Multiple mechanisms downregulate CDKN1C in human bladder cancer
Multiple mechanisms downregulate CDKN1C in human bladder cancer
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DOI：
10.1002/ijc.20749
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发表时间：
2005-04-10
影响因子：
6.4
通讯作者：
Schulz, WA
中科院分区：
文献类型：
--
作者：
Hoffmann, MJ;Florl, AR;Schulz, WA
在Beckwith-Wiedemann综合征和几种人类癌症中，染色体11p15.5处编码细胞周期抑制剂p57（KIP 2）的印迹CDKNIC基因的表达受到不同机制的干扰。许多晚期尿路上皮癌（TCC）显示CDKNIC表达下调。以膀胱移行细胞癌细胞系为研究对象，以培养的正常尿路上皮细胞（UEC）为对照。在12/15的TCC细胞系中，CDKNIC mRNA表达降低，p57（KIP 2）蛋白相应降低。由于CDKNIC仅由母体等位基因表达，因此11 p15.5的洛代表下调机制之一。在3个细胞系中，几个多态性标记侧翼CDKNIC是纯合兼容的这一机制。CDKNIC启动子的超甲基化是其他癌症中下调的一个报道原因，通过亚硫酸氢盐测序在几个细胞系中检测到，并且似乎与至少一个细胞系中的下调相关。甲基化抑制剂5-氮杂-2 '脱氧胞苷诱导CDKNIC在该细胞系和其他细胞系中表达。第三种机制涉及两个等位基因向父系印迹模式的切换，由印迹中心（IC 2）的差异甲基化区域（DMR）的低甲基化表示。这种低甲基化在大多数TCC细胞系中检测到，并且与非编码LIT 1 RNA的重新表达和在几个TCC细胞中与CDKNIC的下调相关。因此，TCC中的CDKNIC下调似乎通过几种不同的机制发生。这一发现和p57（KIP 2）诱导尿路上皮细胞衰老的能力使CDKNIC成为TCC中11 p肿瘤抑制因子的良好候选者。(C)2004 Wiley-Liss，Inc.
Expression of the imprinted CDKNIC gene at chromosome 11p15.5 encoding the cell cycle inhibitor p57(KIP2) is disturbed in Beckwith-Wiedemann syndrome and in several human cancers by different mechanisms. Many advanced urothelial cancers (TCC) display downregulation of CDKNIC expression. The responsible mechanisms were investigated in TCC cell lines, with cultured normal urothelial cells (UEC) as controls. CDKNIC mRNA expression was diminished in 12/15 TCC lines and p57(KIP2) protein was decreased accordingly. Because CDKNIC is expressed from the maternal allele only, LOH at 11p15.5 represents one mechanism of downregulation. In 3 cell lines, several polymorphic markers flanking CDKNIC were homozygous compatible with this mechanism. Hypermethylation of the CDKNIC promoter, a reported cause of downregulation in other cancers, was detected by bisulfite sequencing in several cell lines and appeared associated with downregulation in at least one cell line. The methylation inhibitor 5-aza-2'deoxycytidine induced CDKNIC expression in this cell line and others. A third reported mechanism involves a switch of both alleles toward a paternal imprinting pattern, indicated by hypomethylation of a differentially methylated region (DMR) in the imprinting center (IC2). This hypomethylation was detected in most TCC lines, and was associated with re-expression of the non-coding LIT1 RNA and with downregulation of CDKNIC in several. Thus, CDKNIC downregulation in TCC seems to occur by several different mechanisms. This finding and the ability of p57(KIP2) to induce senescence in urothelial cells make CDKNIC a good candidate for a tumor suppressor at 11p in TCC. (C) 2004 Wiley-Liss, Inc.