Notch1 increases Snail expression under high reactive oxygen species conditions in hepatocellular carcinoma cells

Notch1 and reactive oxygen species (ROS) modulate important pathways associated with tumor development and progression. Notably, Notch1 expression is upregulated in 41.8% of hepatocellular carcinoma (HCC) patients and ROS levels increases as HCC progresses from Grade I to Grade III. It has been established that Notch1 and ROS modulate Snail expression in malignant tumors; however, the mechanism regulating Snail protein expression is not yet known. In this study, we observed that Notch1 and ROS cooperatively increase the levels of Snail protein in Huh7 (hepatoma) cells. On its own, signaling through Notch1 increases transcription of Snail without changing protein levels. In contrast, the combined activation of the Notch1 and ROS-induced phosphoinositide 3-kinase/Akt (PI3K/Akt) signaling pathways resulted in the high expression of Snail protein. This increase in Snail expression was associated with increased Huh7 cells invasiveness. Furthermore, we observed that correlation between Snail and Notch1 expression was the strongest in advanced grade HCC tissue. In conclusion, Notch1 and ROS-induced PI3K/Akt signals cooperatively increase Snail expression and may induce malignancy in HCC.