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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-1522
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 1 322-327
Copyright © 2007 by The Endocrine Society

Thyroid Hormone Signaling in Human Ovarian Surface Epithelial Cells

M. T. Rae, O. Gubbay, A. Kostogiannou, D. Price, H. O. D. Critchley and S. G. Hillier

Centre for Reproductive Biology, The Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom

Address all correspondence and requests for reprints to: Stephen G. Hillier Ph.D., The Queen’s Medical Research Institute, Centre for Reproductive Biology, The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom. E-mail: s.hillier{at}ed.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Ovarian surface epithelial (OSE) cells express multiple nuclear hormone receptor genes, including those encoding thyroid hormone and estrogen receptors (TR and ER, respectively). Ovarian cancer is hormone-dependent, and epidemiological evidence links hyperthyroidism, inflammation of the ovarian surface, and increased risk of ovarian cancer.

Objective: The objective of this study was to assess T3 action on human OSE cells in vitro, asking 1) is there evidence for (pre)receptor control, 2) is T3 inflammatory, and 3) does T3 affect ER expression?

Design: Immunohistochemical analysis of fixed human ovaries and in vitro analysis of human OSE primary cell cultures were performed.

Patients: Twelve women aged 29–50 yr (median, 41 yr) undergoing elective gynecological surgery for nonmalignant conditions were studied.

Results: Messenger RNA transcripts for TR{alpha}1, TR{alpha}2, TRß1, and T3 activating deiodinase 2 and inactivating deiodinase 3 were present in primary OSE cell cultures by RT-PCR. TR{alpha} and TRß proteins were also localized to intact OSE by immunohistochemistry. Treatment of OSE cell cultures for 24 h with T3 caused dose-dependent mRNA expression of inflammation-associated genes: cyclooxygenase-2, matrix metalloproteinase-9, and 11ßhydroxysteroid dehydrogenase type 1, determined by quantitative RT-PCR. Finally, treatment with T3 dose dependently stimulated ER{alpha} mRNA expression without affecting ERß1 or ERß2.

Conclusion: The ovarian surface is a potential T3 target. T3 exerts direct inflammatory effects on OSE cell function in vitro. OSE cell responses to T3 include increased expression of ER{alpha} mRNA, which encodes the ER isoform most strongly associated with ovarian cancer. This could help explain suggested epidemiological links between hyperthyroidism and ovarian cancer.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
OVULATION IS A recurrent inflammatory reaction causing regular and frequent local injury to the ovarian surface during follicular rupture (1, 2). A majority of ovarian cancers are thought to arise from the ovarian surface epithelial (OSE) cell layer (3), possibly due to gene mutation caused by repeat episodes of inflammation-associated DNA damage (4, 5, 6). Suppression of ovulation by e.g. pregnancy, breast feeding, or oral contraception reduces the risk of ovarian cancer, whereas environmental factors and medical conditions such as talc use, endometriosis, ovarian cysts, and hyperthyroidism are associated with increased risk (7, 8).

A previous oligonucleotide microarray screen of normal OSE cells revealed multiple mRNA transcripts encoding nuclear hormone receptors of potential importance to the neoplastic process, including estrogen and thyroid hormone receptors (TR and ER, respectively) (9). The OSE cell layer is not an established thyroid hormone target, but considering the estrogen-dependent nature of ovarian cancer and its reported association with hyperthyroidism (8), the question arises: Does thyroid hormone signaling impact estrogen action on human OSE cells? We therefore set out to determine: 1) which TR proteins are expressed by human OSE cells and whether they also express T3 (in)activating deiodinase (DIO) enzymes, 2) whether T3 action on OSE cells is inflammatory, and 3) whether their exposure to T3 might affect ER expression. Inflammation-associated genes of interest were COX2 (encodes prostaglandin synthase-2, responsible for pro-inflammatory prostaglandin biosynthesis) (10), HSD11B1 [encodes 11ßhydroxysteroid dehydrogenase type 1 (11ßHSD1), responsible for anti-inflammatory cortisol regeneration in OSE cells] (11, 12, 13), and MMP9 [encodes matrix metalloproteinase (MMP)-9, endopeptidase involved in ovulation and implicated in tumor invasion and angiogenesis] (14). Finally, because ER{alpha} to ERß mRNA protein expression ratios are elevated in primary ovarian cancers (15, 16, 17), we determined the effect of T3 on relative expression of different ER isoforms in normal OSE cells.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Experimental subjects

