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Section of Urology, Department of Surgery [H. L. K., D. J. V. G., X. Y., D. A. B., Z. D., B. A. Y., M. A. C., M. H. S., A. L., W. M. S., C. W. R-S.], Department of Health Studies [P. Z., T. K.], Department of Pathology [X. Y.], Section of Hematology/Oncology, Department of Medicine [W. M. S., C. W. R.-S.], The Ben May Institute for Cancer Research [A. L.], and The Genitourinary Oncology Research Program, The University of Chicago Comprehensive Cancer Research Center [X. Y., M. H. S., T. K., W. M. S., A. L., C. W. R-S.], The University of Chicago, Chicago, Illinois 60637; Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109 [M. A. R.]; and Department of Urology, Chiba University School of Medicine, Chiba, 263-8522 Japan [Y. I., T. I.]
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ABSTRACT |
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Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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Metastasis-suppressor genes have been shown to suppress the growth of metastases without affecting the growth of the primary tumor (11)
. Thus, these genes are distinct from tumor-suppressor genes, which suppress primary tumor growth. There is growing evidence that the loss of metastasis-suppressor gene function is an important event during the development of clinically significant metastases. Recently, we have identified the MAPK4
kinase 4/c-Jun NH2-terminal kinase-activating kinase/stress-activated protein/Erk kinase 1 (MKK4/JNKK1/SEK1, hereafter referred to as MKK4) as a metastasis-suppressor gene encoded by human chromosome 17p11.2 (12)
. Transfection of highly metastatic AT6.1 Dunning rat prostate cancer cells with MKK4 cDNA reduces the number of overt metastases by 
80% compared with parental AT6.1 cells and transfection controls, without affecting the growth rate of the primary tumors (12)
. On the basis of these studies, we hypothesized that inactivation of MKK4 or components of its signaling pathway is involved in human prostate cancer progression and metastasis.
To begin to test this hypothesis, we evaluated the expression of MKK4 and components of its signaling cascade in eight human prostate cancer cell lines, all originally derived from metastatic sites. Next, prostate cancer samples obtained from patients undergoing radical prostatectomy were assessed by immunohistochemistry for MKK4 expression. In the simplest scenario, if MKK4 inactivation plays a role in the development of metastasis, then the level of MKK4 expression in human prostate cancers should be decreased with increasing Gleason grade, an established predictor of metastatic propensity. Finally, to determine whether allelic loss might account for decreased expression of MKK4, 24 human metastatic prostate cancer samples were assessed for LOH using four polymorphic markers in the region of MKK4. The coding regions from selected samples with LOH were sequenced to determine whether MKK4 mutations might account for decreased protein expression.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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Immunoblotting.
Cell lines were grown to 80% confluence. Cell lysates were prepared in boiling lysis buffer (100 mM Tris 7.5, 1% SDS, and 100 mM NaVO4), and the protein was quantitated using bicinchoinic assay reduction (Pierce). Thirty µg of total protein from each cell line was subjected to SDS-PAGE (12.5% acrylamide) and transferred onto nitrocellulose membrane. The polyclonal antibodies (Santa Cruz Biotechnology, Inc.) and working dilutions used for immunoblotting were as follows: MKK4 (sc-964, 1:5000), MKK3 (sc-959, 1:10,000), MKK7 (sc-7104, 1:500), MEKK1 (sc-252, 1:1000), JNK1 (sc-571, 1:50,000), p38 (sc-7149, 1:10,000), and c-Jun (sc-1694, 1:5000); cytokeratins 5 and 8 were detected using an antimouse monoclonal antibody (sc-8021, 1:1000).
