Mitochondrial dysfunction induces EMT through the TGF-beta/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 rho(0) cells derived from the Hep3B hepatocarcinoma cell line. The Hep3B/rho(0) cells displayed the EMT phenotype with more aggressive migration and higher invasiveness compared to their parental cells. The Hep3B/rho(0) cells also showed typical expression pattern of EMT markers such as vimentin and E-cadherin. These phenotypes in Hep3B/rho(0) cells were mediated by increased transforming growth factor-beta (TGF-beta) through the canonical Smad-dependent signaling pathway. Additionally, TGF-beta signaling was activated via induction of c-Jun/AP-1 expression and activity. Therefore, mitochondrial dysfunction induces EMT through TGF-beta/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.