Human OSE cells for culture (n = 9) or ovarian tissue for histology (n = 3) were obtained from 12 premenopausal women aged between 29 and 50 yr (median, 41 yr) undergoing surgery for nonmalignant gynecological conditions. Indications for surgery included fibroids, heavy menstruation, and pelvic pain. No subject had evidence of endometriosis. None were receiving medications that would have been likely to influence ovarian function. All had given informed consent, and the study had local ethics committee approval.

OSE cell culture

OSE cells were collected at laparotomy by gently scraping the ovarian surface with a sterile wooden spatula and rinsing it into sterile culture medium, as described previously (18). The primary cell culture system (see below) incorporates a 2–4-wk phase of cell propagation that offsets any in vivo context (e.g. age, hormonal status, or parity) that might be expected to influence cellular function in vitro (18). Primary OSE cell cultures were established in culture medium (OSE1) consisting of medium 199-MCDB105 (1:1 vol/vol) supplemented with fetal calf serum (10% vol/vol), streptomycin (50 µg/ml), penicillin (50 IU/ml), and L-glutamine (1 mM) (all from Sigma-Aldrich Company Ltd., Gillingham, Dorset, UK). Culture flasks (75 cm2, Corning B.V. Life Sciences, Schiphol-Rijk, The Netherlands) were incubated at 37 C in a humidified incubator under an atmosphere of 95% air and 5% CO2 for up to 28 d, with medium renewal every 7 d. Confluent cell monolayers were routinely obtained within 21 d. OSE cell purity was confirmed by immunocytochemical staining for cytokeratins 7, 8, 18, and 19, using a commercially available monoclonal antihuman cytokeratin antibody (Dako Corp., Glostrup, Denmark). The patient OSE cell populations studied consistently contained more than 90% epithelial cells, based on cytokeratin immunocytochemistry (18). OSE cell monolayers from individual patients were dispersed into single-cell suspensions by treatment with 0.05% (wt/vol) trypsin and 0.5 mM EDTA (Invitrogen Ltd., Paisley, Renfrewshire, UK) at 37 C for 5 min. Cell number and viability (75–95%) were determined using a hemocytometer and trypan blue dye (Sigma-Aldrich) exclusion after resuspension in fresh OSE1 culture medium. Four-milliliter portions of cell suspension (400,000 viable cells) were then distributed among six-well polystyrene culture plates (Corning) and incubated for 24 h at 37 C to allow cell attachment. OSE1 medium was then replaced with serum-free medium containing 0.01% wt/vol BSA (Sigma-Aldrich) (OSE2), and incubation continued for a further 24 h to allow adaptation to serum-free conditions. Test incubations were for 24 h at 37 C in fresh OSE2 with or without added T3 (Sigma-Aldrich). Genes of interest were maximally expressed within 24 h of exposure to T3. The T3 doses used were dictated by our aim to test normal (1 nM) and extreme (100 nM) degrees of thyroid hormone stimulation (19).

RNA extraction and analysis

Cell monolayers were lysed by removal of spent medium and addition of RNeasy lysis buffer (QIAGEN, Crawley, Sussex, UK). Lysates were then processed immediately as per the manufacturer’s protocols via RNeasy minispin columns, including on-column DNaseI treatment (QIAGEN). All specimens were subjected to microfluidic analysis (Agilent Bioanalyser 2100; Agilent Technologies, Palo Alto, CA) as a quality control step, and only intact, high-quality RNA (RIN > 8.5) was processed for downstream analyses.

