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Department of Obstetrics and Gynecology, Okayama University Medical School, Okayama, 700-8558, Japan
Address all correspondence and requests for reprints to: Hisashi Masuyama, M.D., Ph.D., Department of Obstetrics and Gynecology, Okayama University Medical School, 2-5-1, Shikata, Okayama, 700-8558, Japan. E-mail: masuyama{at}cc.okayama-u.ac.jp.
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Abstract |
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Introduction |
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Pregnane X receptor (PXR), a new member of the steroid receptor superfamily, has been shown to mediate the genomic effects of several steroid hormones, including progesterone (P), pregnenolone, and estrogen, and of xenobiotics in the mouse, rat, and human (6, 7, 8, 9, 10, 11, 12). Like nonsteroid hormone receptors, it binds as a heterodimer with retinoid X receptor to specific DNA sequences, including the upstream region of the cytochrome P-450 3A (CYP3A) gene family (6, 7, 8, 11), which consists of monooxygenases responsible for the oxidative metabolism of certain endogenous substrates and xenobiotics (13, 14). Because the PXR-CYP3A4 pathway is activated by a large number of prescription drugs for infection, cancer, convulsion, and hypertension (15), PXR is thought to play some roles in drug metabolism and drug-drug interaction. Recent research demonstrated that PXR regulates the metabolism of bile acid, which is essential for the elimination of excess cholesterol from the body and the transport of dietary lipids in the intestine (16). These data suggest that PXR regulates an entire program of genes in the liver and intestine that are involved in the metabolism and elimination of potentially toxic substrates from the body (15). In addition, we have demonstrated the expression of PXR in mouse reproductive tissues, uterine and ovary, as well as liver and intestine, and that the expressions of PXR and CYP3A1 in the liver and ovary significantly increased with the progression of hypersteroidemia evaluated toward term during pregnancy, suggesting that PXR may play a role in regulation of the steroid hormone metabolism during reproduction (17).
In this study, we examined whether PXR was expressed in endometrial cancer tissues and investigated the relationship between PXR expression and the status of the estrogen receptor (ER) and the P receptor (PR). Because both CYP3A4 and CYP3A7 are target genes for human PXR (6, 7, 11) and play important roles of steroid metabolism in human endometrium (18), we also analyzed the expression of CYP3A4/7 in endometrial cancer tissues and compared it with PXR expression. Then we conducted in vitro experiments using endometrial cancer cell lines to examine whether a variety of PXR ligands activated the PXR-mediated transcription and affected the expression of CYP3A. The data suggested that the steroid/xenobiotics metabolism by the tumor tissue through PXR-CYP3A pathway might play an important role in endometrial cancer, especially in an alternative pathway for gonadal hormone and endocrine-disrupting chemical (EDC) effects on endometrial cancer expressing low ER.
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Patients and Methods |
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Isopropylidenediphenol (bisphenol A), phthalic acid bis (2-ethylhexel ester) (phthalic acid), 5-Pregneno-3ß-ol-20-one (pregnenolone), P, and 17ß-estradiol (E2) were purchased from Sigma Co. Ltd. (St. Louis, MO). Ishikawa cells were kindly provided by Dr. M. Nishida; and HEC-1 cells, BeWo cells, and COLO320 cells were obtained from the Health Science Research Resources Bank (Osaka, Japan).
Patients and tissue samples
Endometrial cancer tissues were obtained from 43 patients who had undergone surgical resection at the Department of Obstetrics and Gynecology, Okayama University Hospital. Pathological diagnosis of all patients was endometrioid adenocarcinoma. Eleven nonneoplastic endometrial tissues (four cases at the proliferative phase, four cases at the secretory phase, and three cases who took oral contraceptives for uterine bleeding) were also obtained from patients who had undergone hysterectomy attributable to uterine cervical cancer (stage 0 or Ia). An International Federation of Gynecology and Obstetrics staging system was used for the grading and staging of endometrial carcinoma and cervical cancer in this study. As positive control for PXR and CYP3A4/7, a normal small intestine tissue was obtained from a patient who had undergone surgical resection at the Department of Surgery in our university. Informed consent was obtained from all patients, and this study was approved by the local ethics committee.
