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
The Hippo signaling pathway regulates organ size by regulating cell proliferation and apoptosis with terminal effectors including Yes-associated protein-1 (YAP-1). Dysregulation in Hippo pathway has been proposed as one of the therapeutic targets in hepatocarcinogenesis. The levels of reactive oxygen species (ROS) increase during the progression from early to advanced hepatocellular carcinoma (HCC).
To study the activation of YAP-1 by ROS-induced damage in HCC and the involved signaling pathway.
The expression of YAP-1 in HCC cells (Huh-7, HepG2, and SNU-761) was quantified using real-time polymerase chain reaction and immunoblotting. Human HCC cells were treated with H2O2, which is a major component of ROS in living organisms, and with either YAP-1 small interfering RNA (siRNA) or control siRNA. To investigate the role of YAP-1 in HCC cells under oxidative stress, MTS assays were performed. Immunoblotting was performed to evaluate the signaling pathway responsible for the activation of YAP-1. Eighty-eight surgically resected frozen HCC tissue samples and 88 nontumor liver tissue samples were used for gene expression analyses.
H2O2 treatment increased the mRNA and protein expression of YAP-1 in HCC cells (Huh-7, HepG2, and SNU-761). Suppression of YAP-1 using siRNA transfection resulted in a significant decrease in tumor proliferation during H2O2 treatment both in vitro and in vivo (both P < 0.05). 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 (UPR), 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 (P < 0.05) and were positively correlated with the ATF-6 Levels (Pearson’s coefficient = 0.299; P < 0.05).
This study shows a novel connection between YAP-1 and the UPR through the c-Myc pathway during oxidative stress in HCC. 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.
Core Tip: We found a novel connection between Yes-associated protein-1 (YAP-1) and the unfolded protein response (UPR) through the c-Myc pathway during oxidative stress in hepatocellular carcinoma (HCC). As the Hippo pathway and c-Myc pathway share many important functions, including the regulation of growth, death and survival in cells and the regulation of stress resistance and life spans in organisms, we speculate that the interaction between YAP-1 and c-Myc is a point of convergence that allows HCC proliferation. The reactive oxygen species-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.