Loss of interactions between p53 and survivin gene in mesenchymal stem cells after spontaneous transformation in vitro
Loss of interactions between p53 and survivin gene in mesenchymal stem cells after spontaneous transformation in vitro
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体外自发转化后间充质干细胞中p53和survivin基因之间相互作用的丧失
DOI：
10.1016/j.biocel.2016.03.018
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发表时间：
2016
影响因子：
4
通讯作者：
Song Jian
中科院分区：
文献类型：
--
作者：
He Liu;Zhao Fangyu;Zheng Yong;Wan Yu;Song Jian
来自各种动物的间充质干细胞（MSC）在长期培养中经历自发转化。转化后的骨髓间充质干细胞具有高度的致瘤性，可能是肉瘤的肿瘤起始细胞。为了解释为什么转化的MSC成为致瘤性，本研究调查了大鼠MSC自发转化前后的特性。结果表明，转化后的MSCs虽然保持了典型的MSC表面标志，但具有肿瘤干细胞的特征，如失去了对间充质细胞系的接触抑制和多向分化潜能，获得了非贴壁生长的能力。在转化的MSC中，关键的衰老调节因子p16的表达几乎消失，而另一个因子p53的表达异常增加。ChIP检测结果表明，p53对survivin基因的负调控作用在转化细胞中消失，这是由于p53不能与survivin基因启动子结合所致。DNA测序显示转化MSC中的p53基因不是野生型，而是942 C> T突变体，突变位于编码p53蛋白DNA结合结构域的序列中。这些发现表明，转化的MSC表达高水平的p53突变体，该突变体失去结合生存素基因的能力，导致生存素的异常上调表达，这是细胞无限增殖的关键原因。
Mesenchymal stem cells (MSC) from various animals undergo a spontaneous transformation in long-term culture. The transformed MSCs are highly tumorigenic and are likely to be the tumor-initiating cells of sarcoma. To explain why the transformed MSCs become tumorigenic, the present study investigated the characteristics of rat MSCs before and after spontaneous transformation. It was shown that although the transformed MSCs maintained typical surface markers of MSC, they exhibited some cancer stem cell-like characteristics such as loss of contact inhibition and multi-potency to mesenchymal lineages, and acquirement of ability of anchorage-independent growth. The expression of a key senescence regulator p16 almost disappeared, but the other one, p53 abnormally increased in the transformed MSCs. ChIP assay demonstrated that a normal negative regulation of p53 on survivin gene disappeared in the transformed cells due to a lack of p53 binding to the promoter of survivin gene. DNA sequencing revealed that the p53 gene in transformed MSCs was not a wild-type, but a 942C > T mutant with the mutation located in the sequence coding p53 protein’s DNA-binding domain. These findings indicate that the transformed MSCs express high levels of a p53 mutant that loses the ability to bind survivin gene, leading to an abnormally upregulated expression of survivin, which is a key reason for the cell’s unlimited proliferation.