Immunohistochemical analysis
Formalin-fixed paraffin-embedded sections, 4-µm thick, were deparaffinized with xylene and rehydrated in ethanol. Endogenous peroxidase activity was blocked by methanol containing 0.3% hydrogen peroxidase for 15 min. The sections were then treated at 4 C overnight with primary antibody for PXR (A-20; Santa Cruz Biotechnology, Inc., Santa Cruz, CA) (1:100 dilution) followed by staining using a streptavidin-biotin-peroxidase kit (Nichirei, Tokyo, Japan). For negative control, we used normal goat IgG instead of primary antibody for PXR; and for the immunohistochemical preabsorption test, we used the antibody for PXR, which was incubated with a 5-fold excess of blocking peptide for PXR antibody (Santa Cruz Biotechnology, Inc.) at 4 C overnight. The sections were counterstained with hematoxylin. Two observers, who were blinded for the immunohistochemical-related data, evaluated the PXR labeling index independently. The labeling index was calculated as the percentage of labeled nuclei of the total number of tumor cells counted.
RT-PCR
Frozen tissues of normal endometrium and endometrial cancer were homogenized, and total RNA was extracted using the RNeasy Mini Kits (QIAGEN Gmbh, Hilden, Germany) according to the manufacturer’s instructions. Total RNA was also extracted from endometrial cancer cells using Trizol reagent (Life Technology, Inc., Grand Island, NY). Each sample was treated with deoxyribonuclease I to remove genomic DNA contamination. According to the protocol of the RNA PCR kit (TAKARA Co., Ltd., Kyoto, Japan), 0.1 µg total RNA was reverse transcribed at 42 C for 20 min in 20 µl reaction solution containing 1x PCR buffer, 5 mM MgCl2, 1 mM deoxynucleotide triphosphates, 2.5 µM random 9 mers primer, 10 U ribonuclease inhibitor, and 5 U avian myeloblastosis virus reverse transcriptase. The primers for human CYP3A4/7, PXR, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were as follows: CYP3A4/7 sense: 5'-CAAGACCCCTTTGTGGAAAA-3', 3' antisense: 5'-AAATCCACTCGGTGCTTTTG-3', PXR sense: 5'-TCCGGAAAGATCTGTGTGCTCT-3', 3' antisense: 5'-AGGGAGATCTGGTCCTCGAT-3', GAPDH sense: 5'-CGAGATCCCTCCAAAATCAA-3', 3' antisense: 5'-GTCTTCTGGGTGGCAGTGAT-3'. The primers for human CYP3A4/7 used here amplified both CYP3A4 and 3A7 as the same size of PCR product. Amplification for CYP3A4/7, PXR, and GAPDH was carried out on a GeneAmp PCR system 9700 (Applied Biosystems, Foster City, CA) with initial denaturation at 94 C for 2 min, followed by 25 cycles of 94 C for 30 sec, 60 C for 30 sec, 72 C for 30 sec, and a final extension at 72 C for 2 min. The number of PCR cycles resulting in PCR products in the linear logarithmic phase of the amplification curve was determined. PCR samples were electrophoresed on 3% 
-Sieve agarose gel and visualized by ethidium bromide. The amount of each electrophorectically separated cDNA was quantitated densitometrically using an Image Scanner GT-9500 (Epson, Suwa, Japan) and Bio Image BQ 2.0 software (Bio Image, Ann Arbor, MI).