The RT-PCR protocol (13) was based on RT of 2 µg total RNA with 35 PCR cycles. Complete PCR mix (Promega, Southampton, UK) was used in a total reaction volume of 50 µl, including 2 µl cDNA. TR primer sequences are given in Table 1Go. Annealing temperatures for TR{alpha}1, TR{alpha}2, TRß1, and TRß2 were 55, 57, 55, and 55 C, respectively, optimized on human liver total RNA (Ambion, Huntingdon, Cambs, UK) and in-house human placental mRNA. Prevalidated DIO primers obtained from SuperArray Bioscience Corporation (tebu-bio, Peterborough, Cambs, UK) were used according to the manufacturer’s instructions. PCR products were size-fractionated by agarose (1.5% wt/vol) gel electrophoresis, incorporating ethidium bromide (Sigma-Aldrich) staining to allow visualization under UV light.


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  		TABLE 1. Primer sequences used for RT-PCR analysis of TR isoforms

 
TaqMan quantitative real-time PCR (QRT-PCR) was carried out as before using previously described primer/probe sets [cyclooxygenase (COX) 2, 11ßHSD1] (9, 13) or preconfigured Assay-on-Demand primer/probe kits (MMP9, ERß1, ERß2, ER{alpha}) purchased from Applied Biosystems (Foster City, CA).

Detection and identification of MMPs

Constitutive (MMP2) and inflammation-associated (MMP9) protease activities in OSE cell culture medium were assessed by gelatin zymography (20). Spent culture medium (500 µl) was lyophilized and resuspended in 125 µl 0.01% (wt/vol) SDS. Ten-microliter portions of the concentrate were electrophoresed under native, nondenaturing conditions on a 7.5% (wt/vol) polyacrylamide gel containing 10% (wt/vol) gelatin as the protease substrate. The zymographic protocol, incorporating an 18-h incubation at 37 C in the digestion buffer, was as described previously (21). Gel images were captured using Quantity 1 software on a GS-700 scanning densitometer (Bio-Rad Laboratories Ltd, Hemel Hempstead, Herts, UK).

Immunohistochemistry

Ovarian tissue was fixed in 4% (vol/vol) paraformaldehyde, paraffin-embedded, and sectioned for double-antibody immunohistochemistry. Five-micron sections were dewaxed and rehydrated according to standard protocols and subjected to antigen retrieval by pressure cooking in 0.01 mM sodium citrate (pH 6) for 5 min. Endogenous peroxidase activity was blocked by immersion in 3% (vol/vol) hydrogen peroxide (Merck Chemicals Ltd., Poole, Dorset, UK) for 10 min at room temperature. Nonimmunized block was normal horse serum (Vectorstain, Vector Laboratories, Peterborough, UK) for 20 min at room temperature. Overnight incubation with primary antibody diluted 1:250 in normal horse serum at 4 C was followed by washes and secondary antibody detection as previously described (13). The primary antibodies were rabbit anti-TR{alpha} and anti-TR1 TRß1 (Abcam Ltd., Cambridge, UK). Negative controls were treated with nonimmune mouse IgG1.

Statistical analysis

Data were analyzed by one-way ANOVA and Tukey-Kramer test. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Presence of TR and DIO mRNAs in cultured OSE cells of individual patients

TR{alpha}1, TR{alpha}2, TRß1, DIO2, and DIO3 mRNAs were detected by RT-PCR in untreated OSE cell monolayers from five of five women (Fig. 1Go). None of the specimens measurably expressed DIO1 mRNA under assay conditions that readily detected DIO1 transcript in total RNA from positive control tissue (liver, placenta) (data not shown).