Membranes were then incubated with a horseradish peroxidase-conjugated IgG secondary antibody and detected using enhanced (Femto) chemilluminescence (Pierce). All of membranes were subsequently reprobed for actin as a loading control (Oncogene Research Products; CP01). Total protein lysates from ASPC-1 cells (30 µg), which have a homozygous deletion of MKK4, and rat brain (3 µg), which expresses high endogenous levels of MKK4, served as negative and positive controls, respectively. Mouse F9 teratocarcinoma cells, which have low endogenous levels of c-Jun, served as a negative control for c-Jun (14) . Blocking peptides to MKK3, MKK4, MKK7, and MEKK1 (sc-959P, sc-964P, sc-7104P, and sc-252P, respectively) antibodies were used according to the manufacturer’s instructions to confirm antibody specificity.
Selection of Human Specimens for Immunohistochemistry.
In accordance with a protocol approved by the University of Chicago Institutional Review Board, 69 prostate cancer patient specimens with Gleason patterns 3–5, obtained during radical prostatectomy, were identified from the Department of Pathology database. All of the patient information and linkers were unattainable. Thirty-seven of these patient specimens had multiple tumor loci totaling 112 lesions. The appropriate paraffin blocks, containing tumor and normal prostate tissue, were identified and cut at 5-µm thickness onto statically charged microscope slides for immunohistochemical staining.
Immunohistochemistry.
The slides were treated with xylene and rehydrated by sequential incubations in absolute ethanol, 95% ethanol, and water. After rehydration, the slides were placed in a citrate buffer solution (1.8 mM citric acid, 8.2 mM sodium citrate) at 95°C for 10 min. The slides were then fixed in acetone (5 min) and 0.2% picric acid/2% paraformaldehyde (10 min), and washed in a series of solutions: PBS; 85% ethanol/1.5% PVP; PBS/1.5% PVP; 85% ethanol/0.05% sodium borohydrate/1.5% PVP/PBS; PBS/1.5% PVP; and PBS/1.5% PVP/0.1% gelatin. Endogenous peroxidase was quenched with 3% hydrogen peroxide in methanol for 12 min. Endogenous avidin and biotin were blocked using the Vector Laboratories avidin/biotin blocking kit.
The slides are incubated overnight at 4°C with a primary polyclonal antibody (rabbit anti-MKK4/MEK4; Santa Cruz Biotechnology, Inc.) diluted to 5 µg/ml per manufacturer’s instructions in protein-blocking solution (PBS containing 5% horse serum and 1% goat serum). The slides were incubated for 3 h at 37°C with the secondary antibody (goat antirabbit biotin conjugated IgG; Santa Cruz Biotechnology, Inc.) diluted 3 µg/ml in protein-blocking solution. The regions of antibody binding were visualized using a 3,3'-diaminobenzidine (DAB) peroxidase substrate kit (Vector Laboratories). The slides were counterstained with Fast Green dye (Fisher Scientific).
Several different immunohistochemical controls were performed to verify the sensitivity and specificity of our detection system. ASPC-1 cells, which have a homozygous deletion of the MKK4 gene, were grown on Lab-tek chamber slides (Nalgene) and were used as a negative control, whereas MDA2b prostate cancer cells, which express MKK4 as detected by immunoblotting, were prepared in parallel and were used as a positive control. In addition, sections of normal tissues (e.g., human and rat testes, and human prostate) were used as positive controls. The specificity of the primary antibody used for immunohistochemistry was confirmed by: (a) immunoblotting; (b) the inclusion of isotype controls (using whole rabbit IgG in lieu of the primary antibody); and (c) epitope controls (using the primary antibody preincubated overnight with a 5-fold excess of the peptide; Santa Cruz Biotechnology, Inc.). These controls are summarized in (Table 1)
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To quantitate the staining of the tumor, a numerical scale of "0," "1," "2," and "3" was used, with "3" representing the staining intensity equivalent to the normal histological regions on the same slide and "0" representing no staining. Two independent pathologists (X.Y.) evaluated all of the samples. The average score was taken in the cases in which the scores assigned by the two examiners differed.
LOH Analysis and Mutation Screening.