Enzyme immunoassay (EIA)
Because there are several reports demonstrating that EIA correlated with immunohistochemical analysis and ligand binding assay to evaluate ER and PR status (19, 20, 21) and we clinically used EIA instead of immunohistochemical analysis and ligand binding assay as a laboratory tool, the ER- and PR status were determined by EIA (Dynabott Co., Inc., Tokyo, Japan) in this study. Briefly, tissue samples obtained at surgery were immediately frozen and stored at -80 C until assay. Tissue specimens were thawed quickly, minced, and suspended in 5 vol of the buffer (T-PER Protein Extraction Reagent; Pierce Chemical Co., Rockford, IL) at 4 C. After homonization, samples were prepared by centrifugation at 14,000 rpm for 15 min, and the supernatants were used for the assay. The EIA for ER and PR was carried out by a solid-phase assay based on a sandwich method according to the manufacture’s protocol. We did immunohistochemical analysis for ER- and PR to compare with the EIA data using six cases of endometrial cancer tissues investigated in this study There were positive correlations between EIA and labeling index for ER- and PR (data not shown). Positive ER- status was defined as more than 13 fmol/mg protein, and that of PR status as more than 10 fmol/mg protein. And these EIA assays for both receptors couldn’t detect under 5 fmol/mg protein.
Transient transfection studies
The (CYP3A4)3-tk-chloramphenicol acetyl transferase (CAT) containing three copies of the CYP3A4 motif and pSG5-PXR expression plasmid containing full-length human PXR cDNA were kindly provided by Dr. S. A. Kliewer (University of Texas Southwestern Medical Center) (7). Ishikawa cells and HEC-1 cells were cotransfected with 1 µg of a reporter gene construct [(CYP3A4)3-tk-CAT] or tk-CAT vector. In all transfections, liposome-mediated transfections were accomplished by using lipofectamine (Life Technologies Inc., Gaithersburg, MD) according to the manufacturer’s instructions. Transfected cells were treated either with vehicle alone or with the indicated concentrations of steroid hormones or EDCs for 36 h. The cell extracts were prepared and assayed for CAT activity. The amount of CAT was determined using a CAT ELISA kit (Roche Diagnostics Co., Tokyo, Japan) according to the manufacturer’s instructions.
Cell culture and Western blot analysis
All cell lines except BeWo cells were cultured in DMEM without phenol red, supplemented with 10% charcoal-striped fetal bovine serum. BeWo cells were cultured in F-12K medium without phenol red, supplemented with 15% charcoal-striped fetal bovine serum. All medium and serum were purchased from Invitrogen Corp. (Carlsbad, CA). Nuclear extracts were obtained from both cell types using NE-PER Nuclear and Cytoplasmic Extraction Reagents (Pierce Chemical Co.) according to the manufacture’s protocol and stored at -80 C until analysis. Equivalent amounts of nuclear protein (25 µg/sample) from each extract were determined by bicinchoninic acid protein assay (Pierce Chemical Co.), solubilized in sodium dodecyl sulfate buffer (0.05 M Tris-HCl, 2% sodium dodecyl sulfate, 6% mercaptoethanol, 10% glycerol, pH 6.8) and analyzed by Western blot analysis as previously described (22) using rabbit polyclonal antibody for ER- (MC-20; 1:1000 dilution), PR (H-190; 1:1000 dilution), and ß-actin (H-196; 1:1000 dilution) and goat polyclonal antibody for PXR (A-20; 1:1000 dilution) (Santa Cruz Biotechnology, Inc.). The amount of each band was quantitated densitometrically using Image Scanner GT-9500 (Epson) and Bio Image BQ 2.0 software.
Statistical analysis
Statistical analysis was evaluated by 
2 test and Mann-Whitney U test in Table 1
(also see Figs. 3 and 4), and one-way ANOVA followed by Dunnett’s test (see Figs. 5 and 6). Data are the mean ± SD. P < 0.05 denoted the presence of a statistically significant difference.
