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.
To examine the hypothesis that serum levels of 7α‐hydroxycholesterol reflect bile acid synthesis in the liver, we analyzed serum 7α‐hydroxycholesterol and bile acid output in 13 patients with obstructive jaundice after relief of biliary obstruction. Before biliary drainage, the serum level of 7α‐hydroxycholesterol was 92 ± 12 pmol/ml (mean ± S.E.M.) and was significantly lower than the control value (226 ± 26 pmol/ml, p<0.01). After biliary drainage, serum 7α‐hydroxycholesterol level and biliary bile acid outputs began to rise in some patients, indicating reversible liver dysfunction. In other patients, serum 7α‐hydroxycholesterol levels and bile acid outputs did not increase, suggesting severe or irreversible liver dysfunction. On and after the third day of biliary decompression, serum 7α‐hydroxycholesterol levels correlated well with bile acid excretion (p<0.01, r=0.93). Other liver function parameters, such as serum bilirubin, serum bile acids, albumin, and bile flow, also revealed significant correlation with serum 7α‐hydroxycholesterol levels. We conclude that the serum 7α‐hydroxycholesterol level clearly reflects bile acid synthesis in the liver and that it may serve as a useful parameter for the assessment of hepatic functional recovery in patients with obstructive jaundice after biliary drainage. (Hepatology 1994;20:95–100.)
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