Arsenic-induced sub-lethal stress reprograms human bronchial epithelial cells to CD61¯ cancer stem cells.
Arsenic-induced sub-lethal stress reprograms human bronchial epithelial cells to CD61¯ cancer stem cells.
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DOI：
10.18632/oncotarget.1789
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发表时间：
2014-03-15
期刊：
影响因子：
--
通讯作者：
Chen F
中科院分区：
文献类型：
--
作者：
Chang Q;Chen B;Thakur C;Lu Y;Chen F
在本报告中，我们证明了连续暴露于0.25μM砷(As3+)6个月所产生的亚致死应激可以触发人支气管上皮细胞(BEAS-2B)的重编程，从而形成癌症干细胞(CSCs)，而不需要强制引入干性转录因子。这些CSCs是由As3+诱导的亚致死胁迫形成的，其特征是内源性干基基因表达增加，包括Oct4、Sox2、Klf4、Myc等与CSCs的多能性和自我更新相关的基因。流式细胞仪分析表明，90%的CSC细胞为CD61，而亲代细胞为CD61+。在NOD/SCID Il2rγ−/−小鼠的异种移植试验中，这些CD61‘CSCs具有高度的致瘤性和肺转移能力。进一步的测试还显示，CD61的CSCs对DNA修复和氧化磷酸化至关重要的基因的表达显著减少。为了确定上述发现的临床相关性，我们根据CD61蛋白水平对人类肺癌进行了分层，发现CD61蛋白低的肺癌与患者较差的生存相关。在人类乳腺癌和卵巢癌中也观察到了这种相关性。综上所述，我们的研究结果表明，除了传统的强制导入外源干细胞回路转录因子的方法外，连续低剂量的As3+诱导的亚致死应激也能够将非干细胞转化为CSCs。
In the present report, we demonstrate that sub-lethal stress induced by consecutive exposure to 0.25 μM arsenic (As3+) for six months can trigger reprogramming of the human bronchial epithelial cell (BEAS-2B) to form cancer stem cells (CSCs) without forced introduction of the stemness transcription factors. These CSCs formed from As3+-induced sub-lethal stress featured with an increased expression of the endogenous stemness genes, including Oct4, Sox2, Klf4, Myc, and others that are associated with the pluripotency and self-renewal of the CSCs. Flow cytometry analysis indicated that 90% of the CSC cells are CD61¯, whereas 100% of the parental cells are CD61+. These CD61¯ CSCs are highly tumorigenic and metastatic to the lung in xenotransplantation tests in NOD/SCID Il2rγ−/− mice. Additional tests also revealed that the CD61¯ CSCs showed a significant decrease in the expression of the genes important for DNA repair and oxidative phosphorylation. To determine the clinical relevance of the above findings, we stratified human lung cancers based on the level of CD61 protein and found that CD61low cancer correlates with poorer survival of the patients. Such a correlation was also observed in human breast cancer and ovarian cancer. Taken together, our findings suggest that in addition to the traditional approaches of enforced introduction of the exogenous stemness circuit transcription factors, sub-lethal stress induced by consecutive low dose As3+ is also able to convert non-stem cells to the CSCs.
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影响因子：
50.3
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通讯作者：
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