Cytoglobin ameliorates the stemness of hepatocellular carcinoma via coupling oxidative‐nitrosative stress signals
Cytoglobin ameliorates the stemness of hepatocellular carcinoma via coupling oxidative‐nitrosative stress signals
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DOI：
10.1002/mc.22931
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发表时间：
2018-12
影响因子：
4.6
通讯作者：
Jun Zhang;Yuanyuan Pei;Wen Yang;Wenxiu Yang;Boxin Chen;Xing Zhao;Shiqi Long
中科院分区：
文献类型：
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作者：
Jun Zhang;Yuanyuan Pei;Wen Yang;Wenxiu Yang;Boxin Chen;Xing Zhao;Shiqi Long
癌症干细胞（CSC）解释了肿瘤的自我更新和异质性。氧化-亚硝化应激（ONS）是肿瘤发生过程中的一个独立致病因素。新的证据表明，ONS与CSC的相互作用有助于肿瘤的进展和对放化疗的抵抗。细胞珠蛋白（Cygb）是人类六配位血红蛋白家族的成员，是氧化还原稳态的动态介质。我们观察到Cygb在人肝细胞癌（HCC）组织中显著失调，其减少促进了肝癌干细胞（LCSCs）的生长，并增加了CD 133（+）LCSCs的亚群。Cygb修复抑制HCC增殖和LCSC生长，并减少体外CD 133（+）LCSC亚群。我们发现Cygb缺失促进LCSC表型和PI 3 K/AKT活化，而Cygb恢复抑制LCSC表型和PI 3 K/AKT活化。外源性抗氧化剂可以消除Cygb对LCSC生长和表型的抑制作用，以及对PI 3 K/AKT激活的抑制作用。总的来说，这项研究表明，细胞珠蛋白作为肿瘤抑制因子发挥作用，并以ONS依赖性方式靶向CSC。因此，Cygb恢复可能是一种新的和有前途的治疗策略，对肝癌异常ROS/RNS积累。
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.