Analysis of glucocorticoid receptors in human hepatocellular carcinoma and HepG2 cells

Lui, Wing‐Yiu; P’eng, Fang-Ku; Chang, Yuh‐Fang; Chang, Tsan‐Kuo; Tsai, Ting‐Fan; Hsu, Mei‐Ling; Su, Tsung‐Sheng; Tsay, Shyh‐Haw; Wu, Chew‐Wun; Liu, Tsung‐Yun; Chi, Chin‐Wen

doi:10.1002/hep.1840180524

Cited by 18 publications

(21 citation statements)

References 34 publications

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“…Whether this is physiologically or pathologically relevant, for instance pregnancy maintenance, labor onset or pregnancy-related disease pre-eclampsia, remains to be further elucidated. Furthermore, in the absence of GR overexpression, neither of the human Cbg promoters was responsive to dexamethasone in human hepatoma HepG2 cells, which express endogenous GR [43,44]. However, in the presence of overexpressed GRdexamethasone treatment inhibited Cbg promoter activity.…”

Section: Discussionmentioning

confidence: 95%

Single nucleotide polymorphisms in the human corticosteroid-binding globulin promoter alter transcriptional activity

Lei

et al. 2012

Sci. China Life Sci.

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Corticosteroid-binding globulin (CBG) is a high-affinity plasma protein that transports glucocorticoids and progesterone. Others and we have reported non-synonymous single nucleotide polymorphisms (SNPs) that influence CBG production or steroid-binding activity. However, no promoter polymorphisms affecting the transcription of human CBG gene (Cbg) have been reported. In the present study we investigated function implications of six promoter SNPs, including 26 C/G, 54 C/T, 144 G/C, 161 A/G, 205 C/A, and 443/444 AG/, five of which are located within the first 205 base pairs of 5′-flanking region and close to the highly conserved footprinted elements, TATA-box, or CCAAT-box. Luciferase reporter assays demonstrated that basal activity of the promoter carrying 54 T or 161 G was significantly enhanced. The first three polymorphisms, 26 C/G, 54 C/T, and 144 G/C located close to the putative hepatic nuclear factor (HNF) 1 binding elements, altered the transactivation effect of HNF1. We also found a negative promoter response to dexamethasone-activated glucocorticoid receptor (GR) , although none of the SNPs affected its transrepression function. Our results suggest that human Cbg 26 C/G, 54 C/T, 144 G/C, and 161 A/G promoter polymorphisms alter transcriptional activity, and further studies are awaited to explore their association with physiological and pathological conditions. , both of which are well-known hormones for pregnancy maintenance or labor onset. While CBG mainly binds >80% of cortisol in human peripheral blood [3], at the maternal-fetal interface CBG will be occupied by the very high concentrations of progesterone, which is several fold higher than those of cortisol [6]. In the circulation of women during mid-late pregnancy, approximately 10% of CBG steroid-binding sites are occupied by progesterone, versus <1% in non-pregnant women [5]. Plasma CBG levels rise progressively through gestation until term pregnancy [7], and so do blood cortisol and progesterone levels. Maternal plasma CBG, total and free cortisol concentrations are reduced in pre-eclampsia and gestational hypertension patients, and this may be a consequence of decreased Cbg synthesis driven by cytokines or increased degradation driven by inflammation [7]. SPECIAL TOPIC

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Section: Discussionmentioning

confidence: 95%

Single nucleotide polymorphisms in the human corticosteroid-binding globulin promoter alter transcriptional activity

Lei

et al. 2012

Sci. China Life Sci.

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“…However, as was the case in H4IIE cells, the induction of reporter-gene expression by dexamethasone either alone or in combination with db # cAMP was increased following transfection with constructs CRE2mut\CRE2 and CRE2mut\ CREcons. The data presented ( Figure 5) were obtained in the presence of co-transfected glucocorticoid receptor protein, as controversial data are available in the literature about the extent to which HepG2 cells express functional glucocorticoid receptor protein [15][16][17]. The omission of the co-transfected receptor plasmid had in our hands no significant effect on the results described above (results not shown).…”

Section: The Sequence Between Nt K161 and K152 Is Involved In The Actmentioning

confidence: 56%

Identification of a cAMP response element within the glucose- 6-phosphatase hydrolytic subunit gene promoter which is involved in the transcriptional regulation by cAMP and glucocorticoids in H4IIE hepatoma cells