The tissue samples used for the LOH analysis were collected during rapid autopsies performed on patients with metastatic prostate cancer,. courtesy of Dr. M. Rubin (University of Michigan, Ann Arbor, MI; Ref. 15
) and Dr. Tomo Ichikawa (Chiba University, Chiba, Japan). Metastatic lesions and the corresponding prostate tissue were sampled. Normal human and rat AT6.1 DNA were used as positive and negative controls, respectively. Primers to ß-actin were used to control for the quantity of loading and the integrity of the genomic DNA. PCR primers in the region of MKK4 (D17S954, D17S1303, D17S969, and D17S947) and p53 (D17S796 and D17S938) were purchased from Research Genetics.
Forward primer was end-labeled with (
-32P)dATP (3000 Ci/mmol; Amersham) using 10 units of T4 kinase. Template genomic DNA (50–100 ng) was amplified by PCR in 10 mM Tris-HCl, 1.5 mM MgCl2, 0.025 units/µl Taq DNA polymerase 100 nM each dNTP, 0.5 µM labeled forward primer, and 0.5 µM unlabeled reverse primer. The PCR conditions included an initial denaturation step at 95°C (5 min) followed by 25 cycles of amplification (1 min at 95°C, 1 min at 57°C, and 1 min at 72°C).
Amplified PCR products were diluted 1:1 with loading dye containing 90% formamide, 10 mM EDTA, 0.05% bromphenol blue, and 0.05% xylene cyanol. The diluted products were denatured at 95°C for 5 min, chilled on ice, separated on 7% polyacrylamide urea gel using electrophoresis at 40 watts, and visualized by autoradiography. Two samples with LOH at the D17S969 locus were further analyzed for specific mutations in MKK4. DNA sequencing and mutation screening were performed for exons B–K, as described by Teng et al. (13) .
Statistical Analysis.
Analysis of the association between MKK4 staining score and Gleason pattern was performed using the generalized estimating equations approach of Zeger and Liang (16)
. This method was necessary because many specimens included multiple regions that varied in Gleason pattern, along with their corresponding staining levels. The generalized estimating equations approach allows for potential correlation among the multiple measurements obtained from a single specimen. Mean staining levels and their SEs were derived based on an identity link function and assuming an exchangeable correlation structure for the "working" correlation matrix. The significance of differences among Gleason patterns was determined using Wald-type tests, in which the difference divided by its SE is referred to the tables of the standard normal distribution.
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Results and Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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; Refs. 17
, 18
). In response to extracellular stimuli, MEKK1 is a strong activator of MKK4 and MKK7, and a weaker activator of MKK3 and MKK6 (Fig. 1A
; Ref. 19
). The p38 signaling cascade includes: MKK3, MKK4, and MKK6 (Fig. 1A)
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. Rat brain and short term normal human prostate epithelial cultures were used as positive controls, and the ASPC-1 cells, which do not express MKK4 because of a homozygous deletion from D17S969 to exon C, served as a negative control. DU-145, Du-Pro, and PC-3 cells expressed undetectable levels of MKK4. In contrast, MKK4 expression in LNCaP, MDA PCa 2a and 2b, TsuPr1, and C4–2 cells was comparable with that of primary prostate epithelial cells (Fig. 1B)
. Additional studies were conducted to test the possibility that cell lines might have alterations in additional components of the MKK4 signaling cascade.
