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1Institute of Pathology and 2Department of Gynecology and Obstetrics, Charité Hospital, Berlin, Germany; 3Institute of Public Health–Epidemiology Unit, Technical University of Berlin, Germany; and 4Institute of Pathology, Martin-Luther University Halle-Wittenberg, Halle, Germany
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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ELAV-like proteins of the Hu family are involved in post-transcriptional regulation of mRNA turnover and mRNA stability. In 1998, two groups showed that HuR stabilizes mRNAs containing adenine- and uridine-rich elements in their 3' untranslated region, leading to a prolonged mRNA half-live and increased protein expression (3 , 4) . HuR proteins are mainly located in the nucleus but are able to translocate to the cytoplasm on activation. This suggests that HuR may serve as a nuclear shuttling protein and that the cellular distribution of Hu proteins between the nuclear and cytoplasmic compartment is central to their function and mRNA stabilizing activity.
One of the cellular transcripts containing an adenine- and uridine-rich element is the mRNA of cyclooxygenase-2 (COX-2; Ref. 5 ). The COX-2 enzyme catalyzes the conversion of arachidonic acid to prostaglandin H2. Physiologically, COX-2 expression is tightly regulated and is highly inducible by inflammatory stimuli (6) . In many malignant tumors, an increased expression of COX-2 has been described, which is related to poor prognosis. Several studies have shown that HuR binds to the COX-2 adenine- and uridine-rich element and stabilizes COX-2 mRNA, leading to increased expression of COX-2 protein (7, 8, 9, 10) . Therefore, overexpression of COX-2 in malignant tumors might be the result of a dysregulation of the function of Hu proteins. We have shown recently that COX-2 is expressed in a subset of human ovarian carcinomas and that it is an independent prognostic factor for patient survival (11) . In this study, we investigated the expression and cellular distribution of HuR in human ovarian carcinoma cell lines as well as in primary ovarian carcinomas and the effects of increased HuR levels on patient prognosis.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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PCR.
Subconfluent ovarian carcinoma cells were harvested, and total RNA was prepared with RNAeasy kit (Qiagen, Hilden, Germany) and reverse transcribed. PCR cycling conditions for HuR/HuB/HuC were 30 cycles of denaturation, annealing, and extension (95°C for 60 s, 55°C for 60 s, and 72°C for 60 s). For HuD, an annealing temperature of 60°C was used. The primers used were human HuR sense 5'-ATACAATGTCTAATGGTTATGAAGACC-3' and antisense 5'-GTTATTTGTGGGACTTG-3' (generating an 986 bp band; Ref. 4
), human HuB sense 5'-GTATCCAGGACCGCTAGCT-3' and antisense 5'-TATTAATTCCAGCCAAACTGG-3' (generating a 127 bp band; Ref. 16
), human HuC sense 5'-AACAACCCAAGTCAGAAGAC-3' and antisense 5'-TTGTACACGAAGATGCACCA-3' (generating a 235 bp band; 16
), human HuD sense 5'-CTGCTCTCCCAGCTCTA-3' and antisense 5'-AGGCTTGTCATTCCATC-3' (generating a 196 bp band; Ref. 17
), and glyceraldehydes 3-phosphate dehydrogenase sense 5'-ACCACAGTCCATGCCATCAC-3' and antisense 5'-TCCACCACCCTGTTGCTGTA-3' (generating a 452 bp band).
Immunoblotting.
Western blots were performed as described previously (11)
using a mouse monoclonal anti-HuR (1:1000; Santa Cruz Biotechnology, Santa Cruz, CA) or anti-ß-actin antibody (1:3000; Chemicon, Temecula, CA).
Confocal Microscopy.
Immunohistochemical staining was performed according to standard procedures. Cells were fixed in methanol for 10 min at 20°C. Slides were blocked in PBS/10% BSA/1% normal goat serum for 30 min at 21°C and were incubated for 90 min at 21°C with mouse monoclonal anti-HuR antibody diluted 1:100 in PBS/1% BSA, followed by incubation with a Cy3-conjugated antimouse antibody (Dianova, Hamburg, Germany) diluted 1:200 in PBS/1% BSA. Cell nuclei were stained with 4',6-diamidino-2-phenylindole (1:1000). Confocal laser scanning microscopy was performed using a Leica confocal microscope.
