Epigenetically reprogramming metastatic tumor cells with an embryonic microenvironment.
Epigenetically reprogramming metastatic tumor cells with an embryonic microenvironment.
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DOI：
10.2217/epi.09.25
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发表时间：
2009-12
期刊：
影响因子：
3.8
通讯作者：
Hendrix MJ
中科院分区：
文献类型：
--
作者：
Costa FF;Seftor EA;Bischof JM;Kirschmann DA;Strizzi L;Arndt K;Bonaldo Mde F;Soares MB;Hendrix MJ
我们之前已经证明，人类胚胎干细胞(HESCs)的微环境能够改变侵袭性癌细胞，并将其重新编程为不那么侵袭性的状态。在暴露后观察到的表型变化中的一些机制主要与Nodal信号通路有关，该通路在肿瘤细胞的可塑性中起关键作用。然而，其他几种分子机制可能与这些变化直接和/或间接相关，包括microRNA(MiRNA)调控和DNA甲基化。进一步探索转移性黑色素瘤细胞暴露于hESC微环境后可能发生表型变化的表观遗传学机制。使用TaqMan®低密度阵列筛选了365个miRNAs。我们还评估了DNA甲基化是否可能是调节Nodal抑制物Lefty在hESCs(高表达)与黑色素瘤细胞(不表达)中表达的因素之一。使用这些实验方法，我们鉴定了暴露于hESC微环境中的黑色素瘤细胞中上调和下调的miRNAs，分别为miR-302a和miR-27b。我们还证明了Notch4是Nodal上游的miR-302a的靶标之一。此外，可能解释癌细胞中没有Nodal抑制剂Lefty的机制之一是DNA甲基化沉默，这为研究Nodal在黑色素瘤中的非调控表达提供了新的见解。这些发现表明，表观遗传变化，如DNA甲基化和microRNAs的调节，可能在肿瘤细胞的可塑性和转移表型中发挥重要作用。
We have previously shown that the microenvironment of human embryonic stem cells (hESCs) is able to change and reprogram aggressive cancer cells to a less aggressive state. Some mechanisms implicated in the phenotypic changes observed after this exposure are mainly associated with the Nodal signaling pathway, which plays a key role in tumor cell plasticity. However, several other molecular mechanisms might be related directly and/or indirectly to these changes, including microRNA (miRNA) regulation and DNA methylation. To further explore the epigenetic mechanisms potentially underlying the phenotypic changes that occur after exposing metastatic melanoma cells to a hESC microenvironment. A total of 365 miRNAs were screened using the TaqMan® Low Density Arrays. We also evaluated whether DNA methylation could be one of the factors regulating the expression of the inhibitor of Nodal, Lefty, in hESCs (where it is highly expressed) vs melanoma cells (where it is not expressed). Using these experimental approaches, we identified miRNAs that are up- and down-regulated in melanoma cells exposed to a hESC microenvironment, such as miR-302a and miR-27b, respectively. We also demonstrate that Notch4 is one of the targets of miR-302a, which is upstream of Nodal. Additionally, one of the mechanisms that might explain the absence of the inhibitor of Nodal, Lefty, in cancer cells is silencing by DNA methylation, which provides new insights into the unregulated expression of Nodal in melanoma. These findings suggest that epigenetic changes such as DNA methylation and regulation by microRNAs might play a significant role in tumor cell plasticity and the metastatic phenotype.
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影响因子：
10.5
作者：
Krebs, LT;Iwai, N;Gridley, T
通讯作者：
Gridley, T
DOI：
10.1007/978-0-387-77574-6_8
发表时间：
2008-01-01
期刊：
SUNLIGHT, VITAMIN D AND SKIN CANCER
影响因子：
--
作者：
Leiter, Ulrike;Garbe, Claus
通讯作者：
Garbe, Claus
影响因子：
4.5
作者：
Lin, Shi-Lung;Chang, Donald C.;Ying, Shao-Yao
通讯作者：
Ying, Shao-Yao
影响因子：
20.1
作者：
Kuehbacher, Angelika;Urbich, Carmen;Dimmeler, Stefanie
通讯作者：
Dimmeler, Stefanie
影响因子：
4
作者：
Postovit, Lynne-Marie;Costa, Fabricio F.;Hendrix, Mary J. C.
通讯作者：
Hendrix, Mary J. C.