Examination of six well-established components of the MKK4 signaling module showed that all of the cell lines expressed levels of MEKK1, MKK3, MKK7, JNK1, and p38 similar to those in normal prostate epithelial cells. Representative data for JNK1 and p38 are shown in Fig. 1C
. Interestingly, the MDA PCa 2a and 2b cell lines, which were derived from bone metastases, were negative for c-Jun expression (Fig. 1C)
. In addition, C4–2, a derivative of the LNCaP cell line that is tumorigenic and metastatic in immunodeficient animals, showed a very low level of expression of c-Jun (Fig. 1C)
. F9 cells, which express low endogenous levels of c-Jun (14)
, were used as negative controls (data not shown). In summary, of the eight human prostate cell lines that we examined, six revealed a down-regulation of MKK4 or c-Jun expression, and only TSU-Pr1 and LNCaP expressed all of the major components of the JNK/SAPK signaling cascade. Additional support for a connection between the SAPK/JNK cascade and metastasis suppression comes from a recent paper by Mashimo et al., which demonstrated that the expression of KAI1, the prototypical prostate cancer metastasis suppressor gene, is controlled at the transcriptional level, in part, by c-Jun (20)
. Therefore, taken together, our findings are consistent with the hypothesis that the interruption of the JNK/SAPK signaling cascade is an important event in the development of prostate cancer metastases.
Immunohistochemical Analysis of MKK4 Expression in Human Prostate Cancer.
To test the potential role of MKK4 down-regulation in the progression of clinical human prostate disease, we examined MKK4 expression by immunohistochemistry in normal and cancerous prostate tissues obtained during radical prostatectomy. If decreased expression of MKK4 plays a role in metastasis, we predicted MKK4 expression will correlate with the Gleason pattern, a known marker of metastatic potential.
An immunohistochemical detection method was developed to assess MKK4 specific expression in normal and cancerous tissues (Table 1)
. Evaluation of 16 normal prostate samples revealed strong specific staining for MKK4 in 100% of the epithelial cells in all of the samples and no staining when whole rabbit IgG was used as a negative control (Fig. 2, A and B)
. Therefore, the normal glands contained within each slide of the prostate cancer samples were used as an internal positive control in assessing the tumor staining (Fig. 2, C and D)
. An adenocarcinoma with staining intensity equivalent to the normal glandular epithelia on the same slide was assigned a staining grade of "3" and complete absence of staining was assigned a staining grade of "0" (examples seen in Fig. 2, A and D
, tumor). The grade of the immunohistochemical staining was compared with the Gleason pattern of the tumor, which was assigned by a pathologist (X.Y.) with expertise in urological pathology. The Gleason grading system is the gold standard for histological analysis of prostatic adenocarcinoma in which, based on architectural patterns, a prostate tumor is assigned values between 1 and 5, with higher numbers representing more poorly differentiated and more aggressive tumors. In a clinical setting, because most prostate tumors are heterogeneous, each patient sample is assigned two separate Gleason patterns, corresponding to the two predominant histological patterns. The sum of these two Gleason patterns represents a Gleason score, ranging from 2–10. In clinical outcome studies, the Gleason score strongly correlates with the tumor stage, malignant progression, and clinical prognosis of men with prostate cancer (21)
. In our study, because we were interested in MKK4 expression at the cellular level, we focused on the Gleason pattern rather than the Gleason score.
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; Fig. 2, C and D
), supporting our hypothesis that diminished MKK4 expression would correlate with increased aggressiveness (e.g., Gleason pattern). A statistically significant, direct, inverse relationship between Gleason pattern and MKK4 expression was demonstrated. The mean staining intensities were: 1.76 (± 0.09), 1.35 (±0.10), and 0.73 (±0.16) for Gleason pattern 3, 4, and 5 lesions, respectively (Table 2)
. Our data demonstrated that, as the tumor pattern increased, mean MKK4 staining levels significantly decreased (P < 0.01). Furthermore, MKK4 expression remained the same or decreased as Gleason pattern increased in 36 of the 37 specimens that varied in grade.
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LOH Analysis of MKK4 Locus in Human Prostate Cancer Metastases.