Study Population.
Immunohistochemical examination was performed retrospectively on tissue samples taken for routine diagnostic purposes. For determination of expression of HuR in benign and malignant ovarian tumors, 102 patients with ovarian lesions who were diagnosed at the Institute of Pathology, Charité Hospital, Berlin, Germany or at the Institute of Pathology, RWTH Aachen, Germany between 1989 and 2000 were included in the study. The cases were selected based on the availability of tissue and were not stratified for known preoperative or pathological prognostic factors. The tissue specimens included 83 primary invasive ovarian carcinomas, 16 borderline tumors, and 3 samples of normal ovaries. For additional statistical evaluation and survival analysis, only the patients with invasive ovarian carcinomas were included. The median follow-up time was 37 months. Seventy-seven patients (92.8%) were treated with extensive cytoreductive surgery. Data on intraoperative residual tumor were available for 34 patients with International Federation of Gynecologists and Obstetricians (FIGO) stage II-IV tumors. Of these patients 27 (79.4%) had a postoperative residual tumor of <2 cm. Data on postoperative chemotherapy were available for 61 patients (73.5%); of these patients, 48 (78.7%) received a platinum-based chemotherapy, 5 (8.2%) received other nonplatinum regimens, and 8 (13.1%) did not receive any chemotherapy.
Histopathological Examination.
Tissue samples were fixed in 4% neutral-buffered formaldehyde and embedded in paraffin. Routine H&E sections were performed for histopathological evaluation. The stage of tumors was assessed according to the International Federation of Gynecology and Obstetrics staging system and the Silverberg grading system (18)
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Immunohistochemistry.
Immunohistochemical staining was performed according to standard procedures as described previously for COX-2 (11)
. To evaluate the specificity of the COX-2 antibody (Cayman Chemical, Ann Arbor, MI), we performed additional blocking experiments with the COX-2-blocking peptide (Cayman Chemicals) according to the manufacturer’s instructions. For HuR immunohistochemistry, we used the monoclonal antihuman HuR antibody (3A2; 1:1000; Santa Cruz Biotechnology) with antigen retrieval in citrate buffer in a pressure cooker for 5 min. The intensity of the nuclear and cytoplasmic HuR immunostaining in tumor cells was evaluated independently by two pathologists (W. Weichert and C. Denkert), who were blinded to patient outcome, and scored semiquantitatively as HuR negative, weak, moderate, or strong. For statistical analysis, cases with a negative or weak expression of HuR were combined to one group (HuR negative), whereas cases with a moderate to strong expression were combined to a HuR-positive group. Subsequent statistical analysis was performed comparing positive and negative cases.
Statistical Analysis.
The statistical significance of the correlation between expression of HuR and several clinicopathological parameters as well as COX-1 or COX-2 was assessed by Fisher’s exact test, 
2 test, or 2 test for trends as indicated. The probability of overall survival as a function of time was determined by the Kaplan-Meier method and the log-rank test. Multivariate survival analysis was performed using the Cox regression model. Generally, P values smaller than 0.05 were considered as significant. For the statistical evaluation, the SPSS software version 10.0 was used (SPSS, Inc., Chicago, IL).
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, all cell lines expressed HuR mRNA. In contrast, there was only a weak expression of HuC in one cell line (A27/80), although neither HuB nor HuD was detected. This indicates that HuR is the main Hu protein expressed in ovarian carcinoma cell lines.