Figure 1
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  		FIG. 1. Presence of TR and DIO mRNA transcripts in human OSE cells. OSE cells were cultured for 2–3 wk, and total RNA was analyzed by RT-PCR for TR{alpha}1, TR{alpha}2, TRß1, DIO1, DIO2, and DIO3 mRNA. PCR was performed in the presence (RT+) and absence (RT–) of reverse transcriptase. Reaction products were size-fractionated by electrophoresis on a 1.5% (vol/vol) agarose gel containing 0.002% (vol/vol) ethidium bromide to allow UV visualization, as described in Subjects and Methods. Sample integrity and gel loading were ascertained by amplification of the housekeeping gene GAPDH. Panels show data for five patients (OSE 1–5). All were positive for TR{alpha}1, TR{alpha}2, TRß1, DIO2, and DIO3 but negative for DIO1 (not shown).

 
Detection of TR proteins in ovarian surface epithelium

Strongly positive, nuclear immunostaining of both TR{alpha} and TRß isoforms was detected in the surface epithelial cell layer of human ovary (Fig. 2Go). TRß but not TR{alpha} immunostaining was also evident in underlying ovarian stroma.


Figure 2
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  		FIG. 2. Expression of TR proteins in human OSE cells. Photomicrographs of 5-µ sections of human ovary immunostained with antisera to TR{alpha} and TRß1 receptor isoforms, as described in Subjects and Methods. A, TR{alpha} antiserum; B, TR{alpha} negative control (matched concentration of IgG); C, TRß1 antiserum; D, TRß1 negative control (matched concentration of IgG). Bar, Magnification. Note strong positive staining of the OSE cell layer (running from top right to bottom left) in A and C.

 
Effects of T3 on inflammation-associated gene expression in cultured OSE cells

Treatment of cultured OSE cells from three patients for 24 h with 100 nM T3 increased mean COX2, 11ßHSD1, and MMP9 mRNA levels between 2- and 6-fold relative to control (P < 0.05), as determined by QRT-PCR (Fig. 3Go, A–C). MMP9 mRNA was also significantly increased by 1 nM T3 (Fig. 3BGo). Zymographic analysis of protease activity in OSE culture medium confirmed a functional inflammatory response to thyroid hormone. Thus, both T3 doses induced appearance of MMP9 protease activity, whereas constitutive MMP2 activity was unaffected (Fig. 4Go).


Figure 3
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  		FIG. 3. T3 stimulates inflammation-associated gene expression in human OSE cells. Cultured OSE cells were treated with and without 1 or 100 nM T3 for 24 h, and total RNA was extracted for QRT-PCR analysis of target mRNA transcripts, as described in Subjects and Methods. A, COX2; B, MMP9; C, 11ßHSD1. Combined results from three experiments (three patients), with treatment response (mean ± SEM) expressed as fold-change relative to nonstimulated (0) control. *, P < 0.05.

 

Figure 4
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  		FIG. 4. T3 induces secretion of MMP9 protease activity by OSE cells. Cultured OSE cells were nontreated (control) or exposed to 1 and 100 nM T3 for 24 h. Spent culture media were analyzed by gelatin zymography, as described in Subjects and Methods, to detect and identify MMP9 and MMP2 protease activities. Arrows identify digested areas of the gel corresponding to MMP9 and MMP2, respectively. MMP9 was undetectable in control culture medium, but treatment with both T3 doses caused appearance of a gelatinolytic band corresponding to latent MMP9. Constitutive MMP2 activity was abundantly released both in the presence and absence of T3.

 
Effect of T3 on ER isoform expression in cultured OSE cells

T3 also increased ER{alpha} mRNA levels in OSE cultures, as determined by QRT-PCR (Fig. 5Go). Both 1 and 100 nM T3 stimulated ER{alpha} mRNA on average 3-fold relative to control (P < 0.05) without significantly affecting either ERß1 or ERß2.


