Inhibition of AHR transcription by NF1C is affected by a single-nucleotide polymorphism, and is involved in suppression of human uterine endometrial cancer

D. Li, T. Takao, R. Tsunematsu, Seiichi Morokuma, K. Fukushima, H. Kobayashi, T. Saito, Masutaka Furue, N. Wake, Kazuo Asanoma

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)4950-4959
Number of pages10
JournalOncogene
Volume32
Issue number41
DOIs
Publication statusPublished - Oct 10 2013

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NFI Transcription Factors
Aryl Hydrocarbon Receptors
Uterine Neoplasms
Endometrial Neoplasms
Single Nucleotide Polymorphism
Transcription Factors
Neoplasms
Alleles
Carcinogenesis
Up-Regulation
Nucleic Acid Regulatory Sequences
Genetic Predisposition to Disease
Endometrium
Sequence Analysis

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cancer Research
  • Genetics

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Inhibition of AHR transcription by NF1C is affected by a single-nucleotide polymorphism, and is involved in suppression of human uterine endometrial cancer. / Li, D.; Takao, T.; Tsunematsu, R.; Morokuma, Seiichi; Fukushima, K.; Kobayashi, H.; Saito, T.; Furue, Masutaka; Wake, N.; Asanoma, Kazuo.

In: Oncogene, Vol. 32, No. 41, 10.10.2013, p. 4950-4959.

Research output: Contribution to journalArticle

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