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[Cancer Research 60, 1348-1352, March 1, 2000]
© 2000 American Association for Cancer Research

Molecular Biology and Genetics

Prostate-specific Transcription Factor hPSE Is Translated Only in Normal Prostate Epithelial Cells

Masahiro Nozawa, Kentaro Yomogida, Nobufumi Kanno, Norio Nonomura, Tsuneharu Miki, Akihiko Okuyama, Yoshitake Nishimune and Masami Nozaki1

Department of Urology, Osaka University Medical School [M. Nozaw., N. K., N. N., T. M., A. O.] and Department of Science for Laboratory Animal Experimentation, Research Institute for Microbial Diseases [M. Nozaw., K. Y., Y. N., M. Nozak.], Osaka University, Osaka 565-0871, Japan


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
We recently cloned a novel transcription factor gene, hPSE, which belongs to the Ets gene family. hPSE mRNA was expressed specifically in prostate glandular epithelial cells and also in the human prostate carcinoma cell lines PC-3 and LNCaP. On the other hand, on immunoblot analysis with anti-hPSE antiserum, hPSE protein was detected only in human prostate tissue samples and not in PC-3 or LNCaP culture cells. Immunohistochemistry and in situ hybridization analysis revealed that hPSE protein was translated in normal prostate glandular epithelial cells, but not in carcinoma cells with hPSE transcripts. These findings suggest that expression of hPSE is regulated translationally in prostate epithelial cells and that hPSE protein is a candidate for a marker distinguishing normal cells from cancer cells in the prostate. It appeared that the 5'- and 3'-untranslated regions of hPSE transcripts might be necessary for translational control of hPSE, on the basis of results of transfection analysis in non-prostate lineage cells (HEK-293) using some deletion mutants of hPSE cDNA.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Prostate cancer is a significant health problem in advanced nations. It is the most common cancer diagnosed and is the second leading cause of cancer death among males in the United States (1) . Surgery is one of the most effective radical therapies for this disease. Currently, there is no curative therapy for advanced prostate cancer. On the other hand, it has been revealed by autopsy that as many as 73% of men over the age of 75 years have identifiable prostate carcinomas without clinical symptoms (2) . It is possible that some patients have clinically nonsignificant prostate cancer that has little effect on their lives. If this is true, surgery may be overtreatment for such patients, given its risk of postoperative incontinence and impotence. At present, there is no clinical marker that distinguishes those prostatic carcinomas that are potentially aggressive from those that are unlikely to cause advanced prostatic cancer (3) . Clarification of the molecular mechanisms of prostate carcinogenesis and of invasion and metastasis is an urgent task.

Alterations in normal control of cellular pathways that regulate cell growth and differentiation can lead to cancer. Dysregulation of transcription factor proto-oncogene expression results in the development of several neoplasias (4) . We recently cloned a novel Ets family gene, hPSE, from the PC-3 human prostate carcinoma cell line.2 Members of the Ets family are transcription factors involved in the transcriptional control of genes associated with development, angiogenesis, cell cycle control, and cell proliferation. All Ets family members contain a conserved DNA binding domain of about 85 amino acids that recognizes purine-rich sequences containing a GGAA/T core (5, 6, 7) . We have shown that hPSE mRNA expression is restricted to human prostate epithelial cells. hPSE might play an important role in differentiation and growth of prostate epithelial cells. hPSE mRNA expression is also observed in human prostate carcinoma cell lines. However, it is necessary to investigate hPSE expression at the protein level.

