Inhibition of AHR transcription by NF1C is affected by a single-nucleotide polymorphism, and is involved in suppression of human uterine endometrial cancer
Inhibition of AHR transcription by NF1C is affected by a single-nucleotide polymorphism, and is involved in suppression of human uterine endometrial cancer
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DOI：
10.1038/onc.2012.509
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发表时间：
2013-10
期刊：
影响因子：
8
通讯作者：
D. Li;T. Takao;R. Tsunematsu;Seiichi Morokuma;K. Fukushima;Hiroaki Kobayashi;Tomoko Saito;Masutaka Furue;Norio Wake;K. Asanoma
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文献类型：
--
作者：
D. Li;T. Takao;R. Tsunematsu;Seiichi Morokuma;K. Fukushima;Hiroaki Kobayashi;Tomoko Saito;Masutaka Furue;Norio Wake;K. Asanoma
许多研究表明芳香烃受体(AHR)参与了肿瘤的发生。AHR的上调在一些癌症物种中已被报道，AHR的单核苷酸多态(SNPs)与癌症风险或癌症发展之间的关联也已被报道。这一证据表明，某些特定的SNPs参与了AHR在肿瘤发生或发展过程中的转录调控，但尚未有研究阐明相关机制。在这项研究中，我们确定了转录因子核因子1-C(NF1C)是以一种依赖于多态性的方式调节AHR转录的候选基因。SNP rs10249788被包含在NF1C的共识结合位点中。我们的结果表明，NF1C在rs10249788上更倾向于结合C等位基因而不是T等位基因。强制表达NF1C抑制了AHR启动子的活性，其中C位的抑制作用强于T位。此外，对子宫内膜癌(HEC)标本的表达分析显示，AHR的上调和NF1C的下调明显高于正常子宫内膜。序列分析显示，晚期HEC患者携带T/T等位基因的频率高于健康女性。我们还证实了NF1C抑制HEC细胞的增殖、运动和侵袭。这一功能至少部分由AHR介导。这项研究首次报道了AHR调节区的多态在体外影响了AHR基因的转录调控。由于NF1C是一种肿瘤抑制因子，我们对AHR放松调控及其基因多态性的新见解可能会揭示癌症遗传易感性的新机制。
Involvement of the aryl hydrocarbon receptor (AHR) in carcinogenesis has been suggested in many studies. Upregulation of AHR has been reported in some cancer species, and an association between single-nucleotide polymorphisms (SNPs) of AHR and cancer risk or cancer development has also been reported. This evidence suggests the involvement of some specific SNPs in AHR transcriptional regulation in the process of carcinogenesis or cancer development, but there have been no studies to elucidate the mechanism involved. In this study, we identified the transcription factor Nuclear Factor 1-C (NF1C) as a candidate to regulate AHR transcription in a polymorphism-dependent manner. SNP rs10249788 was included in a consensus binding site for NF1C. Our results suggested that NF1C preferred the C allele to the T allele at rs10249788 for binding. Forced expression of NF1C suppressed the activity of the AHR promoter with C at rs10249788 stronger than that with T. Moreover, expression analysis of human uterine endometrial cancer (HEC) specimens showed greater upregulation of AHR and downregulation of NF1C than those of normal endometrium specimens. Sequence analysis showed HEC patients at advanced stages tended to possess T/T alleles more frequently than healthy women. We also demonstrated that NF1C suppressed proliferation, motility and invasion of HEC cells. This function was at least partially mediated by AHR. This study is the first to report that a polymorphism on the AHR regulatory region affected transcriptional regulation of the AHR gene in vitro. Because NF1C is a tumor suppressor, our new insights into AHR deregulation and its polymorphisms could reveal novel mechanisms of genetic susceptibility to cancer.