title: A role for benzo[a]pyrene and Slug in invasive properties of fibroblast-like synoviocytes in rheumatoid arthritis: a potential molecular link between smoking and radiographic progression.
abstract: OBJECTIVE
  To investigate the effects of benzo[a]pyrene (B[a]P), a major toxic component of cigarette smoke, on the expression of Slug and to determine the effect of B[a]P/Slug on the invasive properties of rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS).
  
  
  METHODS
  The expression of Slug was measured by real-time PCR following the stimulation of FLS with different concentrations of B[a]P or EGF. The phosphorylation of the key enzymes in the signaling pathway was analyzed by western blots. Inhibitors of PI3K/Akt/mTOR pathway were used to confirm the critical pathway for Slug expression. An in vitro cell invasion assay was performed using RA FLS treated with Slug cDNA, Slug small interference RNA, or control.
  
  
  RESULTS
  Slug expression increased significantly following treatment with B[a]P or EGF in a dose-dependent manner. The stimulation of FLS with B[a]P or EGF induced the phosphorylation of Akt kinase, but not in ERK, JNK and p38. The Slug mRNA expression induced by B[a]P and EGF decreased significantly following the treatment with PI3K/Akt/mTOR inhibitors. Slug overexpression using Slug cDNA upregulated the invasive function of FLS, and Slug depletion using siRNA showed the opposite effect compared with the control. In addition, the stimulation with B[a]P increased the invasive function of the control siRNA-treated FLS but not in the Slug siRNA-treated FLS.
  
  
  CONCLUSIONS
  Our data showed that B[a]P regulates the invasive properties of RA FLS through Slug expression. This mechanism may provide a novel molecular link underlying the association between smoking and increased radiographic progression in RA.
authors.affiliation: Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro, Gangnam-Gu, Seoul, 135-710, Republic of Korea. Electronic address: jaejoonlee@samsung.com.
authors.forename: Jaejoon
authors.initials: J
authors.lastname: Lee
authors.forename: Hyemin
authors.initials: H
authors.lastname: Jeong
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Park
authors.forename: Ji Won
authors.initials: JW
authors.lastname: Hwang
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Bae
authors.forename: Joong Kyong
authors.initials: JK
authors.lastname: Ahn
authors.forename: Kwang-Sung
authors.initials: KS
authors.lastname: Ahn
authors.forename: Eun-Mi
authors.initials: EM
authors.lastname: Koh
authors.forename: Hoon-Suk
authors.initials: HS
authors.lastname: Cha
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D001564:Benzo(a)pyrene / Q000009:adverse effects*; D002478:Cells, Cultured; D006801:Humans; D009676:Noxae / Q000009:adverse effects; D015398:Signal Transduction; D012907:Smoking / Q000009:adverse effects; D000071250:Snail Family Transcription Factors; D013583:Synovial Membrane / Q000473:pathology*; D014157:Transcription Factors / Q000096:biosynthesis*
chemical_list: D009676:Noxae; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D001564:Benzo(a)pyrene
keywords: Joint erosions; Rheumatoid Arthritis; Risk factors; Synoviocytes; Tobacco