Induction of human endometrial cancer cell senescence through modulation of HIF-1α activity by EGLN1
Induction of human endometrial cancer cell senescence through modulation of HIF-1α activity by EGLN1
复制标题
DOI：
10.1002/ijc.21488
复制
发表时间：
2006-03-01
影响因子：
6.4
通讯作者：
Wake, N
中科院分区：
文献类型：
--
作者：
Kato, H;Inoue, T;Wake, N
以前的观察表明，人类染色体（chr.）1诱导子宫内膜癌细胞衰老。为了鉴定负责衰老的基因，我们首先分析了来自chr.1转移的HHUA细胞的永生回复突变体中引入的chr.1的结构完整性。这些数据证明了1 q31-qter区域内的非随机缺失与回复永生之间的相关性。接下来，通过使用一组12个微卫星标记，我们发现在特定的1 q区域（1 q41 -42）的杂合性丢失的高频率，在手术切除的样本。然后，我们用子宫内膜癌小组筛查了该区域相关基因的基因突变。其中，EGLN 1是脯氨酰羟化酶的成员，并且可以通过HIF-1的羟基化通过泛素化促进HIF-1的降解，其以显著更高的频率突变（12/20，60%）。将野生型EGLN 1导入携带EGLN 1基因突变的子宫内膜癌细胞系（HHUA、石川和HWCA）中诱导衰老。这是通过HIF-1表达的负调控来实现的。此外，通过抑制HIF-1的因子（FIH）、针对HIF-1的SiRNA和HIF-1抑制剂YC-1负调节HIF-1的替代方式也可以诱导衰老。因此，EGLN 1可以被认为是chr. 1 q上的一个候选肿瘤抑制因子，我们的观察为探索HIF-1信号转导相关的衰老诱导机制开辟了新的方向。这些结果也表明HIF-1信号的负调节对于子宫癌治疗的有效性，特别是对于预后差且显示出高频率EGLN 1基因异常的子宫肉瘤。(c)2005 Wiley-Liss，Inc.
Previous observations indicate that transfer of human chromosome (chr.) 1 induces senescence of endometrial cancer cells. To identify the gene(s) responsible for the senescence, we first analyzed the structural integrity of the introduced chr.1 in immortal revertant from chr.1-transferred HHUA cells. The data demonstrated a correlation between nonrandom deletions within the 1q31-qter region and reversion to immortality. Next, by using a panel of 12 microsatellite markers, we found high frequencies of loss of heterozygosity in the particular 1q region (1q41-42), in surgically removed samples. Then, we screened the genetic mutation of the genes involved in this region, with endometrial cancer panel. Among them, EGLN1, that is a member of prolyl hydroxylase and can facilitate HIF-1 degradation by ubiquitination through the hydroxylation of HIF-1, was mutated at significantly higher frequencies (12/20, 60%)., Introduction of wild-type EGLN1 into endometrial cancer cell lines (HHUA, Ishikawa and HWCA), that carry EGLN1 gene mutations induced senescence. This was invoked through the negative regulation of HIF-1 expression. In addition, alternative way of negative regulation of HIF-1 by Factor inhibiting HIF-1(FIH), SiRNA against HIF-1, and HIF-1 inhibitor, YC-1, could also induce senescence. Thus, EGLN1 can be considered as a candidate tumor suppressor on chr. 1q, and our observation could open the new aspect in exploring the machinery of senescence induction associated with HIF-1 signal transduction. These results also suggested the availability of negative regulation of HIF-1 signals for uterine cancer treatment, especially for uterine sarcomas that have worse prognosis and show a high frequency of EGLN1 gene abnormality. (c) 2005 Wiley-Liss, Inc.