Novel approach for detecting global epigenetic alterations associated with tumor cell aneuploidy
Novel approach for detecting global epigenetic alterations associated with tumor cell aneuploidy
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DOI：
10.1002/ijc.22847
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发表时间：
2007-10-01
影响因子：
6.4
通讯作者：
Nakamura, Shin-Ichi
中科院分区：
文献类型：
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作者：
Habano, Wataru;Sugai, Tamotsu;Nakamura, Shin-Ichi
虽然在人类癌症中普遍观察到非整倍体，但非整倍体的分子机制尚不清楚。我们使用在同一癌组织中具有二倍体和非整倍体癌细胞的多倍体癌症模型，并试图检测与肿瘤细胞非整倍体相关的特定表观遗传改变。对34例多倍体结直肠癌进行隐窝分离和细胞分选，分别从癌组织中分离成对的二倍体和非整倍体癌细胞。甲基化的CpG岛扩增提供了相当数量的CpG序列，这些序列在上述两个细胞群体中显示出不同的甲基化状态。BLAST同源性搜索从这些序列中发现了24个不同的候选序列（11个高甲基化，13个低甲基化）。在34例多倍体癌症中，非整倍体细胞（62%）比二倍体细胞（35%）的假设启动子序列SALL4 （sal-样4，人类与果蝇的同源物）的高甲基化频率更高。此外。在美国，这种高甲基化在非整倍体癌症（8 / 16.50%）中比在二倍体癌症（3 / 18.17%）中更常见。结合对培养细胞的去甲基化研究，这些结果暗示SALL4的表观遗传沉默与肿瘤细胞非整倍体之间可能存在关联。SALL4可能是染色体稳定性的“看护者”之一。我们的新方法是全球识别这些关键参与者的有力工具。(C) 2007 Wiley-Liss, Inc。
Although aneuploidy is commonly observed in human cancers, the molecular mechanism underlying aneuploidization remains unclear. We used multiploid cancer model that had diploid and aneuploid cancer cells within the same cancerous tissue and attempted to detect specific epigenetic alterations associated with tumor cell aneuploidy. Thirty-four multiploid colorectal cancers were subjected to crypt isolation and cell sorting, and paired diploid and aneuploid cancer cells were separated from each cancerous tissue. A methylated CpG island amplification provided a considerable number of CpG sequences that showed different methylation status between the above 2 cell populations. BLAST homology search revealed 24 different candidates (11 hypermethylated and 13 hypomethylated) from these sequences. The putative promoter sequence of the SALL4 (sal-like 4, a human homolog to Drosophila spalt) gene was particularly more frequently hypermethylated in aneuploid cells (62%) than diploid ones (35%) in the 34 multiploid cancers. Moreover., such hypermethylation occurred more often in aneuploid cancers (8 of 16, 50%) than diploid cancers (3 of 18, 17%). In combination with demethylation study on cultured cells, these results implied a possible association between epigenetic silencing of SALL4 and tumor cell aneuploidy. SALL4 may be one of important key players that act as "care-takers" for chromosomal stability. Our new approach is a powerful tool for the global identification of such key players. (C) 2007 Wiley-Liss, Inc.