Cytoglobin ameliorates the stemness of hepatocellular carcinoma via coupling oxidative‐nitrosative stress signals

• Published in: Molecular carcinogenesis Vol. 58; no. 3; pp. 334 - 343
• Main Authors: Zhang, Jun, Pei, YuanYuan, Yang, Wen, Yang, WenXiu, Chen, BoXin, Zhao, Xing, Long, Shiqi
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.03.2019
• Subjects: Activation; AKT protein; Antioxidants; Cell self-renewal; Chemoradiotherapy; cytoglobin; Hemoglobin; Hepatocellular carcinoma; Hepatocytes; Heterogeneity; Homeostasis; Liver; Liver cancer; liver cancer stem cells; oxidative‐nitrosative stress; Phenotypes; PI3 K/AKT signal; Reactive oxygen species; Stem cells; Tumor suppressor genes; Tumorigenesis; oxidative-nitrosative stress; PI3 K/AKT signal; cytoglobin; hepatocellular carcinoma; liver cancer stem cells
• ISSN: 0899-1987; 1098-2744
• DOI: 10.1002/mc.22931

Cancer stem cells (CSCs) account for tumor self‐renewal and heterogeneity. Oxidative‐nitrosative stress (ONS) is an independent etiologic factor throughout tumorigenesis. Emerging evidences indicated that the interaction of ONS with CSCs contributes to tumor progression and resistance to chemoradiotherapy. Cytoglobin (Cygb) is a member of human hexacoordinate hemoglobin family and acts as a dynamic mediator of redox homeostasis. We observed that Cygb is significantly deregulated in human hepatocellular carcinoma (HCC) tissue and its decrease aggravates the growth of liver cancer stem cells (LCSCs) and increases the subpopulation of CD133(+) LCSCs. Cygb restoration inhibits HCC proliferation and LCSC growth, and decreases the subpopulation of CD133 (+) LCSCs in vitro. We found that Cygb absence promotes LCSC phenotypes and PI3 K/AKT activation, whereas Cygb restoration inhibits LCSC phenotypes and PI3 K/AKT activation. Furthermore, exogenous antioxidants can eliminate the inhibitory effect of Cygb to LCSC growth and phenotypes, as well as PI3 K/AKT activation. Collectively, this study demonstrated that cytoglobin functions as a tumor suppressor and targets CSCs at an ONS‐dependent manner. Thus, Cygb restoration could be a novel and promising therapeutic strategy against HCC with aberrant ROS/RNS accumulation.