The decrease in MKK4 expression in human prostate cancer may be due to allelic loss or mutations of the MKK4 gene. To assess this possibility, we conducted an LOH study using normal and metastatic prostate tumor samples from 24 patients; however, these samples were not amenable to immunohistochemical staining. Four polymorphic markers within the MKK4 locus were analyzed for LOH in normal and metastatic prostate tumor samples. Of the 16 specimens that were informative at the D17S969 locus, 5 samples (31%) had lost this marker, which is located within the MKK4 gene, 15,060 kbp from the p terminus. Markers distal to D17S969 (D17S954 14,007 kbp and D17S1303 14,074 kbp) and proximal to D17S969 (D17S947 16,186 kbp) were also analyzed. For D17S954, LOH was detected in 4 (40%) of 10 informative cases; for D17S1303 1 (33%) of 3 had LOH; for D17S947 2 (18%) of 11 had LOH. To exclude the possibility that the observed LOH reflected losses targeted to the nearby p53 gene, we also analyzed two markers within the p53 locus (D17S796 7,383 kbp and D17S938 7,584 kbp). In one case, LOH was restricted to the MKK4 region and did not involve the distal p53 gene.
Sequencing MKK4 exons B–K of the sample with LOH restricted to the D17S969 locus, as well as an additional case with more extensive LOH on chromosome 17, did not reveal any coding region mutations. These results suggest that the decreased expression of MKK4 in prostate cancer is not attributable to allelic loss or mutations of the MKK4 coding region. This finding is in agreement with previous studies of MKK4 and the known biology of other metastasis-suppressor genes, which are infrequently mutated (12 , 13 , 23) .
The data from the current study support a role for the inactivation of MKK4 and its signaling cascade in the development of human prostate cancer metastases. In sum, we demonstrated that MKK4 or c-Jun, one of its signaling partners, was down-regulated in six of eight human prostate cancer cell lines, which were all derived from metastatic lesions. Because of the paucity of spontaneously immortalized human prostate primary tumor cell lines, this initial study focused on cell lines derived from metastatic lesions.
Our finding that MKK4 expression in primary prostate cancer correlates inversely with Gleason pattern supports the clinical relevance of this observation. Ongoing studies are designed to define the mechanism of MKK4 inactivation in clinical specimens, including testing the kinase activity of MKK4, which may be a more relevant measure, and testing the prognostic and clinical implications of abnormalities in the stress-signaling cascade in human prostate cancer.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by American Cancer Society Institutional Grant, IGR41-35-3, NIH P20 CA 66132, University of Chicago Surgery Research Committee Grant; Cancer Research Foundation Young Investigator Award and NIH First Award R29 CA69487 02 (to C. W. R-S.); National Cancer Institute (NCI)/NIH Predoctoral Cancer Biology Training Grant (to D. J. V. G.); American Foundation for Urologic Disease (to B. A. Y., C. W. R-S.); The University of Chicago RESCUE Fund (to B. A. Y., Z. D., M. A. C.); Grant-in-Aid for Scientific Research 11207029 from the Japan Society for the Promotion of Science (to Y. I., T. I.); American Cancer Society RPG-99-171-01-CCG, Department of Defense, PC991167, NIH CA73740 (to A. L.); University of Chicago Cancer Research Center-Cancer Center Support Grant, NCI 5P30 CA14599-27 (to T. K.); and Specialized Program for Research Excellence in Prostate Cancer (SPORE), NCI Grant CA69568 (to M. A. R.). 
2 H. L. K. and D. J. V. G. contributed equally to this work.
3 To whom requests for reprints should be addressed, at The University of Chicago, Department of Surgery, Section of Urology, 5841 South Maryland MC6038, Chicago, IL 60637. Phone: (773) 702-3140; Fax: (773) 702-1001; E-mail: crinker{at}surgery.bsd.uchicago.edu
4 The abbreviations used are: MAP, mitogen-activated protein; MAPK, MAP kinase; MKK4, MAPK kinase 4; LOH, loss of heterozygosity; BRFF, Biological Research Faculty and Facility; PVP, polyvinyl pyrrolidine; ERK, extracellular signal-regulated protein kinase; JNK, c-Jun NH2-terminal protein kinase; SAPK, stress-activated protein kinase; MEK, MAP/ERK kinase; MEKK, MEK kinase.
Received 12/15/00. Accepted 2/ 8/01.
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