TNF-a stimulation enhances ROS-dependent cell migration via NF-?B activation in liver cells.

Development of hepatocellular carcinoma (HCC) is accompanied by a continuous increase in generation of reactive oxygen species (ROS). TNF-a was used in murine hepatocytes as stimulus to identify the primary source of ROS generation. Using specific inhibitors targeting the different complexes of the respiratory chain we detected the mitochondria as main producer of ROS. TNF-a altered mitochondrial integrity by mimicking a mild uncoupling effect in liver cells. siRNA mediated downregulation of essential assembly factors for complex I and complex III led to an inhibition of ROS production. Therefore, ROS is generated by the mitochondrial respiratory chain upon TNF-a stimulation. ROS activated NF-?B and subsequently enhanced migration of liver cells. Thus, we identified complex I and complex III of the respiratory chain as point of ROS release after TNF-a treatment in hepatocytes which enhances cell migration by activating NF-?B signaling.