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Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, Colorado 80262
Address all correspondence and requests for reprints to: Bryan R. Haugen, M.D., Box B151, 4200 East Ninth Avenue, Denver, Colorado 80262. E-mail: bryan.haugen{at}uchsc.edu.
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Abstract |
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, -ß, -
and RXR, -ß, -) was measured in four human thyroid cell lines, and protein expression was subsequently measured in 10 thyroid cancer cell lines. Two isoforms, RARß and RXR, were differentially expressed in the four cell lines. Comparison of 10 thyroid tumors and matched normal thyroid tissue confirmed differential tumor expression of RARß and RXR and lack of the RXR isoform in normal thyroid tissue. Cell lines expressing both RARß and RXR demonstrated significant growth suppression when treated with retinoids, whereas cell lines lacking these isoforms were unaffected. Expression of RARß, the isoform associated with suppression of tumor growth in other cancer types, was not affected by treatment with retinoids in the thyroid cancer cell lines. LG346 increased apoptosis and decreased cells in the S-phase in an anaplastic carcinoma cell line, suggesting that this retinoid causes growth suppression of these cells by multiple mechanisms. In summary, we identified the RARß and RXR isoform to be differentially expressed in thyroid cancer cell lines and tumor tissue. These isoforms seem to predict response to retinoid therapy in thyroid cancer cell lines. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Retinoids influence cell growth and differentiation through retinoid receptors, retinoic acid (RAR) and retinoid X receptor (RXR). Six major subtypes of receptor have been identified, which are encoded by separate genes (RAR, -ß, - and RXR, -ß, -). In vitro studies have shown variable expression of mRNA and protein for the different receptors in thyroid cancer tissue and cell lines as well as variable responses to natural retinoids [all-trans retinoic acid (RA), 13-cis RA, and 9-cis RA] (10, 11, 12, 13, 14, 15, 16). In this study, we have measured mRNA expression of the retinoid receptors by quantitative RT-PCR in three thyroid cancer cell lines and one noncancer cell line. We further measured receptor protein expression in 10 thyroid cancer cell lines. We identified differential expression of two receptor isoforms, RARß and RXR, in the thyroid cell lines. We also demonstrated variable expression of the RARß and RXR isoforms in thyroid cancer, compared with matched normal tissue. Expression of these receptors seems to predict response to natural (9-cis RA) and synthetic [TTNPB ([E]-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)propen-1-yl]benzoic acid), LG346] retinoid ligands.
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Materials and Methods |
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Cells were grown in RPMI 1640 media (Invitrogen Life Technologies, Carlsbad, CA) with 2% fetal bovine serum (Hyclone, Logan, UT). 9-cis retinoic acid (9-cis RA) was obtained from Sigma Chemical Corp. (St. Louis, MO). TTNPB and LG 346 were provided by Ligand Pharmaceuticals (San Diego, CA).
Cell lines and tissues
DRO-90 (anaplastic), MRO-87 (follicular), WRO-82 (follicular), and NPA-87 (papillary) cell lines were kindly provided by Dr. G. J. Juillard [University of California Los Angeles (UCLA), Los Angeles, CA], and TAD-2 (fetal thyroid) cells were kindly provided by Dr. T. F. Davies (Mt. Sinai, New York, NY). The BHP papillary carcinoma cell lines (5–16, 2–7, 14–9, 7–13, 10–3, and 17–10) were kindly provided by Dr. J. M. Hershman (UCLA, Los Angeles, CA). The BHP cell lines were obtained from primary papillary thyroid carcinomas from six different patients.
Thyroid tumor tissues and products from fine-needle aspiration biopsy (FNAB) were obtained through the Cooperative Human Tissue Network and the University of Colorado Pathology Department. Institutional Review Board approval was obtained for the collection of tissues and FNAB.
