title: Mitochondrial dysfunction induces EMT through the TGF-β/Smad/Snail signaling pathway in Hep3B hepatocellular carcinoma cells.
abstract: Mitochondrial dysfunction has been found to be associated with various pathological conditions, particularly cancer. However, the mechanisms underlying tumor malignancy induced by mitochondrial dysfunction are not fully understood. In the present study, the effects of mitochondrial dysfunction on epithelial-mesenchymal transition (EMT), were investigated using mitochondrial-depleted ρ(0) cells derived from the Hep3B hepatocarcinoma cell line. The Hep3B/ρ(0) cells displayed the EMT phenotype with more aggressive migration and higher invasiveness compared to their parental cells. The Hep3B/ρ(0) cells also showed typical expression pattern of EMT markers such as vimentin and E-cadherin. These phenotypes in Hep3B/ρ(0) cells were mediated by increased transforming growth factor-β (TGF-β) through the canonical Smad-dependent signaling pathway. Additionally, TGF-β signaling was activated via induction of c-Jun/AP-1 expression and activity. Therefore, mitochondrial dysfunction induces EMT through TGF-β/Smad/Snail signaling via c-Jun/AP-1 activation. These results indicate that mitochondrial dysfunction plays an important role in the EMT process and could be a novel therapeutic target for malignant cancer therapy.
authors.affiliation: Department of Molecular Biology, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Eui-Yeun
authors.initials: EY
authors.lastname: Yi
authors.affiliation: Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University School of Medicine, Incheon 406‑840, Republic of Korea.
authors.forename: Shi-Young
authors.initials: SY
authors.lastname: Park
authors.affiliation: Department of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea.
authors.forename: Seung-Youn
authors.initials: SY
authors.lastname: Jung
authors.affiliation: College of Pharmacy, Keimyung University, 1000 Sindang-Dong, Dalseo-Gu, Daegu 704-701, Republic of Korea.
authors.forename: Won-Jun
authors.initials: WJ
authors.lastname: Jang
authors.affiliation: Department of Molecular Biology, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Yung-Jin
authors.initials: YJ
authors.lastname: Kim
mesh_terms: D015820:Cadherins / Q000096:biosynthesis; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008928:Mitochondria / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction; D051785:Smad Proteins / Q000235:genetics; D000071250:Snail Family Transcription Factors; D018808:Transcription Factor AP-1 / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics*
chemical_list: D015820:Cadherins; D051785:Smad Proteins; D000071250:Snail Family Transcription Factors; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D048031:JNK Mitogen-Activated Protein Kinases