Schmoll

Wasner

Hinds

et al. 1999

Biochemical Journal

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The expression of a luciferase reporter gene under the control of the human glucose 6-phosphatase gene promoter was stimulated by both dexamethasone and dibutyryl cAMP in H4IIE hepatoma cells. A cis-active element located between nucleotides -161 and -152 in the glucose 6-phosphatase gene promoter was identified and found to be necessary for both basal reporter-gene expression and induction of expression by both dibutyryl cAMP and dexamethasone. Nucleotides -161 to -152 were functionally replaced by the consensus sequence for a cAMP response element. An antibody against the cAMP response element-binding protein caused a supershift in gel-electrophoretic-mobility-shift assays using an oligonucleotide probe representing the glucose 6-phosphatase gene promoter from nucleotides -161 to -152. These results strongly indicate that in H4IIE cells the glucose 6-phosphatase gene-promoter sequence from -161 to -152 is a cAMP response element which is important for the regulation of transcription of the glucose 6-phosphatase gene by both cAMP and glucocorticoids.

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“…It is well known that the effects of glucocorticoids were mediated through glucocorticoid-receptor (GR). We and others have found the level of GR and its mRNA were significantly higher in human HCC than that in the adjacent non-tumor liver tissue (29,30). These results indicated that glucocorticoid and GR played an important role in regulating growth of hepatoma.…”

Section: Introductionmentioning

confidence: 59%

Glucocorticoid protects hepatoma cells against metabolic stress-induced cell death

Lui¹

1992

Int J Oncol

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Abstract. Hepatocellular carcinoma is one of the most common cancers in the world. Previously, we found that the level of glucocorticoid receptor was significantly higher in hepatocellular carcinoma than in adjacent liver tissues. Moreover, in vitro and in vivo studies showed that glucocorticoid stimulated the growth of hepatoma cells. On the other hand, endogenous metabolites such as 2-methoxyestradiol, a metabolite of estrogen produced in liver, and lactic acid, an end-product of glycolysis can result in apoptosis of tumor cells. There are studies that glucocorticoid inhibited apoptosis induced by different chemotherapeutic drugs, whether glucocorticoid could block endogenous stresses, such as 2-methoxyestradiol-or lactic acid-induced apoptosis in human and murine hepatoma cells is not known. In this study, the antagonistic effects of dexamethasone on 2-methoxyestradiol-and lactic acid-induced apoptosis were investigated in human HepG2 and murine Hepa1-6 hepatoma cells. Treatment of hepatoma cells with 2.5-10 μM 2-methoxyestradiol or 25 mM lactic acid resulted in growth inhibition and decreased viability. In addition, results of cell cycle analysis, annexin V binding assay and DNA fragmentation formation showed that 2-methoxyestradiolor lactic acid-induced apoptosis of hepatoma cells but these effects were partially blocked by dexamethasone. Combined treatment of hepatoma cells with dexamethasone and 2-methoxyestradiol or lactic acid partially reduced the 2-methoxyestradiol-or lactic acid-induced apoptosis signal. Treatment of hepatoma cells with 2-methoxyestradiol or lactic acid resulted in up-regulation of caspase-8, -9 and -3.Dexamethasone partially suppressed the caspase expression. The Bcl-2 level was induced by dexamethasone treatment but decreased after treatment with 2-methoxyestradiol or lactic acid. These results together suggest that glucocorticoids may protect hepatoma cells from metabolic stress-induced cell damage via anti-apoptotic pathways.

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Analysis of glucocorticoid receptors in human hepatocellular carcinoma and HepG2 cells

Cited by 18 publications

References 34 publications

Single nucleotide polymorphisms in the human corticosteroid-binding globulin promoter alter transcriptional activity

Single nucleotide polymorphisms in the human corticosteroid-binding globulin promoter alter transcriptional activity

Identification of a cAMP response element within the glucose- 6-phosphatase hydrolytic subunit gene promoter which is involved in the transcriptional regulation by cAMP and glucocorticoids in H4IIE hepatoma cells

Glucocorticoid protects hepatoma cells against metabolic stress-induced cell death

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