Kim H S, Jung G
Department of Biological Sciences, Seoul National University , Seoul , Republic of Korea.
Free Radic Res. 2014 Jul;48(7):806-13. doi: 10.3109/10715762.2014.909595. Epub 2014 Apr 30.
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.
Notch1和活性氧（ROS）调节与肿瘤发生和进展相关的重要信号通路。值得注意的是，41.8%的肝细胞癌（HCC）患者中Notch1表达上调，且随着HCC从I级进展到III级，ROS水平升高。已知Notch1和ROS调节恶性肿瘤中Snail的表达；然而，调节Snail蛋白表达的机制尚不清楚。在本研究中，我们观察到Notch1和ROS协同增加Huh7（肝癌）细胞中Snail蛋白的水平。单独而言，Notch1信号传导增加Snail的转录，但不改变蛋白水平。相反，Notch1和ROS诱导的磷酸肌醇3激酶/蛋白激酶B（PI3K/Akt）信号通路的联合激活导致Snail蛋白的高表达。Snail表达的这种增加与Huh7细胞侵袭性增加相关。此外，我们观察到在高级别HCC组织中，Snail和Notch1表达之间的相关性最强。总之，Notch1和ROS诱导的PI3K/Akt信号协同增加Snail表达，并可能诱导HCC发生恶变。