In this study, we demonstrated that hPSE transcripts were translated only in normal prostate glandular epithelial cells, and not in malignant ones. Furthermore, we showed that the 5'- and 3'-UTRs3 of hPSE transcripts are necessary for translational control of hPSE. Our findings suggest that the expression of hPSE is regulated translationally in prostate epithelium. Clarification of the regulation of hPSE expression may aid understanding of prostatic carcinogenesis.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Cell Lines and Tissue Samples
Human embryonic kidney epithelial cell line HEK-293 and human prostate carcinoma cell lines PC-3 and DU145 were grown in DMEM (Life Technologies, Inc., Grand Island, NY), and human prostate carcinoma cell line LNCaP was grown in RPMI 1640 (Life Technologies, Inc.) supplemented with 10% fetal bovine serum, 200 units/ml penicillin, 200 µg/ml streptomycin, and 0.5 µg/ml amphotericin B (Sigma, St. Louis, MO) at 37°C and 5% CO2.

Human prostate tissue samples were obtained through surgeries such as total cystectomy for bladder cancer, radical prostatectomy for prostate cancer, and retropubic prostatectomy or transurethral resection of the prostate for benign prostate hyperplasia.

Polyclonal Antiserum Preparation
The GST-fusion hPSE proteins were produced in Escherichia coli using the pGEX-2T vector system (Pharmacia, Piscataway, NJ). Polyclonal antisera were obtained by injection of the GST-fusion hPSE proteins into two New Zealand White rabbits. Antisera (anti-PSE1 and anti-PSE2) were reacted with the GST-fusion proteins and the T7-tagged protein (see "Constructs for hPSE Expression").

Immunoblot Analysis
Cultured cell lines on the dishes were collected in radioimmunoprecipitation buffer [10 mM Tris-HCl (pH 7.4), 150 mM NaCl, 1 mM EDTA, 1% NP40, 0.1% sodium deoxycholate, 0.1% SDS, 10 mg/ml aprotinin, 0.5 mM phenylmethylsulfonyl fluoride, and 1 mM DTT]. Human prostate tissue pieces were homogenized in radioimmunoprecipitation buffer, and the supernatant was collected by centrifugation. The supernatant was boiled in SDS/DTT buffer and separated by 10% SDS-PAGE. The proteins in the gel were transferred electrophoretically onto polyvinylidene difluoride membranes (Millipore, Saint Quentin en Yvelines, France). The membranes were blocked with 5% skimmed milk in TBS-T [50 mM Tris-HCl (pH 7.5), 150 mM NaCl, and 0.05% Tween 20]. Anti-PSE1 antiserum was used for detection of hPSE. After incubation with primary antibodies, the membranes were washed and incubated with peroxidase-conjugated antirabbit IgG antibodies (Jackson ImmunoResearch Laboratories, Inc., West Grove, PA). After extensive washing in TBS-T, reactive bands were detected by development with diaminobenzidine in 50 mM Tris-HCl (pH 7.5) plus 0.3% H2O2. For detection of the T7-tagged protein, we used an anti-T7 monoclonal antibody (CN Biosciences, Inc., Darmstadt, Germany) as a primary antibody and peroxidase-conjugated antimouse IgG antibody (Jackson ImmunoResearch Laboratories, Inc.) as a secondary antibody.

Immunohistochemistry
Human prostate tissue samples were frozen in OCT embedding compound (Tissue-Tek; Sakura Finetechnical Co., Ltd., Tokyo, Japan), and cryosections (7 µm) were placed on silane-coated slides (Matsunami Glass Inc., Ltd., Osaka, Japan). The sections were air-dried and fixed in 4% paraformaldehyde. Specimens were blocked with 2% normal donkey serum in PBS and incubated with anti-PSE1 antiserum (1:100 dilution) in PBS. The slides were rinsed with PBS and incubated with antirabbit immunoglobulin antibody conjugated with horseradish peroxidase (1:200; Jackson ImmunoResearch Laboratories, Inc.) in PBS. A positive reaction was detected by incubating with 3,3'-diaminobenzidine and counterstaining with 1% methyl green (Muto Pure Chemicals, Ltd., Tokyo, Japan).

