Mitochondrial dysfunction induces EMT through the TGF-β/Smad/Snail signaling pathway in Hep3B hepatocellular carcinoma cells

Yi,Eui-Yeun; Park,Shi-Young; Jung,Seung-Youn; Jang,Won-Jun; Kim,Yung-Jin

doi:10.3892/ijo.2015.3154

Mitochondrial dysfunction induces EMT through the TGF-β/Smad/Snail signaling pathway in Hep3B hepatocellular carcinoma cells

Authors:
- Eui-Yeun Yi
- Shi-Young Park
- Seung-Youn Jung
- Won-Jun Jang
- Yung-Jin Kim
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Affiliations: Department of Molecular Biology, Pusan National University, Busan 609-735, Republic of Korea, Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University School of Medicine, Incheon 406‑840, Republic of Korea, Department of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea, College of Pharmacy, Keimyung University, 1000 Sindang-Dong, Dalseo-Gu, Daegu 704-701, Republic of Korea
Published online on: September 10, 2015 https://doi.org/10.3892/ijo.2015.3154
Pages: 1845-1853

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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 ρ0 cells derived from the Hep3B hepatocarcinoma cell line. The Hep3B/ρ0 cells displayed the EMT phenotype with more aggressive migration and higher invasiveness compared to their parental cells. The Hep3B/ρ0 cells also showed typical expression pattern of EMT markers such as vimentin and E-cadherin. These phenotypes in Hep3B/ρ0 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.

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