title: Mitochondrial Respiratory Dysfunction Induces Claudin-1 Expression via Reactive Oxygen Species-mediated Heat Shock Factor 1 Activation, Leading to Hepatoma Cell Invasiveness.
abstract: Although mitochondrial dysfunction has been implicated in tumor metastasis, it is unclear how it regulates tumor cell aggressiveness. We have reported previously that human hepatoma cells harboring mitochondrial defects have high tumor cell invasion activity via increased claudin-1 (Cln-1) expression. In this study, we demonstrated that mitochondrial respiratory defects induced Cln-1 transcription via reactive oxygen species (ROS)-mediated heat shock factor 1 (HSF1) activation, which contributed to hepatoma invasiveness. We first confirmed the inverse relationship between mitochondrial defects and Cln-1 induction in SNU hepatoma cells and hepatocellular carcinoma tissues. We then examined five different respiratory complex inhibitors, and complex I inhibition by rotenone most effectively induced Cln-1 at the transcriptional level. Rotenone increased both mitochondrial and cytosolic ROS. In addition, rotenone-induced Cln-1 expression was attenuated by N-acetylcysteine, an antioxidant, and exogenous H2O2 treatment was enough to increase Cln-1 transcription, implying the involvement of ROS. Next we found that ROS-mediated HSF1 activation via hyperphosphorylation was the key event for Cln-1 transcription. Moreover, the Cln-1 promoter region (from -529 to +53) possesses several HSF1 binding elements, and this region showed increased promoter activity and HSF1 binding affinity in response to rotenone treatment. Finally, we demonstrated that the invasion activity of SNU449 cells, which harbor mitochondrial defects, was blocked by siRNA-mediated HSF1 knockdown. Taken together, these results indicate that mitochondrial respiratory defects enhance Cln-1-mediated hepatoma cell invasiveness via mitochondrial ROS-mediated HSF1 activation, presenting a potential role for HSF1 as a novel mitochondrial retrograde signal-responsive transcription factor to control hepatoma cell invasiveness.
authors.affiliation: From the Departments of Biochemistry and the Department of Biomedical Science, Graduate School, Ajou University, Suwon 443-380, Korea.
authors.forename: Jong-Hyuk
authors.initials: JH
authors.lastname: Lee
authors.affiliation: From the Departments of Biochemistry and the Department of Biomedical Science, Graduate School, Ajou University, Suwon 443-380, Korea.
authors.forename: Young-Kyoung
authors.initials: YK
authors.lastname: Lee
authors.affiliation: From the Departments of Biochemistry and the Department of Biomedical Science, Graduate School, Ajou University, Suwon 443-380, Korea.
authors.forename: Jin J
authors.initials: JJ
authors.lastname: Lim
authors.affiliation: From the Departments of Biochemistry and the Department of Biomedical Science, Graduate School, Ajou University, Suwon 443-380, Korea.
authors.forename: Hae-Ok
authors.initials: HO
authors.lastname: Byun
authors.affiliation: From the Departments of Biochemistry and the Department of Biomedical Science, Graduate School, Ajou University, Suwon 443-380, Korea.
authors.forename: Imkyong
authors.initials: I
authors.lastname: Park
authors.affiliation: From the Departments of Biochemistry and the Department of Biomedical Science, Graduate School, Ajou University, Suwon 443-380, Korea.
authors.forename: Gyeong-Hyeon
authors.initials: GH
authors.lastname: Kim
authors.affiliation: Surgery, Ajou University School of Medicine, Suwon, 443-380, Korea and.
authors.forename: Wei Guang
authors.initials: WG
authors.lastname: Xu
authors.affiliation: Surgery, Ajou University School of Medicine, Suwon, 443-380, Korea and.
authors.forename: Hee-Jung
authors.initials: HJ
authors.lastname: Wang
authors.affiliation: From the Departments of Biochemistry and the Department of Biomedical Science, Graduate School, Ajou University, Suwon 443-380, Korea ypeace@ajou.ac.kr.
authors.forename: Gyesoon
authors.initials: G
authors.lastname: Yoon
mesh_terms: D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D019069:Cell Respiration; D062445:Claudin-1 / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D000076249:Heat Shock Transcription Factors; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D062445:Claudin-1; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D017382:Reactive Oxygen Species; D014157:Transcription Factors
keywords: cell invasion; heat shock factor protein 1 (HSF1); hepatocellular carcinoma; mitochondrial respiratory chain complex; reactive oxygen species (ROS)