Northern Blot Analysis
Total RNA was prepared from cultured cells and frozen tissue samples using the Trizol reagent (Life Technologies, Inc.). RNA (15 µg) was resolved on a 1% agarose gel containing 6.7% formaldehyde, transferred to a Zeta-probe blotting membrane (Bio-Rad Laboratories, Hercules, CA), and hybridized to a [{alpha}-32P]dCTP-labeled hPSE cDNA probe.

In Situ Hybridization
In situ hybridization was performed with the digoxigenin-labeled Riboprobe system (Boehringer Mannheim, Mannheim, Germany) as described previously (8 , 9) . hPSE probes were generated from a 1.0-kb EcoRI/BamHI fragment cloned into pBluescript II SK+. After hybridization, the bound probe was detected with anti-digoxigenin-Fab fragments conjugated with alkaline phosphatase (Boehringer Mannheim). Sections were counterstained with 1% methyl green (Muto Pure Chemicals, Ltd.).

Constructs for hPSE Expression
The T7-tagged hPSE protein was expressed in HEK-293 cells with the pPSE-T7 expression construct. pPSE-T7 was constructed by inserting the hPSE coding region and double T7 tag (MASMTGGQQMGAAMASMTGGQQMG) into pRCCMV (Invitrogen, Carlsbad, CA). pRCCMV-T7, which contained a double-T7 tag, was used as a control vector. We recently demonstrated transcriptional activity of hPSE with the expression vector.2 To examine control of the expression of hPSE, we prepared several expression constructs (Fig. 4A)Citation . We first subcloned a 5'-UTR-deleted clone (E17) and full-length hPSE cDNA into pSG5 (Stratagene, La Jolla, CA) as an expression vector (designated vectors g and f, respectively). The construct, designated construct d, contained only the coding region of hPSE, which was generated by PCR with primers 5'-GGGAATTCCAGCGGCATGGGCAGCGCCAGC-3' (forward) and 5'-CGGGATCCTCAGATGGGGTGCACGAACTGG-3' (reverse) with construct g as a template. The constructs consisting of the coding region with the full-length 5'-UTR or with the deleted 5'-UTR (192 bp), named constructs a and c, respectively, were generated by recombination of construct d with vector g or f, using the XhoI restriction site. Construct e was generated by recombination of construct d with vector f. Construct b was obtained by digestion of construct a with Tth111I restriction enzyme.



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  		Fig. 4. A, schema of constructs for transfection. Deletion mutants (a–f) of full-length hPSE cDNA (g) were prepared as described in "Materials and Methods." {square}, the ORF; {blacksquare}, the UTR. a, full-length 5'-UTR (413 bp) and the ORF. b, 360 bp of the deleted 5'-UTR and the ORF. c, 192 bp of the deleted 5'-UTR and the ORF. d, the ORF alone. e, the ORF and full-length 3'-UTR. f, 192 bp of the deleted 5'-UTR, the ORF, and full-length 3'-UTR. These constructs were subcloned into vector pSG5. The arrowhead indicates the position of the XhoI restriction site. B, expression of mutant mRNAs in transiently transfected HEK-293 cells. The intensity of each mRNA was nearly the same. C, immunoblot analysis using anti-PSE1 for hPSE protein expression 24 h after transfection. hPSE protein was expressed most strongly in HEK-293 cells transfected with the expression vector including construct c. MW, approximate molecular weight in thousands. D, evaluation of efficiency of translation by densitometry. The expression level against mRNA of hPSE in HEK-293 cells transfected with the expression vector including construct d was arbitrarily assigned a value of 100%. Each band density in the immunoblot was standardized with the level of mRNA expression in the Northern blot. Results represent the mean of four independent experiments. Bars, SD. a–g in B–D correspond to a–g in A.