Quantitative RT-PCR
Sense-strand RNAs were generated for each of the RAR and RXR isoforms to use as absolute standards for quantitative RT-PCR. Oligonucleotides to each corresponding human ligand-binding domain (LBD) were synthesized: RAR (sense 5'-CAGCTGGGCAAATACACTAC-3', antisense 5'-CCCTCTGAGTTCTCCAACAT-3'), RARß (sense 5'-GCCAGCTGGCTAAATACACC-3', antisense 5'-TTATTGCACGAGTGGTGACT-3'), RAR (sense 5'-CCAGCTGGGCAAGTATACCA-3', antisense 5'-CATTTCAGGGTTCTCCAGCA-3'), RXR (sense 5'-CGAACGACCCTGTCACCAA-3', antisense 5'-CCTCCAGCAT CTCCATAAG-3'), RXRß (sense 5'-GCCCAAATGACCCTGTGACT-3', antisense 5'-CCAGTTGATGGGGAGCCTCA-3'), RXR (sense 5'-CGACAAATGACCCTGTTACCA-3', antisense 5'-GGTGATCTGCAGCGGGGTCT-3'). RAR, -ß, and - sense-strand RNAs were generated from human cDNAs (kindly provided by Dr. R. Evans, Salk Institute, San Diego, CA). PCR was carried out with 1 ng plasmid DNA and 2.5 U Taq polymerase (Roche Molecular Biochemicals, Mannhein, Germany) at 94 C for 30 sec, 55 C for 30 sec and 72 C for 60 sec over 35 cycles. Amplified cDNAs were ligated into pCR 2.1 TA cloning vector (Invitrogen) and sequenced to verify fidelity of the PCR. Resultant cDNA was digested with EcoR1 and subcloned into pGEM7zf+ (Promega, Madison, WI). The insert orientation was verified by restriction enzyme digestion, and plasmids were linearized. cRNA for each LBD and generated using the MaxiScript kit (Ambion, Austin, TX) according to manufacturer’s instructions. RXR sense-strand RNAs were generated by RT-PCR using RNA from a human TSH-producing adenoma. Total RNA was obtained (TriReagent; Sigma Chemical Corp.), and 5 µg were reverse transcribed using random hexamers and AMV reverse transcriptase (Promega). The reverse transcription product was divided into four PCRs (RXR, RXRß, RXR, and glyceraldehyde-3-phosphate dehydrogenase), and PCR was carried out as described above except that the annealing temperature was 58 C. PCR products were initially ligated into pCR 2.1, sequenced, and subcloned into pGEM7zf+ for generation of LBD sense-strand RNA as described above for RAR.
Total RNA was prepared from cells or tissue using Tri Reagent (Sigma Chemical Corp.) according to the manufacturer’s recommendations. Quantitative RT-PCR (single-tube RT-PCR) was performed using an ABI PRISM 7700 Sequence detector [Perkin-Elmer Corp./Applied Biosystems (PE ABI), Foster City, CA] that allows continuous measurement of fluorescent spectra during amplification. The reactions were monitored in real time. Primers and probes for RXR, -ß, and - and RAR, -ß, and - were designed with the assistance of the Prism 7700 sequence detection software (Primer Express; PE ABI), and the sequences of the oligonucleotides used are shown in Table 1
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After amplification, real-time data acquisition and analysis were performed. The fluorescence data were expressed as Rn or 
Rn. Normalized reporter signal (Rn) is calculated by dividing the amount of reporter signal by the amount of passive reference signal. Rn represents the amount of normalized reporter signal minus the amount of reporter signal before PCR. The detection threshold was set above the mean baseline fluorescence determined from the first 15 cycles. Amplification reactions in which the fluorescence intensity increased above the threshold were defined as a positive reaction. Threshold cycle represents the PCR cycle at which an increase in reporter fluorescence above a baseline signal can first be detected. A standard curve was generated using the fluorescence data from the 10-fold serial dilutions of the corresponding control RNAs. This is then used to calculate the relative amounts of RXR, -ß, and - and RAR , -ß, and - in the test samples and then were normalized to the amount of 18s rRNA (PE ABI, P/N 4308310) in the sample.