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. In OVCAR-3 (Fig. 1C)
and SKOV-3 (not shown) cells, HuR was predominantly expressed in the cell nucleus, as determined by confocal microscopy. Expression of HuR protein was further detected by immunoblot in tissue samples of eight human primary ovarian carcinomas as well as in one borderline tumor (Fig. 2)
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. The mean (median) overall survival time was 62.7 (47.7) months with a 95% confidence interval of 50.6 to 74.8 (35.4 to 62.0) months. Data on progression-free survival were available for 53 patients (64.0%). The mean (median) overall survival time was 38.9 (27.4) months with a 95% confidence interval of 30.1 to 47.7 (20.3 to 34.5) months. For determination of COX-2 and COX-1 immunoreactivity, a total of 78 cases had been investigated (11)
. The percentage of different tumor types and tumor stages was comparable with the samples investigated for HuR.
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. In the majority of the carcinomas, a nuclear immunoreactivity of HuR was observed. In addition, there was a subgroup of 45% of invasive carcinomas where a cytoplasmic expression of HuR was observed as well. On the basis of the hypothesis that the different localization of HuR might be related to a different functional activity, we evaluated both staining patterns separately. In addition to the staining of tumor cells, a nuclear expression of HuR in stromal fibroblasts was observed as well, which did not show any association with clinicopathological or prognostic parameters (not shown).
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. Although 81% of invasive ovarian carcinomas were positive for nuclear HuR, a nuclear reactivity was observed in only 56% of borderline tumors and in none of the normal ovaries. Similarly, cytoplasmic HuR expression was observed in 45% of invasive carcinomas but only in 13% of borderline tumors and in none of the normal ovaries (Table 2)
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. Expression of COX-2 had been determined in a previous study for 78 of the ovarian carcinomas (11)
. To evaluate the specificity of the COX-2 antibody, additional blocking experiments were performed. COX-2 immunoreactivity was completely blocked after preincubation with a COX-2 peptide (Fig. 3, E and F)
. We found a significant correlation between cytoplasmic HuR expression and expression of COX-2 (P = 0.025, Fisher’s exact test; Table 3
; Fig. 4A
). In contrast, there was no significant association between nuclear expression of HuR and COX-2 (data not shown).
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2 test for trends; Table 3
; Fig. 4B
). Because the Silverberg grading system used for classification of ovarian carcinomas is based on the three morphological parameters (nuclear polymorphism, mitotic rate, and growth pattern), we evaluated the association between cytoplasmic HuR expression and each of these parameters separately. There was a significant correlation between cytoplasmic HuR expression and mitotic rate (P = 0.002, 2 test for trends; Fig. 4C
), but no correlation between HuR and nuclear polymorphism or tumor growth pattern. No significant correlations were observed between other clinicopathological parameters and cytoplasmic HuR expression (Table 3)
or nuclear HuR expression (not shown).
Cytoplasmic HuR Expression Is a Prognostic Factor for Overall Survival and Progression-Free Survival in Univariate Kaplan-Meier Analysis.
As shown in Table 4
and Fig. 5
, an increased cytoplasmic expression of HuR was a negative prognostic factor for progression-free survival (P = 0.03) as well as for overall survival (P = 0.007). There was no prognostic effect of nuclear HuR expression. Other prognostic factors for progression-free survival in univariate analysis are shown in Table 4
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60 years (P = 0.02; Table 5
; Fig. 5
). For progression-free survival, cytoplasmic HuR expression was still a prognostic factor in the subgroup of patients with serous carcinomas (P = 0.03), FIGO stage III tumors (P = 0.04), and an age 60 years at the time of surgery (P = 0.01; Table 5
; Fig. 5
).
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. The intraoperative residual tumor, which was found to be a strong prognostic factor in univariate analysis, could not be included in this analysis because data on residual tumor was available only for a subset of cases. In our multivariate analysis, cytoplasmic expression of HuR was an independent prognostic parameter for reduced overall survival with a relative risk of 2.62 (95% confidence interval, 1.32–5.19). Other independent parameters were FIGO stage as well as patient age (Table 6)
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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On the basis of these data on the function of HuR, we systematically evaluated the cellular distribution of HuR in primary ovarian carcinomas and found an increased cytoplasmic expression of HuR in a subset of tumors. These tumors showed a significantly higher mitotic rate and were poorly differentiated. Patients with tumors that were positive for cytoplasmic HuR had a reduced progression-free and overall survival rate. Furthermore, expression of COX-2 was significantly increased in the cytoplasmic HuR-positive tumors. Our results suggest that there is a dysregulation of mRNA stability in a subset of invasive ovarian carcinomas and that this dysregulation may result in an increased proliferative rate, increased expression of COX-2, as well as reduced survival time.
