title: Protein Inhibitor of Activated STAT3 Regulates Migration, Invasion, and Activation of Fibroblast-like Synoviocytes in Rheumatoid Arthritis.
abstract: The aggressive phenotype displayed by fibroblast-like synoviocytes (FLSs) is a critical factor of cartilage destruction in rheumatoid arthritis (RA). Increased FLSs migration and subsequent degradation of the extracellular matrix are essential to the pathology of RA. Protein inhibitor of activated STAT (PIAS), whose family members include PIAS1, PIAS2 (PIASx), PIAS3, and PIAS4 (PIASy), play important roles in regulating various cellular events, such as cell survival, migration, and signal transduction in many cell types. However, whether PIAS proteins have a role in the pathogenesis of RA is unclear. In this study, we evaluated the role of PIAS proteins in FLSs migration, invasion, and matrix metalloproteinases (MMPs) expression in RA. We observed increased expression of PIAS3, but not PIAS1, PIAS2, or PIAS4, in FLSs and synovial tissues from patients with RA. We found that PIAS3 knockdown by short hairpin RNA reduced migration, invasion, and MMP-3, MMP-9, and MMP-13 expression in FLSs. In addition, we demonstrated that PIAS3 regulated lamellipodium formation during cell migration. To gain insight into molecular mechanisms, we evaluated the effect of PIAS3 knockdown on Rac1/PAK1 and JNK activation. Our results indicated that PIAS3-mediated SUMOylation of Rac1 controlled its activation and modulated the Rac1 downstream activity of PAK1 and JNK. Furthermore, inhibition of Rac1, PAK1, or JNK decreased migration and invasion of RA FLSs. Thus, our observations suggest that PIAS3 suppression may be protective against joint destruction in RA by regulating synoviocyte migration, invasion, and activation.
authors.affiliation: Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Minxi
authors.identifier: http://orcid.org/0000-0002-5106-3402
authors.initials: M
authors.lastname: Lao
authors.affiliation: Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Maohua
authors.initials: M
authors.lastname: Shi
authors.affiliation: Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Yaoyao
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Mingcheng
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Yujin
authors.identifier: http://orcid.org/0000-0002-2522-7813
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Qiu
authors.affiliation: Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Youjun
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Zeng
authors.affiliation: Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Liuqin
authors.initials: L
authors.lastname: Liang
authors.affiliation: Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Xiuyan
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China xuhanshi@mail.sysu.edu.cn.
authors.forename: Hanshi
authors.initials: H
authors.lastname: Xu
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D002465:Cell Movement; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones / Q000378:metabolism*; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology*
chemical_list: D018832:Molecular Chaperones; C484745:PIAS3 protein, human; D050828:Protein Inhibitors of Activated STAT