 
Transfection Analysis
Cultured cells were transfected with each expression vector using LipofectAMINE Plus Reagent (Life Technologies, Inc.) according to the manufacturer’s recommendations. The levels of expression of mRNA and protein were evaluated with the Microcomputer Imaging Device MCID/mcid image analyzing system (Imaging Research Inc., St. Catharines, Ontario, Canada). The protein expression level was standardized with the mRNA expression level. All of the results shown in this study were obtained from at least four independent experiments.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Identification of hPSE Protein
To examine the expression of hPSE protein, we generated hPSE-specific antisera (anti-PSE1 and anti-PSE2) using the GST-fusion protein. Each antiserum detected the GST-fusion protein on immunoblot analysis (data not shown). To confirm the specificity of these antisera, the T7-tagged hPSE was expressed in HEK-293 cells with the pPSE-T7 expression construct. On immunoblot analysis, anti-PSE1 and anti-PSE2 recognized two protein bands (Mr 56,000 and Mr 47,000), which were identical to those detected by anti-T7 antibody, against total lysates of HEK-293 cells transfected with pPSE-T7 (Fig. 1, A and B)Citation . Each antiserum detected no band against total lysates of HEK-293 cells transfected with an expression vector containing only the T7 tag (Fig. 1B)Citation . These findings indicate that both anti-PSE1 and anti-PSE2 specifically recognize hPSE protein. Immunohistochemistry with anti-PSE1 demonstrated that hPSE protein was expressed in normal prostate epithelial cells, especially in the nuclei (Fig. 1, C and D)Citation . The localization of hPSE protein suggested that hPSE might be a prostate-specific transcription factor.



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  		Fig. 1. Identification of hPSE protein by anti-PSE1 antiserum. Immunoblot analysis using anti-T7 monoclonal antibody (A) and anti-PSE1 antiserum (B). Lanes represent lysates of HEK-293 cells transfected with pPSE-T7 (A and B, Lane 1) or the control vector pRCCMV-T7 (B, Lane 2). The T7-tagged hPSE protein was detected as a major band of approximately Mr 56,000 and as an additional minor band of approximately Mr 47,000 by anti-PSE1 antiserum and anti-T7 antibody. MW, approximate molecular weight in thousands. C and D, results of immunohistochemistry in a normal human prostate tissue specimen using preimmunized serum (C) or anti-PSE1 (D). hPSE protein is specifically expressed in prostate epithelial cells. C and D, x100 (bars, 100 µm).

 
hPSE Transcripts Were Not Translated in Human Prostate Carcinoma Cell Lines
hPSE mRNA was strongly expressed in human prostate carcinoma cell lines PC-3 and LNCaP (Fig. 2A)Citation . However, hPSE protein expression was detected in neither PC-3 nor LNCaP cells on immunoblot analysis (Fig. 2B)Citation . In another human prostate carcinoma cell line, DU145, hPSE expression was not detectable by Northern blot analysis or by immunoblot analysis (Fig. 2, A and B)Citation .



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  		Fig. 2. Expression of hPSE in human prostate carcinoma cell lines and human prostate tissue samples. A, Northern blot analysis. A 1.9-kb fragment was detected in both human prostate carcinoma cell lines and human prostate tissue samples, but not in DU145 cells. B, immunoblot analysis using anti-PSE1 antiserum. hPSE protein was detected in all human prostate tissue samples (Mr 39,000) but was not detected in any human prostate carcinoma cell line. Patients 1 and 2, pathologically benign prostate hyperplasias. Patients 3 and 4, poorly differentiated adenocarcinoma and moderately differentiated adenocarcinoma, respectively. Patients 5 and 6, normal human prostate tissues obtained from total cystectomy for bladder cancer. MW, approximate molecular weight in thousands.

