The contribution of mitochondrial retrograde signaling to hepatoma cell invasiveness

Abstract

Mitochondrial dysfunction is a hallmark of tumors. Recently, several reports have described that cancer cell with mitochondrial defects have higher invasion activity and metastatic properties. However, detailed mechanisms of how mitochondrial defects contribute to tumor invasiveness have yet to be elucidated. In this study, we identified major genes to control hepatoma cell invasiveness in response to mitochondrial respiratory defects. To address this, the cDNA microarray was performed using SNU hepatoma cells with and without mitochondrial defects. To further identify genes specifically up-regulated in response to respiratory defects, additional mitochondrial defects models were employed using mitochondrial respiratory inhibitors and mitochondrial DNA depletion. Among 10 genes commonly up-regulated in the three models, three transcription factors were further evaluated. SiRNA-mediated knockdown of these three factors in SNU354 cell significantly decreased its invasion activity. Interestingly, these factors were induced by retrograde signaling-mediated second messengers, especially Ca++ and ROS. Taken together, these results suggested that these three transcription factors have controlled hepatoma cell invasiveness in response to mitochondrial retrograde signaling.