Figure 5
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  		FIG. 5. T3 selectively enhances ER{alpha} gene expression in human OSE cells. Cultured OSE cells were treated with and without 1 and 100 nM T3 for 24 h, and total RNA was extracted for QRT-PCR analysis of ER isoform mRNA transcripts, as described in Subjects and Methods. A, ER{alpha}; B, ERß1; C, ERß2. Combined results from four experiments (three patients), with treatment response (mean ± SEM) expressed as fold-change relative to nonstimulated (0) control. *, P < 0.05.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We provide proof-of-concept that thyroid hormones participate in the hormonal regulation of the OSE in vitro and might thereby directly influence ovarian function in vivo. Ovulation failure is linked with severe hypothyroidism, and menstrual irregularities occur in both hypo- and hyperthyroidism (22). However, mechanisms by which thyroid hormones impact ovarian function remain poorly understood because they have such broad ranging effects throughout the body (23, 24). Direct action in or on ovarian follicles seems likely because free thyroid hormones are present in follicular fluid (25), and TR mRNA and proteins are expressed in granulosa cells, cumulus cells, and oocytes (26). Moreover, there is experimental evidence for modulation of gonadotropin action by T3 in porcine (27) and rodent (28) granulosa cell culture models. Here, we show that human OSE cells also possess thyroid hormone prereceptor control machinery and respond directly to T3 in vitro, thereby qualifying them as potential thyroid hormone targets in vivo.

We previously discovered by oligonucleotide microarray transcriptional profiling that TR{alpha} and TRß mRNAs are among the most strongly expressed nuclear hormone receptor genes in cultured human OSE cells (9). Here, we confirm presence of TR{alpha}1, TR{alpha}2, and TRß1 transcripts in cultured OSE cells and, importantly, demonstrate presence of TR{alpha} and TRß proteins in the OSE cell layer. Although TR{alpha} and ß isoforms are encoded by separate genes, differential promoter usage gives rise to two different TR{alpha} receptors, TR{alpha}1 and TR{alpha}2 (29). Unlike TR{alpha}1 and TRß1, which are conventional ligand-activated receptors, TR{alpha}2 (also called c-erbA{alpha}-2) is a ligand-independent negative regulator of active TRs. Thus, the presence of all three TR isoforms, in conjunction with the potential for prereceptor metabolism of thyroid hormones through expression of activating and inactivating DIOs, strengthens the likelihood that the OSE is a physiologically important thyroid hormone target tissue (9). Note, these results do not rule out potential for thyroid hormone signaling in OSE cells via rapid, nongenomic mechanisms not requiring the nucleus or binding to DNA (30).

Presence of DIO transcripts in OSE cells implies prereceptor metabolism is a feature of thyroid hormone action at the ovarian surface. The precise functional relevance of the DIO gene expression profile we report remains to be established. DIO1, not expressed by OSE, is expressed in liver, kidney, thyroid, and pituitary, where its classic function is to generate T3 from T4 (31). DIO2, now shown to be present in OSE, also activates T3 from T4 and was previously located to heart, skeletal muscle, placenta, fetal brain, and several regions of the adult brain. DIO3, also present in OSE, is the physiological inactivator of thyroid hormones, catalyzing deiodination of T3 to rT3 and T3 to T2 in thyroid hormone target tissues (32). Uterine endometrium and placenta were previously the only normal tissues known to express high levels of DIO3 activity in women (33). The absence of DIO1 implies DIO2 and DIO3 are the main enzymes involved in the maintenance of thyroid hormone homeostasis in OSE cells, which would be similar to the situation for human brain (34).

Our discovery that T3 stimulates expression of inflammation-associated genes in OSE cells is novel and has potential clinical relevance. The duration (24 h) and dose (1–100 nM) of T3 treatment used to achieve stimulation of COX2, MMP9, and 11ßHSD1 mRNA in OSE cells were very similar to those used by others to investigate target gene expression in human liver (35), skin (36), and fat (37) cells in vitro. These all produced evidence for inflammation-associated gene responses to T3, including fibrinogen and tissue plasminogen activator in a TR{alpha}-overexpressing hepatoma cell line (35); haptoglobin, orosomucoid, and interleukin in human skin fibroblasts (36); and lipopolysaccharide binding protein and lipopolysaccharide receptor in human adipocytes (37). Thus, the inflammatory mode of thyroid hormone action seems not to be confined to OSE cells and may have ramifications beyond reproductive health.