 
hPSE Transcripts Were Translated Only in Normal Prostate Cells
To investigate the expression of hPSE mRNA and protein in human prostate tissues, we obtained specimens from 12 patients: (a) 5 transurethral resections and 3 retropubic prostatectomies from patients with benign prostate hyperplasia; (b) 2 normal prostate tissue samples from total cystectomies for bladder cancer; and (c) 2 clinically localized prostate cancer specimens from radical prostatectomies (pathologically, a moderately differentiated adenocarcinoma and a poorly differentiated adenocarcinoma). hPSE expression was observed at the levels of transcription and translation in all human prostate tissue samples (Fig. 2, A and B)Citation . We hypothesized that the efficacy of translation of hPSE was much lower in prostate cancer cells than in normal prostate epithelial cells, on the basis of the finding that hPSE protein was not detected in prostate carcinoma cell lines PC-3 and LNCaP. To test this hypothesis, we performed in situ hybridization and immunohistochemistry to check the expression of hPSE at the cellular level in human prostate tissues. In situ hybridization revealed that hPSE was specifically expressed in prostate epithelial cells in normal glands including those with hyperplasia (data not shown) and in cancer cells (Fig. 3, A and B)Citation . Immunohistochemistry demonstrated that hPSE protein was expressed only in normal prostate epithelial cells and not in prostate cancer cells (Fig. 3, C, D, G, and H).Citation These findings suggest that transcripts of hPSE are translated only in normal prostate epithelial cells.



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  		Fig. 3. Histological analysis of hPSE expression in prostate cancer tissues. A and B, in situ hybridization of poorly differentiated adenocarcinoma of the prostate with the antisense probe and sense probe, respectively. hPSE mRNA was expressed in prostate carcinoma cells. C and D, immunohistochemistry using anti-PSE1 antiserum. The same portion of tissue as shown for the in situ hybridization above (C) and the normal prostate glands of the same specimen (D) were used. hPSE protein was observed in the normal glandular cells, but not in the carcinoma cells. E, H&E staining of the same portion as shown in A. F, H&E staining of moderately differentiated adenocarcinoma of the prostate. The arrowheads indicate the carcinomatous portion. G and H, immunohistochemistry of the same portion as shown in F using anti-PSE1 antiserum. A, C–E, and H, x100. B, F, and G, x50 (bars, 100 µm).

 
Identification of the Region Controlling hPSE Translation
We found that hPSE protein was expressed only in normal prostate epithelial cells (Fig. 3, C, D, G, and H).Citation It is possible that the expression of hPSE is regulated at the translational level. To study the regions controlling translation of hPSE transcripts, we produced several deletion mutants, as indicated in Fig. 4ACitation , and transfected each of them into HEK-293 cells. Northern blot analysis revealed nearly equal levels of expression of mRNA of each mutant (Fig. 4B)Citation . However, the degree of expression of hPSE protein differed according to the length of the 5'-UTR and the presence of the 3'-UTR (Fig. 4, C and D)Citation . Deletion of 221 bp from the 5'-end of the 5'-UTR and deletion of the 3'-UTR significantly enhanced translation of hPSE, indicating that these portions might be concerned with the translational regulation of hPSE in prostate epithelial cells.


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
hPSE is a novel Ets family gene that is specifically transcribed in prostate epithelial cells. Ets family members are transcription factors that regulate the transcription of genes involved in development, differentiation, and cell proliferation (10 , 11) . Dysregulation of such genes should cause cancerous changes in normal cells. A relationship between Ets family genes and human cancer has been demonstrated for leukemias and solid tumors (5, 6, 7) . ETS2 has previously been reported as a member of the Ets family involved in prostate cancer (12 , 13) . ETS2 was shown to be expressed at elevated levels in prostate cancer (12) and was shown to be required for maintenance of the transformed state in prostate cancer cells (13) . In the present study, we demonstrated that transcripts of hPSE were translated only in normal prostate epithelial cells and not in prostate cancer cells. hPSE appears to play roles in determining the properties of normal prostate epithelial cells, given its specificity of expression. Interestingly, the expression of hPSE is suppressed at the translational level in PC-3 and LNCaP cells and at the transcriptional level in DU145 cells. It has been reported that DU145 and PC-3 cells are invasive, whereas LNCaP cells are not, as measured by migration through Matrigel-coated membranes (14) . There may be a correlation between the malignancy of prostate cancer cells and the level of regulation of hPSE expression.