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Results |
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Because we found that the PXR was expressed in uterine tissues of mouse by RT-PCR (17) and mouse endometrium by immunohistochemistry (data not shown), immunohistochemical analysis was performed to examine whether PXR was expressed in normal endometrium and endometrial cancer tissues in human. In normal endometrium, we could not detect PXR expression of all patients at the proliferative phase (n = 4, Fig. 1A) or the secretory phase (n = 4, Fig. 1B), but PXR was expressed in glandular cells of the endometrium of all three patients who took oral contraceptives for uterine bleeding (Fig. 1C). These contraceptives consisted of ethinylestradiol and norethisterone, estrogen and P derivatives, could be PXR ligands (7, 15), and have been known to be substrates for CYP3A4 (23, 24). Next, we checked the expression of PXR in endometrial cancer tissues. Various proportions of nuclear staining were observed among samples from 43 endometrial cancer patients. Representative staining of high PXR expression in endometrial cancer tissues is shown in Fig. 1D, and that of low PXR expression is shown in Fig. 1E. Fig. 1F was described as positive control using normal human small intestine; and Fig. 1, G and H, were also described as negative control for verifying specificity of the antibody used in this study. The distribution of PXR labeling index in endometrial cancer tissues is illustrated in Fig. 2; and based on the staining, we divided these cases into two groups, a low-PXR-expression group including 15 PXR negative cases and a high-PXR-expression group, for further analysis. In 16 ER-negative cases, there are nine cases in the low-PXR-expression group and seven cases in the high-PXR-expression group. Also, in 13 PR-negative cases, there were six cases in the low-PXR-expression group and seven cases in the high-PXR-expression group. There were no significant differences of PXR expression between ER- or PR-negative cases and positive cases. In addition, no significant differences were observed between low- and high-PXR-expression groups in terms of clinicopathological factors such as grading, staging, and age (Table 1
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To examine whether PXR expression could affect the hormonal status in endometrial cancer tissues, we investigated the relationship of PXR expression to steroid hormone receptors; that is, the ER and PR status. The ER- and PR status were measured by EIA. A statistically significant inverse relationship was found between PXR expression and ER- status (Fig. 3A). In contrast, no significant relationship was observed between PXR expression and PR status (Fig. 3B).
Relationship of PXR expression to expression of CYP3A4/7 mRNA in endometrial cancer tissues
Next, the expression of CYP3A4/7 mRNA, which is one of target genes regulated by PXR (6, 7, 8, 11), was analyzed in normal endometrium and endometrial cancer tissues. We used the semiquantitative RT-PCR method because we had not previously been able to obtain an appropriate antibody for CYP3A4/7 for immunohistochemical analysis. The housekeeping gene, GAPDH, was used to determine the relative level of CYP3A4/7 gene transcription and to control for variations in RNA recoveries from each specimen. Normalization of the data was accomplished by quantifying the amount of amplified cDNA products by calculating the ratio of the amount of CYP3A4/7 cDNA relative to the amount of GAPDH cDNA. This ratio was used to compare the relative amount of CYP3A4/7 mRNA in each tissue specimen. CYP3A4/7 expression in normal endometrium was low (CYP3A4/7/GAPDH mRNA = 0.02 ± 0.01) and significantly increased in endometrial cancer tissues (P < 0.01). In endometrial cancer tissues, the CYP3A4/7 expression in the high-PXR-expression group was significantly higher than that in the low-PXR-expression group (Fig. 4). As a positive control for CYP3A4/7, we used the RNA extraction of human small intestine tissue, which has been used to show the expression of CYP3A4 and CYP3A7 (25). Comparison of PXR mRNA expression between two groups, low- and high-PXR-expression groups, by semiquantitative RT-PCR (n = 8) demonstrated that the mRNA level of PXR correlated with the protein level of PXR in our cases (data not shown).