To our knowledge, this is the first study investigating expression of HuR in ovarian carcinoma cell lines and showing that cytoplasmic HuR expression is an independent prognostic factor in malignant tumors. An up-regulation of HuR has been shown in highly malignant brain tumors such as glioblastoma multiforme and medulloblastoma (20) as well as in lung carcinoma cell lines (21) .
Other studies have shown that HuR is involved in regulation of mRNA stability of several targets, such as the angiogenic factor vascular endothelial growth factor; the proto-oncogene c-fos; the protein kinase C substrate MARCKS (22)
; and the cytokines interleukin-8, interleukin-6, transforming growth factor-ß, and tumor necrosis factor-
(20)
. These targets are products of immediate early genes that are involved in inflammation and stress response. Expression of HuR might be an important step in the adaptation of tumors to the tumor microenvironment and in the regulation of tumor-host interaction.
The cellular mechanisms responsible for the worst prognosis of tumors with an increased cytoplasmic expression of HuR are thus far unknown. Our statistical analysis, together with results from other authors, suggests a link between cytoplasmic overexpression of HuR and increased expression of COX-2. However, in the light of other studies, it is likely that HuR is also involved in regulation of mRNA stability of several other targets. This is supported by our analysis showing an association between HuR expression and increased mitotic rate. Because COX-2 expression is not correlated with mitotic activity, it is likely that another HuR target is involved, which is important for cell proliferation. Additional studies will be required to analyze the subset of mRNAs that is regulated by HuR in ovarian carcinoma.
It should be emphasized that the present study is a retrospective study with some limitations. In our study group, data on therapy as well as intraoperative residual tumor were retrospectively not available for all patients and could therefore not be included in the multivariate analysis. Additional large-scale prospective and retrospective studies are needed to investigate whether HuR expression is indeed of practical utility as a prognostic predictor.
Our investigations are focused on the role of HuR, because HuR is the only Hu protein that is known to be expressed in non-neural tissues. However, we cannot exclude that other members of the Hu protein family that are usually restricted to neural tissues may be ectopically expressed in some ovarian carcinomas and might be responsible for the dysregulation of mRNA stability. Because all human Hu proteins show a high similarity on the protein level, these neural Hu proteins might also be detected by the monoclonal anti-HuR antibody. A more exact determination of Hu isoforms will only be possible if more specific antibodies directed against single Hu protein isoforms become available.
Interestingly, we observed that cytoplasmic expression of HuR was a prognostic factor for patients that were <60 years of age at the time of diagnosis but not for patients >60. A similar relation had also been observed for the prognostic effect of COX-2. These results suggest that in younger patients, hormonal influences on ovarian carcinoma cells act together with an expression of HuR to worsen the prognosis. Neither the precise mechanisms nor the differences between ovarian carcinoma biology in younger and older patients are known thus far. It has been shown for HepG2 cells that the level and subcellular distribution of HuR is regulated by androgens (23) ; however, the regulation of HuR by other hormones has not yet been evaluated.
The determination of the immunoreactive pattern of HuR expression, in combination with other clinicopathological factors, may improve the prognostic evaluation of ovarian carcinoma patients and enhance the ability to identify individuals who are at high risk for poor survival.
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FOOTNOTES |
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Requests for reprints: Carsten Denkert, Institute of Pathology, Charité Hospital, Campus Mitte, Schumannstr. 20/21, D-10117 Berlin, Germany. Phone: 49-30-450-536047; Fax: 49-30-450-536900; E-mail: carsten.denkert{at}charite.de
Received 7/ 4/03. Revised 8/31/03. Accepted 9/23/03.
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