Western blot analysis
Cells incubated under appropriate conditions were washed with ice-cold PBS. Nuclear protein extracts were prepared using a nuclear extraction kit (Active Motif, Carlsbad, CA). Nuclei were collected by exposing cells to hypotonic buffer, followed by centrifugation and lysis of nuclei according to the manufacturer’s instructions. Protein content of nuclear lysates was measured using a commercial protein assay kit (DC; Bio-Rad Laboratories, Hercules, CA). Diluted samples containing equal amounts of protein were mixed with 2 x Laemmli sample buffer. Proteins were separated on a 10% SDS-polyacrylamide gel and transferred to polyvinyl difluoride membranes. The membranes were blocked with Tris-buffered saline/Tween 20 [20 mM Tris-HCl (pH 7.6), 8.5% NaCl, and 0.1% Tween 20] containing 5% nonfat dry milk at room temperature for 2 h and incubated with the corresponding primary antibody (Santa Cruz Biotechnology, Inc., Santa Cruz, CA; for all receptors, except RXR, Lab Vision, Fremont, CA) in Tris-buffered saline/Tween 20 containing 5% milk at 4 C overnight. After washing, membranes were incubated with antirabbit IgG conjugated to peroxidase for 1 h at room temperature. The enhanced chemiluminescence (Amersham Pharmacia, Uppsala, Sweden) detection reagents were used for immunodetection.
Cell growth and proliferation
Cells were grown to approximately 70% confluence in 100-mm plates and then transferred into 60-mm plates (cell number) or 96-well plates (cell proliferation). The following day, media were aspirated and fresh media with vehicle or retinoid were added to each well. Media were changed every 3 d, adding fresh vehicle or retinoid. At the completion of each time point, cells were harvested for cell count or the 96-well plates were treated according to manufacturer’s instructions using the Cell Titer 96 aqueous nonradioactive cell proliferation assay (G5430; Promega). Briefly, cells were grown in 200 µl of media. On the day of the proliferation assay, media were removed, 100 µl of fresh media were added followed by 20 µl of the MTS/PMS solution. After a 2-h incubation at 37 C, each plate was analyzed for absorbance at 490 nM by a MRX Microplate Reader (Dynatech Laboratories, Chantilly, VA) using Revelation software.
Apoptosis
DRO cells were grown to approximately 70% confluence in 100-mm plates. Cells were subsequently transferred to a 6-well plate at a concentration of 150,000 cells/well, 50,000 cells/well, and 25,000 cells/well for the 1 d, 3 d, and 6 d time points, respectively. The next day the media were aspirated and fresh media were added containing vehicle [dimethylsulfoxide (DMSO)] or 1 µM LG 346. At each time point, media and adherent cells were collected and analyzed by flow cytometry using the Vybrant apoptosis assay kit 2 (Molecular Probes, Eugene, OR). Samples were prepared according to the manufacturer’s instructions.
Cell cycle analysis
Cells were grown in the absence or presence of LG346 or vehicle for 6 d in 60-mm plates as described above. Cells were harvested and rinsed twice in 1 ml cold PBS, fixed in 1 ml 70% ethanol overnight at 4 C, rinsed twice in cold PBS, and resuspended in saponin-propidium iodide (0.3% saponin, 25 µg/ml propidium iodide, 0.1 mM EDTA, 125 U/ml RNAase A in PBS). Flow cytometry for cell cycle analysis was performed by the University of Colorado Cancer Center Core Facility.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Quantitative RT-PCR was performed using sense-strand RNA corresponding to the LBD of each retinoid receptor isoform as a standard. Each specific cRNA standard was tested against all of the primer-probe sets to determine potential cross-reactivity (Table 2). No significant cross-reactivity was observed (the highest cross-reactivity measured was 0.017 pg using the RAR primer-probe set and 25 pg input RARß RNA, 0.07% cross-reactivity). One microgram of total RNA from each cell line was tested for RAR (Fig. 1A) and RXR (Fig. 1B) isoform expression. RAR and RAR isoform RNA was detectable and equivalent in each of the four thyroid cell lines (Fig. 1A). Expression of RARß mRNA was lower in all cell lines and barely detectable in MRO (3.5 ± 1.0 attg/ng rRNA) and WRO (6.2 ± 1.4 attg/ng rRNA) cells. RXR and RXRß isoform RNA was detectable in all four cell types, and both isoforms had lower expression in the DRO (anaplastic) cells. Surprisingly, RXR RNA was undetectable in TAD-2, MRO, and WRO cell lines but was highly expressed in DRO cells.
