Several mechanisms may underlie this phenomenon: First, mtDNA content alteration may be involved in this attenuation, as reducing mtDNA with EtBr treatment or TFAM knockdown can activate calcineurin-mediated mitochondrial retrograde signals, and up-regulates the IGF-Akt and TGF-β pathways, and promotes EMT [33]; Second, reprogrammed metabolism accompanying mitochondrial biogenesis may drive ZNF281-mediated EMT and metastasis in HCC. This evidence concerns the gene ZNF281 and hepatocellular carcinoma.