Epigenetic regulation of CpG promoter methylation in invasive prostate cancer cells.
Epigenetic regulation of CpG promoter methylation in invasive prostate cancer cells.
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DOI：
10.1186/1476-4598-9-267
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发表时间：
2010-10-07
期刊：
影响因子：
37.3
通讯作者：
Farrar WL
中科院分区：
文献类型：
--
作者：
Mathews LA;Hurt EM;Zhang X;Farrar WL
最近，人们的注意力集中在更好地了解肿瘤内不同的细胞群及其对癌症进展的贡献上。一种最常用的方法来分离更具侵略性的细胞亚群利用细胞分选基于某些细胞粘附分子的表达。我们最近开发的一种方法是隔离这些更具侵袭性的细胞，因为它们具有增强侵袭能力的特性。这些更具侵袭性的细胞以前被描述为肿瘤起始细胞（tic），它们具有干细胞样的基因组特征，表达包括Oct3/4和Nanog在内的许多干细胞基因，与“非侵入性”细胞相比，它们更具致瘤性。它们也有一个让人想起细胞经历上皮到间质转化或EMT的经典模式的轮廓。利用这种入侵模型，我们试图研究在这种罕见的细胞群体中哪些基因受表观遗传控制。表观遗传修饰，特别是DNA甲基化，是调节人类正常发育过程的关键事件。为了确定这些侵袭性前列腺细胞中的特定甲基化模式，以及是否有任何发育基因受到差异调节，我们分析了CpG启动子甲基化的差异。测定差异甲基化基因，并选择部分基因进行进一步分析。发现非受体酪氨酸激酶BMX和转录因子SOX1在侵袭中起重要作用。独创性通路分析显示，甲基化基因列表中经常显示来自IL-6/STAT3通路的基因。靶BMX和SOX1水平降低的细胞也表现出STAT3活性的丧失。最后，使用Oncomine，研究人员确定，人类中更具侵袭性的转移性前列腺癌也具有更高水平的Stat3和Sox1。使用这种方法，我们可以开始了解哪些基因在侵袭性人群中受到表观遗传调控，而不是在大块肿瘤细胞中。这些具有侵略性的细胞亚群可能与癌症干细胞假说有关，使它们的表观遗传调控模式对生物标志物分析非常有吸引力。
Recently, much attention has been focused on gaining a better understanding of the different populations of cells within a tumor and their contribution to cancer progression. One of the most commonly used methods to isolate a more aggressive sub-population of cells utilizes cell sorting based on expression of certain cell adhesion molecules. A recently established method we developed is to isolate these more aggressive cells based on their properties of increased invasive ability. These more invasive cells have been previously characterized as tumor initiating cells (TICs) that have a stem-like genomic signature and express a number of stem cell genes including Oct3/4 and Nanog and are more tumorigenic compared to their 'non-invasive' counterpart. They also have a profile reminiscent of cells undergoing a classic pattern of epithelial to mesenchymal transition or EMT. Using this model of invasion, we sought to investigate which genes are under epigenetic control in this rare population of cells. Epigenetic modifications, specifically DNA methylation, are key events regulating the process of normal human development. To determine the specific methylation pattern in these invasive prostate cells, and if any developmental genes were being differentially regulated, we analyzed differences in global CpG promoter methylation. Differentially methylated genes were determined and select genes were chosen for additional analyses. The non-receptor tyrosine kinase BMX and transcription factor SOX1 were found to play a significant role in invasion. Ingenuity pathway analysis revealed the methylated gene list frequently displayed genes from the IL-6/STAT3 pathway. Cells which have decreased levels of the targets BMX and SOX1 also display loss of STAT3 activity. Finally, using Oncomine, it was determined that more aggressive metastatic prostate cancers in humans also have higher levels of both Stat3 and Sox1. Using this method we can begin to understand which genes are epigenetically regulated in the invasive population compared to the bulk tumor cells. These aggressive sub-populations of cells may be linked to the cancer stem cell hypothesis, making their patterns of epigenetic regulation very attractive for biomarker analysis.
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CD44+ CD24（ - ）前列腺细胞是早期的癌症祖/干细胞，为预后不良的患者提供了模型。
影响因子：
8.8
作者：
Hurt, E. M.;Kawasaki, B. T.;Klarmann, G. J.;Thomas, S. B.;Farrar, W. L.
通讯作者：
Farrar, W. L.
影响因子：
2.8
作者：
Garraway, Isla P.;Sun, Wenyi;Tran, Chau P.;Perner, Sven;Zhang, Bao;Goldstein, Andrew S.;Hahm, Scott A.;Haider, Maahum;Head, Christian S.;Reiter, Robert E.;Rubin, Mark A.;Witte, Owen N.
通讯作者：
Witte, Owen N.
影响因子：
15.9
作者：
He, Yun;Luo, Yan;Min, Wang
通讯作者：
Min, Wang
影响因子：
4.8
作者：
Abassi, YA;Rehn, M;Vuori, K
通讯作者：
Vuori, K
影响因子：
9.8
作者：
Busby, J. E.;Shih, S.-J.;Evans, C. P.
通讯作者：
Evans, C. P.