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isoforms in thyroid tumors and normal thyroid tissue
Because RARß and RXR mRNA were variably expressed in four different thyroid cell types, we examined expression of these two isoforms in total RNA from resected thyroid tumors and matched normal thyroid tissue. RARß was differentially expressed in all 10 normal thyroid tissues (Fig. 2A) but was lower in seven of eight malignant thyroid tumors when compared with matched normal tissue. Two benign adenomas expressed levels of RARß mRNA comparable with matched normal tissue. Decreased expression of RARß has been observed in other malignancies (17, 18, 19, 20).
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mRNA were very low in all normal thyroid tissue tested, but expression was higher in five of eight malignant thyroid tumors when compared with matched normal tissue (Fig. 2B
). Both benign thyroid adenomas had very low expression of RXR mRNA.
To corroborate the expression of RXR in a subset of human thyroid tumors and extend the observations of RXR mRNA levels in thyroid tissue to products of FNAB, RXR mRNA levels were measured on products from FNAB in 26 benign and 11 malignant thyroid nodules (provided by M. Sugawara, UCLA, Los Angeles, CA). Mean values were 12.5 ± 5.0 attg RXR mRNA/ng rRNA for benign nodules and 254.2 ± 107.8 attg RXR mRNA/ng rRNA for malignant nodules (Fig. 3). None of the benign nodules had RXR mRNA levels greater than 100 attg/ng rRNA and four of 11 malignant nodules (36%) expressed RXR mRNA levels greater than 300 attg/ng rRNA (approaching the level of expression in the DRO cell line). In clinical studies, 20–40% of patients with advanced thyroid cancer responded to retinoid therapy by redifferentiation or inhibited growth (2, 3, 4, 5, 6, 7, 21).
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To determine the effect of retinoids and receptor expression on cell growth in the thyroid cell lines, each cell line was treated for 7 d with the panreceptor (RAR and RXR) agonist 9-cis RA or vehicle (ethanol). Figure 4 shows the growth response of each cell line to 1 µM 9-cis RA at 1, 4, and 7 d of treatment. At d 4 and 7, DRO cells (expressing RXR) showed significant growth inhibition in response to 9-cis RA. The cell lines lacking RXR expression had either no growth response (MRO and WRO) or growth stimulation (TAD-2) in the presence of 9-cis RA when compared with vehicle control. The TAD-2 cells were the only cell line lacking RXR and expressing RARß protein, which may explain the unexpected growth response of this cell line to 9-cis RA.
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shows that T47D cells have significantly increased RARß mRNA levels in response to 1 µM 9-cis RA treatment. The MRO and WRO (retinoid-unresponsive) cells showed no increase in RARß mRNA. The DRO cells (retinoid-responsive) did not show increased RARß mRNA levels suggesting that up-regulation of RARß by retinoids is not a mechanism for growth suppression in this thyroid cancer cell line.
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To corroborate the relationship between RARß/RXR expression and response to treatment with retinoids, Western blot analysis was performed for all six retinoid receptor isoforms on nuclear protein extracts from 10 thyroid cancer cell lines representing anaplastic (DRO), papillary (BHP 5–16, 2–7, 14–9, 7–13, 10–3, 17–10, NPA) and follicular (WRO, MRO) thyroid carcinoma. All 10 cell lines expressed low levels of RAR and RXRß protein and high levels of RXR protein, indicating that these receptors are not differentially expressed in different thyroid cancer cell lines (Fig. 6). RAR was expressed in all 10 cell lines, but the level of expression was variable. The most striking pattern of receptor expression was the coexpression of RARß and RXR in some cell lines and the complete absence of these two receptors in other cell lines.
