Peroxiredoxin II Is Essential for Maintaining Stemness by Redox Regulation in Liver Cancer Cells

Abstract

Redox regulation in cancer stem cells (CSCs) is viewed as a good target for cancer therapy because redox status plays an important role in cancer stem-cell maintenance. Here, we investigated the role of Peroxiredoxin II (Prx II), an antioxidant enzyme, in association with maintenance of liver CSCs. Our study demonstrates that Prx II overexpressed in liver cancer cells has high potential for self-renewal activity. Prx II expression significantly corelated with expression of epithelial-cell adhesion molecules (EpCAM) and cytokerain 19 in liver cancer tissues of hepatocellular carcinoma (HCC) patients. Downregulation of Prx II in Huh7 cells with treatment of siRNA reduced expression of EpCAM and CD133 as well as Sox2 in accordance with increased ROS and apoptosis, which were reversed in Huh7-hPrx II cells. Huh7-hPrx II cells exhibited strong sphere-formation activity compared with mock cells. Vascular endothelial growth factor (VEGF) exposure enhanced sphere formation, cell-surface expression of EpCAM and CD133, and pSTAT3 along with activation of VEGF receptor 2 in Huh7-hPrx II cells. The result also emerged in Huh7-H-ras G12V and SK-HEP-1-H-ras G12V cells with high-level expression of Prx II. Prx II was involved in regulation of VEGF driving cancer stem cells through VEGFR-2/STAT3 signaling to upregulate Bmi1 and Sox2. In addition, knockdown of Prx II in Huh7-H-ras G12V cells showed significant reduction in cell migration in vitro and in tumorigenic potential in vivo. Taken together, all the results demonstrated that Prx II plays a key role in the CSC self-renewal of HCC cells through redox regulation. STEM CELLS 2016;34:1188-1197 SIGNIFICANCE STATEMENTThis study demonstrates that Peroxiredoxin II (Prx II), an antioxidant enzyme, overexpressed in liver cancer cells has high potential for self-renewal activity. Prx II expression significantly correlated with expression of epithelial-cell adhesion molecules and cytokine 19 in liver cancer tissues of hepatocellular carcinoma patients, induced expression of stem cell markers, and exhibited strong sphere-formation activity in liver cancer cells. In addition, Prx II was involved in regulation of vascular endothelial growth factor (VEGF) driving cancer stem cells through VEGFR-2/STAT3 signaling to upregulate Bmi1 and Sox2. Thus, our finding suggests that Prx II may be essential for maintenance of stemness by redox regulation in liver cancer.

Peroxiredoxin 2 is essential for maintaining cancer stem cell-like phenotype through activation of Hedgehog signaling pathway in colon cancer

“…Prdxs function as a protector of ESC stemness by opposing ROS during neurogenesis and Prdxs depletion leads to differentiation into neurons [47]. Prdx2 depletion attenuated stemness of CSCs in hepatocellular carcinoma [48]. Prdx3 depletion resulted in a smaller percentage of CD133 + cells, a significant reduction in sphere formation, and enhanced sensitivity to 5-FU [46].…”

Calotropis gigantea extract induces apoptosis through extrinsic/intrinsic pathways and upregulation of reactive oxygen species in non-small-cell lung cancer cells

“…4D) were performed by flow cytometry. Cells in the sub-G1 phase showed fragmented DNA, which is a marker of apoptosis [23, 24]. In our study, the cell cycle analysis showed that cells in the sub-G1 phase and S phase increased in a dose-dependent manner with CG treatment for A549 cells (Fig.…”

“…To determine how apoptosis occurs in p53-independent death of NCI-H1299 cells, we examined the generation of ROS, which is a main cause of apoptosis [23, 30]. There are many studies on ROS related to apoptosis.…”

Peroxiredoxin 2 is associated with colorectal cancer progression and poor survival of patients

“…Shiota et al [32] demonstrated that PRDX2 increased the growth and castration resistance of prostate cancer by regulating the androgen/androgen receptor signaling pathway. Kwon et al [33] reported that PRDX2 maintains cancer stem cells selfrenewal through VEGF signaling and protects oxidative inactivation of VEGFR2 in hepatocellular carcinoma cells. Stresing et al [19] concluded that inhibiting PRDX2 expression decreased the growth of breast cancer metastatic cells in lungs by specifically regulating the oxidative and metabolic stress response.…”