Published online Nov 14, 2020. doi: 10.3748/wjg.v26.i42.6599
Peer-review started: June 26, 2020
First decision: August 22, 2020
Revised: August 27, 2020
Accepted: September 23, 2020
Article in press: September 23, 2020
Published online: November 14, 2020
Reactive oxygen species (ROS) contribute to tumor progression by promoting DNA damage and altering cell signaling pathways. It has been recently suggested that ROS are involved in tumor metastasis, which is a complex process that includes epithelial-to-mesenchymal transition, migration, invasion, and angiogenesis within the tumor microenvironment.
Oxidative stress is the most important causative factor of hepatocellular carcinoma (HCC). The major etiologies of HCC, including chronic hepatitis B or C, alcohol-related liver disease, and nonalcoholic fatty liver disease, increase ROS levels. Thus, the activation of yes-associated protein-1 (YAP-1) by ROS-induced damage has been hypothesized to exacerbate the progression of HCC.
We investigated the activation of YAP-1 by ROS-induced damage in HCC and the involved signaling pathway.
The expression of YAP-1 was quantified using real-time PCR and immunoblotting. Human HCC cells were treated with H2O2, and with either YAP-1 small interfering RNA (siRNA) or control siRNA. MTS assays were performed to evaluate HCC cell proliferation. To investigate the signaling pathway, immunoblotting was performed. Eighty-eight surgically resected frozen HCC tissues and 88 nontumor paired liver tissues were used for gene expression analyses.
H2O2 treatment increased the mRNA and protein expression of YAP-1 in HCC cells. Suppression of YAP-1 resulted in a significant decrease in tumor proliferation during H2O2 treatment both in vitro and in vivo. The oncogenic action of YAP-1 occurred via the activation of the c-Myc pathway, leading to the upregulation of components of the unfolded protein response, including 78-kDa glucose-regulated protein and activating transcription factor-6 (ATF-6). The YAP-1 mRNA levels in human HCC tissues were upregulated by 2.6-fold compared with those in nontumor tissues and were positively correlated with the ATF-6 Levels.
This study shows a novel connection between YAP-1 and the unfolded protein response (UPR) through the c-Myc pathway during oxidative stress in HCC. We speculate that the interaction between YAP-1 and c-Myc is a point of convergence that allows HCC proliferation.
The ROS-induced activation of YAP-1 via the c-Myc pathway, which leads to the activation of the UPR pathway, might be a therapeutic target in HCC.