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protein expression was corroborated at the RNA level in these cell lines by quantitative RT-PCR (data not shown). Interestingly, RAR mRNA levels were high in all cell lines, suggesting that RNA and protein levels do not directly correlate for this retinoid receptor. Thyroid cell line proliferation in response to retinoid treatment
Thyroid cancer cell lines were treated with 1 µM of LG 346 (RXR-selective) or TTNPB (RAR-selective) for 6 d, and cell growth was measured by a proliferation assay. Figure 7 shows a clear relationship between RARß/RXR expression and growth suppression in response to the synthetic retinoids. Results from the proliferation assay were confirmed using standard cell count (data not shown). Levels of RAR protein (Fig. 6) was not associated with response to retinoid treatment. One cell line, NPA, did not respond to retinoid treatment yet expressed both RARß and RXR.
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shows a dose-response effect on suppression of cell proliferation in the cells. One hundred nanomoles of LG346 suppressed cell proliferation by 40 to 50% in these thyroid cancer cell lines.
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DRO and 5–16 cells were treated with 1 µM LG346 for 6 d, and apoptosis was measured by annexin staining. Figure 9A shows that LG 346 increased apoptosis in the DRO cells but not the 5–16 cells, suggesting different mechanisms of decreased cell proliferation in these two cancer cell lines. Figure 9B shows that the apoptotic effect of LG346 on the DRO cells was dose dependent.
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). The effects on cell cycle were modest but reproducible and significant.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) that are variably expressed in thyroid cancer cell lines and human thyroid tumors. Expression of these receptor isoforms seems to predict the response to 9-cis RA treatment. Moreover, an RXR-selective retinoid (LG346) and an RAR-selective retinoid (TTNPB) suppressed cell growth, suggesting that either liganded receptor is sufficient to mediate this response.
Retinoids seem to play a significant role in cancer chemoprevention and therapy (25, 26). The best model of retinoid therapy in cancer is acute promyelocytic leukemia (APL). Patients with APL respond to treatment with the natural retinoid all-trans RA (27, 28). The mechanism of response seems to be through a unique pathway involving a specific retinoid receptor, RAR (29, 30). In vitro treatment of breast and prostate cancer cells with all-trans RA also affects cell growth and may require RAR but not through the same mechanism as APL (31, 32, 33). All-trans RA selectively activates RAR, but this natural retinoid can be converted to 9-cis RA, which activates both receptor isoforms (RAR and RXR). Animal models of breast cancer demonstrate that 9-cis RA is an effective agent at prevention of breast cancer (34, 35). In the current study, four of the 10 thyroid cancer cell lines responded to retinoid treatment with suppression of growth. Indeed, clinical trials using 13-cis RA revealed that only 20–40% of patients with advanced thyroid cancer responded to retinoid therapy (3, 4, 5, 6, 7, 8, 9). There are four major types of follicular cell-derived thyroid cancer: papillary, follicular, Hurthle, and anaplastic. Clinical responses to 13-cis RA did not seem to be different in the various tumor types, although this therapy has not been tested in patients with anaplastic thyroid carcinoma. We have now shown that retinoid receptors are differentially expressed in different thyroid-derived cell lines and cancer subtypes. Retinoid receptor expression and not cancer subtype may therefore dictate tumor response to retinoid therapy.
Xu et al. (19) examined retinoid receptor expression in 31 patients with head and neck squamous cell carcinoma (HNSCC) by in situ hybridization. One receptor isoform, RARß, showed consistent decreased expression in HNSCC tissue when compared with normal tissue. The RXR isoform was not examined in this study. Decreased RARß expression has also been observed in patients with breast carcinoma and patients with premalignant oral lesions (17, 18, 20). The patients with premalignant oral lesions who were treated with 13-cis RA demonstrated increased expression of RARß, suggesting that this receptor isoform may play a role in tumor development and response to retinoid therapy (20). This effect has also been observed in cell culture experiments using HNSCC cells (36). Furthermore, in vitro experiments of RARß overexpression or down-regulation confirm that this receptor isoform is important in mediating growth suppression in these cancers (22, 24). In the present study, we measured expression of RARß before and after treatment with 9-cis RA in a retinoid-responsive and two retinoid-unresponsive cell lines. RARß mRNA levels did not change in any of the cell lines, suggesting that up-regulation of RARß is not a mechanism of growth suppression in thyroid carcinoma cell lines.