Several genes containing Ets elements in their regulatory region are up-regulated in prostate cancer. For example, c-met, the receptor for hepatocyte growth factor/scatter factor, is regulated by Ets (15) , and the presence of met protein is associated with higher-grade adenocarcinomas (16) . Mitogenic signaling through the ErbB/neu receptor is mediated through Ets (17 , 18) , and elevated neu expression is associated with metastatic conversion of prostate cancer (19 , 20) . Maspin, a tumor-suppressing protease inhibitor that is expressed in normal prostate epithelial cells but not in prostate cancer cell lines, is also transcriptionally regulated by Ets (21) . Because the pattern of expression of hPSE protein is identical with that of maspin, hPSE might be involved in the regulation of transcription of maspin. hPSE may be a candidate for a negative maker of prostate cancer.

Our transfection analysis of HEK-293 cells with several expression constructs suggested that the 5'- and 3'-UTRs of hPSE transcripts should contain translational regulatory regions. A system that overcomes translational suppression should function in normal prostate epithelial cells. The process of translation can be divided into three distinct stages: (a) initiation; (b) elongation; and (c) termination (22 , 23) . The primary target for translational control is the initiation step. Control of translation initiation on individual mRNAs is determined primarily by the structural properties of the mRNA, particularly the 5'-UTR (24) . IREs are a well-characterized case in which the secondary structure located within the 5'-UTR plays a role in translational regulation. Ferritin mRNA contains an IRE in its 5'-UTR to which the IRE-binding protein binds when intracellular concentrations of iron are low and inhibits translation of ferritin mRNA (25) . It is becoming clear that 3'-UTRs of some mRNAs can play important roles in translation of these mRNAs. A domain within the pseudoknot in the 3'-UTR of the tobacco mosaic virus RNA regulates its translation (26 , 27) . A pyrimidine-rich motif in the 3'-UTR of 15-lipoxygenase mRNA interacts with a RNA-binding protein (28) . An AU-rich sequence within the 3'-UTR of human cytokine mRNA inhibits its translation (29) . The selenocysteine insertion sequence within the 3'-UTR of a number of eukaryotic mRNAs directs insertion of selenocysteine at in-frame UGA codons (30) . In addition, mammalian histone mRNAs terminate in stem-loop structures that are functionally similar to the poly(A) tail (31) . The direct molecular communication between the 5'- and 3'-ends of mRNAs is thought to play an important role in regulation of their translation. For example, mRNAs with base complementarity between the 5'- and 3'-UTRs and that form a stable secondary structure are translated poorly, if at all, in COS cells (32) . To our knowledge, there is no consensus motif in the 5'- and 3'-UTRs of hPSE cDNA.

In future, if we can express hPSE protein in prostatic cancer cells, these cancer cells might regain properties of normal prostate cells. Clarification of the mechanism of regulation of hPSE expression in prostate lineage cells will aid in understanding of human prostatic carcinogenesis and in developing new methods for the diagnosis and therapy of prostate cancer.


   ACKNOWLEDGMENTS
 
We thank Dr. Masaru Shin for advice on pathological examination.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom requests for reprints should be addressed, at Department of Science for Laboratory Animal Experimentation, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan. Phone: 81-6-6879-8338; Fax: 81-6-6879-8339; E-mail: mnozaki{at}biken.osaka-u.ac.jp Back

2 M. Nozaki, N. Kanno, N. Yamada, S. Amekawa, K. Yomogida, M. Nozawa, H. Miyamoto, T. Fujiwara, N. Nonomura, T. Miki, A. Okuyama, and Y. Nishimune. PSE: an Ets-related transcription factor is preferentially expressed in the human prostate epithelium, submitted for publication. Back

3 The abbreviations used are: UTR, untranslated region; GST, glutathione S-transferase; ORF, open reading frame; IRE, iron-responsive element. Back

Received 8/31/99. Accepted 12/28/99.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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