The effect of PXR ligands on the PXR-mediated transcription in endometrial cancer cells
To examine the effect of ligands for PXR on the PXR-mediated transcription in endometrial cancer cells, Ishikawa cells and HEC-1 cells, endometrial cancer cell lines, were used to determine which cell line expressed PXR. The normalization of the data was accomplished by quantifying the amount of the band by calculating the ratio of the amount of ER-, PR, or PXR protein relative to the amount of ß-actin protein. As shown in Fig. 5A, PXR was abundant in HEC-1 cells and in COLO320 DM cells (a colon cancer cell line) but was weakly detected in Ishikawa cells and in BeWo cells (a choriocarcinoma cell line). And there were inverse relationships between ER- and PXR in all cell lines tested here. We used some EDCs (phthalate and bisphenol A) as well as the endogenous steroids estradiol, pregnenolone, and P, as PXR ligands because these chemicals have been demonstrated to activate PXR-mediated transcription in other cell lines (26, 27). A reporter gene construct [(CYP3A4)3-tk-CAT] was introduced into Ishikawa cells and HEC-1 cells. The endogenous steroids E2, pregnenolone, and P significantly activated native PXR-mediated transcription (P < 0.01); and the EDCs, bisphenol A and phthalate, also significantly activated the transcription (P < 0.01 or 0.05), but the fold increases were lower compared with those in the presence of endogenous steroids in both cell lines (Fig. 5, B and C). Dichlorodiphenyltrichloroethane (DDT), however, had no effect on this transcription in both cell lines. In this transient transfection assay, the ranges of fold increase in HEC-1 cells (5.0- to 10.0-fold, Fig. 5B) were much higher than those in Ishikawa cells (1.9- to 4.8-fold, Fig. 5C).
The effect of PXR ligands on the expression of PXR and CYP3A4/7 in endometrial cancer cells
To examine the effect of PXR ligands on the expression of CYP3A4/7 in vitro, the mRNA level of CYP3A4/7 was qualitatively examined in HEC-1 cells and Ishikawa cells that had been exposed to steroids and EDCs as described in Fig. 4. In HEC-1 cells, CYP3A4/7 mRNA level was significantly increased in the presence of PXR ligands, which activated PXR-mediated transcription in the transient transfection assay (percent increase relative to ethanol treatment, 150–200%; Fig. 6A). There were no differences between endogenous steroids and EDCs. In contrast, the CYP3A4/7 mRNA level did not change in response to DDT, which did not enhance PXR-mediated transcription. In Ishikawa cells, EDCs showed a significant, but weaker, effect on CYP3A4/7 expression (percent increase, 140–150%) compared with that in HEC-1 cells (percent increase, 170–180%), but the endogenous steroids E2, P, and pregnenolone, had a significant and slightly stronger positive effect on CYP3A4/7 expression (percent increase, 195–260%) compared with that in HEC-1 cells (percent increase, 150–200%) (Fig. 6B). Next, we examined whether PXR ligands affected the PXR expression in both cell lines. The normalization of the data was accomplished by quantifying the amount of the band by calculating the ratio of the amount of PXR protein or cDNA product relative to the amount of ß-actin protein or GAPDH cDNA product. There were no significant differences in the protein and mRNA levels of PXR in HEC-1 cells exposed to any PXR ligands (Fig. 6C). However, both levels of PXR were significantly increased in the Ishikawa cells exposed to endogenous PXR ligands E2, P, and pregnenolone (3.5- to 4.5-fold). EDC, bisphenol A, and phthalate had significant, but weaker, effect (2.5- to 2.8-fold) compared with that in the presence of endogenous steroids (Fig. 6D).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The CYP3A subfamily is involved in the metabolism of endogenous substrates such as steroid hormones and bile acids (13, 14). In addition, this subfamily also plays important roles in the metabolism of procarcinogens and pharmaceutical agents, including innumerable drugs, chemical carcinogens, mutagens, and other environmental contaminants (13, 14, 29). In humans, CYP3A4 and CYP3A7 mRNA has been demonstrated to be expressed in uterine endometrium by RT-PCR (18, 30), but there have been no reports on the CYP3A4 and CYP3A7 expression in endometrial cancer tissue. In this study, we found that the expression of CYP3A4/7 mRNA in endometrial cancer tissue was significantly higher than that in normal endometrium, and that CYP3A4/7 expression positively correlated with PXR expression. Moreover, PXR ligands, especially the endogenous steroids pregnenolone, estradiol, and P, activated PXR-mediated transcription and enhanced CYP3A4/7 expression in endometrial cancer cell lines. And EDCs strongly enhanced PXR-mediated transcription and CYP3A expression in HEC-1 cells, which express high PXR and low ER and PR, compared with those in Ishikawa cells, which express low PXR and high ER and PR. Taken together, these findings encouraged us to speculate that the PXR-CYP3A4/7 pathway might regulate the metabolism of steroid hormones under a local high steroid hormone condition and might play some roles in the intratumoral metabolism of steroid hormones, which may be involved in the growth and development of cancer tissue expressing low ER-. In this study, we used a primer set that amplified both CYP3A4 and CYP3A7 as a same-size PCR product to show CYP3A expression by RT-PCR. Because both CYP3A subtypes have been demonstrated to play important roles in endometrium (18), and other metabolic enzymes including phase II enzymes and transporters as well as these CYP3A subtypes were reported to be regulated by PXR (6, 7, 11, 15), further analysis will be required to investigate roles of each CYP3A subtype and other metabolic enzymes regulated by PXR in endometrial cancer tissues. In addition, there were no reports that demonstrated the correlations between CYP3A and ER/PR in normal endometrium and endometrial cancer tissues. It is important to get additional data on the relationship between CYP3A and ER/PR in detail to understand the steroidogenesis in normal and neoplastic endometrium.