The first in vitro study of retinoids in thyroid cancer showed that a large dose of 13-cis RA (10 µM) inhibited cell growth and increased iodine uptake in a follicular carcinoma cell line (37). Multiple subsequent in vitro studies using 13-cis RA and all-trans RA demonstrated variable effects of these retinoids on thyroid cancer cell growth and markers of differentiation in many different cell lines (1, 10, 11, 12, 13, 16, 38, 39). In one study of a papillary thyroid carcinoma cell line, cell growth increased in the presence of all-trans RA (13). Taken together, these studies suggest that we need a better understanding of the effects of retinoid therapy in advanced thyroid cancer. In the current study, we evaluated retinoid receptor isoform expression in 11 thyroid cell lines to determine whether we could predict response to retinoid treatment. Two receptor isoforms, RARß and RXR, were identified as variably expressed in these cell lines. When we examined expression of these two isoforms in matched normal thyroid and tumor tissue, we observed that RARß expression is generally lower in thyroid cancer when compared with normal tissue. One previous study demonstrated decreased protein expression of RARß in papillary thyroid carcinoma, which is consistent with our observations (14). Another study did not detect significant decreased expression of RARß mRNA when compared with matched normal tissue (15). To our knowledge, this is the first demonstration of RXR mRNA and protein expression in thyroid cancer cell lines as well as mRNA expression in thyroid cancer tissue, compared with normal tissue. Schmutzler et al. (15) showed no RXR mRNA in four different thyroid carcinoma cell lines, but the oligonucleotides used were directed against mouse RXR. Our primer-probe set and positive control were designed specifically for human RXR, which may explain some of the observed differences. Our cell line and tumor tissue data suggest that RXR may play a role in the development of a subset of thyroid carcinomas, and this receptor may predict response to retinoid therapy. Indeed, we observed that the retinoid-responsive cell lines (DRO, BHP 5–16, BHP 14–9, BHP 17–10) were the only cell lines that expressed both RARß and RXR mRNA and protein.
In summary, we have identified a unique retinoid receptor expression in thyroid carcinoma cell lines and human thyroid tumor tissue. The RXR isoform is not expressed in normal thyroid tissue but is highly expressed in a subset of human thyroid carcinoma cell lines and tissues. Expression of RARß and RXR seems to predict response to natural retinoid (9-cis RA) and RXR-selective synthetic retinoid (LG346 or TTNPB) treatment in these cell lines. Mechanisms of action include increased apoptosis and decreased DNA synthesis (S phase of the cell cycle). Additional studies of these receptors in thyroid cancer cell lines, animal models, and clinical human studies will dissect mechanisms of RARß and RXR expression in human thyroid tumors, specific pathways in which retinoids affect these tumor cells, and serve as a molecular model to apply rational strategies of retinoid therapy for patients with advanced thyroid carcinoma.
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Acknowledgments |
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Footnotes |
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Abbreviations: APL, Acute promyelocytic leukemia; 9-cis RA, 9-cis retinoic acid; DMSO, dimethylsulfoxide; FBS, fetal bovine serum; FNAB, fine-needle aspiration biopsy; HNSCC, head and neck squamous cell carcinoma; LBD, ligand-binding domain; RA, retinoic acid; RAR, RA isoform; RXR, retinoid X receptor isoform.
Received April 30, 2003.
Accepted September 25, 2003.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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mRNA. Life Sci 53:1039–1048[CrossRef][Medline]
in acute promyelocytic leukemia cells. Cell 76:345–356[CrossRef][Medline]
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