A further novel finding with likely clinical implications is that T3 strongly and selectively enhances expression of ER{alpha} without affecting ERß mRNA in OSE cells. Up-regulation of ER{alpha} by T3 was previously reported in the GH3 rat pituitary cell line (38), and T3 prevented estradiol-mediated 26S proteosomal degradation of ER{alpha} in a human pituitary cell line (39). Thus, there is emerging evidence for isoform-specific up-regulation of ER in thyroid hormone target cells in the pituitary gonadal axis. Most importantly, there is a growing appreciation that estrogens promote ovarian tumor development, growth, invasion, and metastasis via selective activation of ER{alpha} (40). Normal OSE cells express both ER{alpha} and ERß (9, 18, 41), but specific roles for individual ER isoform(s) at this site have yet to be assigned. However, ER{alpha} to ERß ratios are increased in ovarian tumors compared with normal OSE (15, 16), and use of ER{alpha}- and ERß-specific ligands with human ovarian cancer cell lines indicates that ER{alpha} activation is mainly responsible for estrogen-induced changes in gene expression. Thus, it has been suggested that estrogen-driven growth of epithelial ovarian carcinoma is mediated by activation of ER{alpha}-mediated, and not ERß-mediated, transcription (17).

Finally, these data suggest a mechanistic basis for the epidemiological evidence, indicating that a woman with hyperthyroidism has an 80% higher risk of developing ovarian cancer (8). Serial episodes of inflammation-associated injury and repair naturally undergone by the OSE during ovulation are thought to render these cells particularly susceptible to genetic damage and neoplastic progression (5) and thereby explain the established link between ovulation frequency and ovarian cancer risk (3, 7). Given the inflammatory mode of thyroid hormone action and associated up-regulation of ER{alpha} described here, it is evident how chronic hyperthyroidism might contribute to a smoldering, low-level form of inflammation that could make OSE cells more susceptible to neoplastic transformation and estrogen-driven tumor development (42). Challenges for the future are to identify the key cancer-related genes regulated by estrogen in normal OSE cells and to determine whether they are also affected by thyroid hormone status.

In conclusion, we present evidence that the OSE is a thyroid hormone responsive tissue, expressing genes involved in thyroid hormone prereceptor metabolism and reception in vitro. T3 activates expression of genes associated with inflammation, including COX2, MMP9, and HSD11B1. T3 also selectively enhances expression of ER{alpha}, encoding the ER isoform most strongly implicated in estrogen-mediated progression of epithelial ovarian cancers. These findings suggest a mechanism whereby thyroid hormone status might affect the inflammatory state and estrogenic sensitivity of the ovaries and thereby impact gynecological health and disease.


   Acknowledgments
 
We gratefully acknowledge the advice on statistical methods given by Dr. David Miller, helpful discussion on TR tissue effects with Dr. Geoff Beckett, and assistance with patient recruitment and consent for tissue collection provided by our clinical research nurse, Catherine Murray. We also acknowledge the gift of real-time PCR reagents for ER isoforms from Professor Philippa Saunders.


   Footnotes
 
This work was supported by the Medical Research Council Program (Grant G0500047) and by the European Commission Framework 5 Program (EURISKED EVK1-CT-2002-00128 to S.G.H.).

The authors have nothing to disclose.

First Published Online October 10, 2006

Abbreviations: COX, Cyclooxygenase; DIO, deiodinase; ER, estrogen receptor; 11ßHSD1, 11ßhydroxysteroid dehydrogenase type 1; MMP, matrix metalloproteinase; OSE, ovarian surface epithelial; QRT-PCR, quantitative real-time PCR; TR, thyroid hormone receptor.

Received July 13, 2006.

Accepted September 29, 2006.


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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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