We recently demonstrated that the endocrine-disrupting chemicals phthalate and nonylphenol activated PXR-mediated transcription, perhaps through interaction with coactivators (26), and another group also showed that bisphenol A is a ligand for human PXR (27). PXR is thought to regulate CYP3A family genes, which play important roles in steroidogenesis (13, 14, 29), suggesting that there may be a novel pathway of endocrine-disrupting chemicals that affect endocrine functions. In this study, we also demonstrated that the EDCs bisphenol A and phthalate activated endogenous human PXR-mediated transcription and enhanced CYP3A4/7 expression in endometrial cancer cells, albeit weakly. This data suggested that EDCs might affect steroidogenesis in endometrial cancer tissue through the PXR-CYP3A pathway. Because some EDCs may have the potential to influence the risk for hormone-dependent breast cancer (31, 32), further analysis of the potential roles of the PXR-CYP3A pathway in EDC-induced carcinogenesis and the growth and development of endometrial cancer will be required. Moreover, PXR and CYP3A4 have been demonstrated to be involved in the acquisition of resistance to anticancer drugs. And paclitaxel, which is a commonly used chemotherapeutic agent, has been demonstrated to activate PXR-mediated transcription and to enhance P-glycoprotein-mediated drug clearance (33). Also, intratumoral CYP3A4 mRNA levels might be useful as a predictor of response to docetaxel, which is another active antineoplastic drug, in breast cancer tissues (34). Therefore, because PXR-CYP3A4 pathway might be involved in drug clearance in endometrial cancer, the PXR-CYP3A expression in endometrial cancer tissues may cause resistance to anticancer agents, which results in affecting the prognosis of endometrial cancer patients. Additional clinical and basic data are required for this issue.
In summary, we examined the expression and potential role of the PXR-CYP3A pathway in endometrial cancer tissues. Tissues of endometrial cancer in which high expression of PXR was shown also showed significantly high expression of CYP3A4/7 and low expression of ER compared with levels of the substances in tissues in which low PXR expression was shown. As summarized in Table 2, HEC-1 cells, which express high PXR and low ER and PR, show a stronger transcriptional response of the PXR-CYP3A pathway to the PXR ligands, especially EDCs, than Ishikawa cells, which express low PXR and high ER and PR. These data suggest that the PXR-CYP3A pathway may play a role in the biology of endometrial cancer by affecting the intratumoral steroid metabolism and may be an alternative pathway for gonadal hormone and EDC effects specific to endometrial cancers expressing low ER.
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Acknowledgments |
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Footnotes |
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Abbreviations: CAT, Chloramphenicol acetyl transferase; CYP3A, cytochrome P-450 3A; DDT, dichlorodiphenyltrichloroethane; E2, 17ß-estradiol; EDC, endocrine-disrupting chemical; EIA, enzyme immunoassay; ER, estrogen receptor; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; P, progesterone; PR, P receptor; PXR, pregnane X receptor.
Received February 7, 2003.
Accepted May 29, 2003.
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