by hyperproliferation of responsive fibroblasts with vigorously continuous synthesis of extracellular matrix (ECM) components. Although the process by which keloids develop is poorly understood, most theories of the etiology are referred to fibroblast dysfunction. A central event in dermal repair is the release of growth factors in response to skin injury, which leads to the dysregulation of several crucial pathways that initiate the activation of keloid fibroblasts (KFs) and promote ECM accumulation. Hence, strategies aimed at reducing the production of these cytokines and/or disrupting their intracellular signal transduction have potential clinical significance for curing keloid. As the first oral multikinase inhibitor, sorafenib blocks a number of intracellular signaling pathways which are also pivotal for keloid pathogenesis. Therefore, evaluation of the effects of sorafenib on keloid disease seems timely and pertinent. In this study, we reported the identification of sorafenib that antagonized TGF-β/Smad and MAPK/ERK signaling pathways in primary KFs. Impressively, treatment with sorafenib inhibited KF cell proliferation, migration, and invasion, and simultaneously reduced collagen production in KFs. Furthermore, we present ex vivo evidence that sorafenib induced the arrest of KF migration, the inhibition of angiogenesis, and the reduction of collagen accumulation. These preclinical observations suggest that sorafenib deserves systematic exploration as a candidate agent for the future treatment of keloids.
  
  
  
  The intracellular TGF-β/Smad and MAPK/ERK signaling pathways is blocked by sorafenib. Sorafenib inhibits the proliferation, migration, invasion, and ECM deposition in keloid fibroblasts. Sorafenib reduces KF migration and concomitantly angiogenesis in keloid explants. Sorafenib is a promising agent for the treatment of keloids and hypertrophic scars.
authors.affiliation: Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Tissue Engineering, 639 Zhi Zao Ju Road, Shanghai, 200011, People's Republic of China.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Tissue Engineering, 639 Zhi Zao Ju Road, Shanghai, 200011, People's Republic of China.
authors.forename: Miao
authors.initials: M
authors.lastname: Qu
authors.affiliation: Stem Cell Bank/Stem Cell Core Facility, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, People's Republic of China.
authors.forename: Lan
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Tissue Engineering, 639 Zhi Zao Ju Road, Shanghai, 200011, People's Republic of China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Tissue Engineering, 639 Zhi Zao Ju Road, Shanghai, 200011, People's Republic of China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Stem Cell Bank/Stem Cell Core Facility, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, People's Republic of China.
authors.forename: Tingyu
authors.initials: T
authors.lastname: Gu
authors.affiliation: Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Tissue Engineering, 639 Zhi Zao Ju Road, Shanghai, 200011, People's Republic of China.|National Tissue Engineering Center of China, Shanghai, People's Republic of China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Stem Cell Bank/Stem Cell Core Facility, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, People's Republic of China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Ding
authors.affiliation: Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Tissue Engineering, 639 Zhi Zao Ju Road, Shanghai, 200011, People's Republic of China. liuwei_2000@yahoo.com.|National Tissue Engineering Center of China, Shanghai, People's Republic of China. liuwei_2000@yahoo.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Stem Cell Bank/Stem Cell Core Facility, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, People's Republic of China. chenyl@sibcb.ac.cn.
authors.forename: Yue-Lei
authors.initials: YL
authors.lastname: Chen
mesh_terms: D000328:Adult; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007627:Keloid / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D012844:Sincalide / Q000378:metabolism; D051785:Smad Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077157:Sorafenib; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055815:Young Adult
chemical_list: D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D009536:Niacinamide; D000077157:Sorafenib; D020928:Mitogen-Activated Protein Kinases; D012844:Sincalide
keywords: Keloid fibroblast; Keloids; MAPK/ERK signaling; Sorafenib; TGF-β/Smad signaling