Silencing of the retinoid response gene TIG1 by promoter hypermethylation in nasopharyngeal carcinoma
Silencing of the retinoid response gene TIG1 by promoter hypermethylation in nasopharyngeal carcinoma
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DOI：
10.1002/ijc.20593
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发表时间：
2005-01-20
影响因子：
6.4
通讯作者：
Huang, DP
中科院分区：
文献类型：
--
作者：
Kwong, J;Lo, KW;Huang, DP
他扎罗汀诱导基因1（TIG 1）和他扎罗汀诱导基因3（TIG 3）是维甲酸（RA）靶基因，也是人类癌症的候选肿瘤抑制基因。在我们的研究中，我们研究了TIG 1和TIG 3在鼻咽癌（NPC）中的表达。在80%的NPC细胞系和33%的异种移植物中发现TIG 1表达缺失，而TIG 3在所有NPC样品和永生化鼻咽上皮细胞中表达。为了阐明TIG 1基因在鼻咽癌中的表观遗传沉默，采用基因组亚硫酸氢盐测序和甲基化特异性PCR（MSP）检测了TIG 1基因启动子的甲基化状态。我们在5个TIG 1阴性的鼻咽癌细胞系（C666-1、CNE 1、CNE 2、HONE 1和X666）和移植瘤中检测到TIG 1 5 'CpG岛的高甲基化。在1个NPC细胞系HK 1中观察到部分甲基化，显示TIG 1表达显著降低。启动子甲基化在2个TIG 1表达的NPC异种移植物和正常上皮细胞中不存在。5-氮-2 '-脱氧胞苷处理后，在NPC细胞系中观察到TIG 1表达和未甲基化等位基因的恢复。MSP法检测43例原发性NPC肿瘤中39例（90.7%）TIG 1基因甲基化。总之，我们的研究结果表明，TIG 1的表达在大多数NPC细胞系和异种移植物中丢失，而启动子超甲基化是TIG 1沉默的主要机制。此外，原发性NPC肿瘤中TIG 1的频繁表观失活暗示其可能在NPC肿瘤发生中起重要作用。
Tazarotene-induced gene 1(TIG1) and Tazarotene-induced gene 3 (TIG3) are retinoid acid (RA) target genes as well as candidate tumor suppressor genes in human cancers. In our study, we have investigated the expression of TIG1 and TIG3 in nasopharyngeal carcinoma (NPC). Loss of TIG1 expression was found in 80% of NPC cell lines and 33% of xenografts, whereas TIG3 was expressed in all NPC samples and immortalized nasopharyngeal epithelial cells. In order to elucidate the epigenctic silencing of TIG1 in NPC, the methylation status of TIG1 promoter was examined by genomic bisulfite sequencing and methylation-specific PCR (MSP). We have detected dense methylation of TIG1 5'CpG island in the 5 TIG1-negative NPC cell lines and xenograft (C666-1, CNE1, CNE2, HONE1 and X666). Partial methylation was observed in 1 NPC cell line HK1 showing dramatic decreased in TIG1 expression. Promoter methylation was absent in 2 TIG1-expressed NPC xenografts and the normal epithelial cells. Restoration of TIG1 expression and unmethylated alleles were observed in NPC cell lines after 5-aza-2'-deoxycytidine treatment. Moreover, the methylated TIG1 sequence was detected in 39 of 43 (90.7%) primary NPC tumors by MSP. In conclusion, our results showed that TIG1 expression is lost in the majority of NPC cell lines and xenografts, while promoter hypermethylation is the major mechanism for TIG1 silencing. Furthermore, the frequent epigenctic inactivation of TIG1 in primary NPC tumors implied that it may play an important role in NPC tumorigenesis.