Intracellular redox status controls spherogenicity, an in vitro cancer stem cell marker, in thyroid cancer cell lines
Intracellular redox status controls spherogenicity, an in vitro cancer stem cell marker, in thyroid cancer cell lines
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DOI：
10.1016/j.yexcr.2018.07.036
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发表时间：
2018-09
影响因子：
3.7
通讯作者：
M. Shimamura;Kazuo Yamamoto;T. Kurashige;Y. Nagayama
中科院分区：
文献类型：
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作者：
M. Shimamura;Kazuo Yamamoto;T. Kurashige;Y. Nagayama
肿瘤干细胞（Cancer stem cells, CSCs）是肿瘤组织的一小部分，在肿瘤的发生、复发和转移中起着至关重要的作用。我们最近发现醛脱氢酶（ALDH） 1A3在一些甲状腺癌细胞系中是一个CSC标记物，但其功能活性与甲状腺癌的发生无关。鉴于以往对其他器官恶性肿瘤的研究表明，细胞内活性氧（ROS）可能是一种功能性的、可靶向的CSC标志物，本研究旨在阐明ROS作为功能性CSC标志物在甲状腺癌细胞系中的意义。我们首先发现ROS水平控制球状性；即ROSlowcells比ROShighcells更呈球形。然而，与其他癌症中的典型CSCs不同，甲状腺癌细胞中的csc样ROSlowcells具有可塑性，不伴有去分化状态（即干细胞标记物/甲状腺特异性转录因子的表达）或化疗/放射抵抗。较低的ROS水平在功能上是关键的，因为l -丁硫氨酸-s、r -亚砜胺（一种谷胱甘肽（GSH）合成抑制剂）和辐射抑制了ROS水平的增加。ROS水平也与53BP1染色测定的双链DNA断裂数相关。较低的ROS水平似乎是线粒体氧化磷酸化减少和GSH含量升高的结果。鉴于csc靶向治疗通过耗尽癌组织的自我更新和生长潜力来实现长期根除疾病的重要性，ROS可能是csc靶向治疗甲状腺癌的一个很好的候选者。
Cancer stem cells (CSCs), a small fraction of a tumor mass, are proposed to be highly crucial for cancer initiation, recurrence and metastasis. We have recently found that aldehyde dehydrogenase (ALDH) 1A3 is a CSC marker in some thyroid cancer cell lines, whose functional activity is, however, not relevant for thyroid cancer stemness. Since previous studies on malignancies in other organs suggest that intracellular reactive oxygen species (ROS) might be a functional and targetable CSC marker, the present study was conducted to elucidate the significance of ROS as a functional CSC marker in thyroid cancer cell lines. We first found that ROS levels controlled spherogenicity; that is, ROSlowcells were more spherogenic than ROShighcells. However, unlike typical CSCs in other cancers, CSC-like ROSlowcells in thyroid cancer cells were plastic and were not accompanied by de-differentiation status (i.e., expression of stemness markers/thyroid-specific transcription factors) or chemo-/radio-resistance. The lower levels of ROS were functionally critical because a forced increase in ROS levels byL-buthionine-S,R-sulfoximine, an inhibitor of glutathione (GSH) synthesis, and irradiation suppressed spherogenicity. ROS levels were also correlated with the number of double strand DNA breaks determined by 53BP1 staining. Lower ROS levels appear to be a result of decreased mitochondrial oxidative phosphorylation and elevated GSH contents. Given the importance of CSC-targeted therapy for achieving long-term disease eradication by exhausting self-renewal and growth potential of cancer tissues, ROS may be a good candidate for CSC-targeted therapy in thyroid cancer.