Japanese Journal of Clinical Oncology 32:233-237 (2002)
© 2002 Foundation for Promotion of Cancer Research
Expression of PTTG (Pituitary Tumor Transforming Gene) in Esophageal Cancer
Department of Surgery II, Nagoya City University Medical School, Nagoya, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Background: Recently, a vertebrate securin [pituitary tumor transforming gene (PTTG) in humans] has been identified that inhibits sister chromatid separation and is involved in malignant transformation and tumorigenesis. Abundance of this protein would disrupt cell division, generate chromosomal instability and thereby increase cell susceptibility to acquisition of further mutations during subsequent division. Esophageal cancer is a disease with poor prognosis with early local invasion and lymph node metastasis. It is important to identify factors that influence the aggressiveness of esophageal cancer.
Methods: Expression of PTTG messenger ribonucleic acid (mRNA) was evaluated by real-time reverse transcription polymerase chain reaction in 48 esophageal cancer specimens and matched normal esophageal mucosa. The data were analyzed with reference to clinicopathological factors.
Results: Tumor tissue expressed a significantly higher level of PTTG1 mRNA than the corresponding normal tissue (P < 0.0001). PTTG1 mRNA expression was significantly higher in tumors with higher pathological stage (IV vs 0–III, P = 0.0442) or more extensive lymph node metastasis (pathological N factor; N4 vs N0–3, P = 0.003). The median survival for patients with high PTTG1 expression (8.5 months) was less than that for patients with low PTTG1 expression (14.0 months, P = 0.039). PTTG1 expression was one of the significant predictors of survival on univariate analysis (hazard ratio 2.225; 95% confidence interval 1.007–4.915).
Conclusions: Detection of high PTTG1 expression in surgically excised esophagus tumor tissues might help to identify patients with aggressive disease who require adjuvant therapy and provide prognostic information.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Esophageal squamous cell carcinoma is one of the most common cancers worldwide. In Japan, it is the sixth most common cancer in males and the number of persons who die of this cancer has increased in recent years. Patients with this cancer generally have a poor prognosis, because most patients have advanced cancers at presentation. This is partially because of the lack of serous membrane on the outer surface of the esophagus, which permits esophageal cancer to invade rapidly into surrounding tissues (1,2). Recent molecular biological studies have clearly indicated that esophageal cancer is a disease caused by the accumulation of multiple genetic defects in dominant oncogenes and tumor suppressor genes, which are involved in various cellular processes such as cell cycle regulation, growth signal transduction and induction of apoptotic cell death (3). In addition, cytogenetic studies have shown that esophageal cancer frequently contains chromosomal abnormalities, as are also seen in most other cancers (4,5).
Aneuploidy represents a numerical imbalance in chromosomes caused by missegregation of chromosomes during cell division. Recent investigations have identified several genes involved in regulating mitotic targets, which are involved in the induction of aneuploidy in tumor cells. One of the critical events that ensures equal partitioning of chromosomes during mitosis is the proper and timely separation of sister chromatids that are attached to each other and to the mitotic spindle. Cohesion of sister chromatids is established during replication of chromosomes and is retained until the next metaphase/anaphase transition. It has been shown that during metaphase/anaphase transition, the anaphase promoting complex/cyclosome triggers the degradation of a group of proteins called securins that inhibit sister chromatid separation (6,7).
A vertebrate securin has recently been identified that inhibits sister chromatid separation and is involved in transformation and tumorigenesis (8). Subsequent analysis revealed that the human securin is identical with the product of the gene called pituitary tumor transforming gene (PTTG). PTTG1 shows very low or undetectable expression in most normal human tissues but is abundantly expressed in malignant cell lines and pituitary tumors (9–12). Pei and Melmed showed that overexpression of PTTG in mouse fibroblast cells, NIH 3T3, results in cellular transformation in vitro and promotes tumor formation in vivo (13). It is proposed that elevated expression of this PTTG gene may contribute to the generation of malignant tumors due to chromosome gain and loss produced by errors in chromatid separation (8).
In the present study we investigated human PTTG1 expression in 48 esophageal cancer specimens. We found that PTTG1 is overexpressed in tumors compared with normal esophageal mucosa and there was a significant correlation between the PTTG1 expression and the stage or lymph node metastasis of the tumor. The median survival for patients with high PTTG1 expression (8.5 months) was less than that for patients with low PTTG1 expression (14.0 months, P = 0.039).
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Patients and Specimens
Forty-eight patients with primary esophageal squamous cell carcinomas underwent resection at Nagoya City University Hospital from January 1996 to December 2000. Tumors were classified histologically using Japanese staging system of the Japanese Society for Esophageal Disease (14). All patients had a single tumor and no distant metastasis. None of the patients died of postoperative complications within 30 days. There were 36 males and 12 females and the mean age was 62.2 years (range: 46–80 years). There were two stage 0, five stage I, seven stage II, 18 stage III and 16 stage IV tumors.
cDNA Synthesis
Samples of the tumors and paired normal esophageal tissues were collected at resection and immediately frozen in liquid nitrogen. RNA was extracted using Trizol Reagent (Life Technologies, Tokyo, Japan), following the manufacturer’s recommendations.
Reverse transcription reactions contained 1 µg total RNA, 5xRT buffer, oligo(dT) primer, 30 U RNA guard RNase inhibitor (Pharmacia Biotech, Tokyo, Japan) and 200 U Superscript II reverse transcriptase (Life Technologies) in a final volume of 20 µl. RT reactions were carried at 42°C for 50 min and at 70°C for 15 min. Synthesized cDNA was adjusted to 100 ng/µl.
Real-time Reverse Transcription Polymerase Chain Reaction (RT-PCR) with the LightCycler
Real-time RT-PCR was performed with a single-step method using PTTG1-specific oligonucleotide primers, which were designed to recognize sequences in coding regions [corresponding to positions 77–202 of the PTTG1 mRNA (GenBank accession number AF095287); Table 1]. Fluorescent probes were designed to hybridize to the target sequence in a head-to-tail arrangement on the same strand of amplified product. The donor probe was labeled at the 3' end with fluorescence, while the acceptor probe was labeled at the 5' end with LC Red 640 and modified at the 3' end by phosphorylation to block extension. The gap between the 3' end of the donor probe and the 5' end of the acceptor probe was one base. To quantify and prove the integrity of isolated RNA, real-time RT-PCR analysis for glyceraldehydes-3-phosphate dehydrogenase (GAPDH) was carried out using hybridization probes and primers that generate a 118 bp fragment of GAPDH mRNA. Details of the primers and probes used in this study are summarized in Table 1. Hybridization probes were synthesized and purified by reversed-phase HPLC by Nihon Gene Research Laboratories (Sendai, Japan).
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PCR amplification using a LightCycler instrument (Roche, Mannheim, Germany) was carried out in 20 µl containing 2 µl of reaction mixture consisting of Taq DNA polymerase, dNTP mixture and buffer (LightCycler DNA Master hybridization probes, Roche), 4.0 mM MgCl2, 0.5 µM each of primers Sense and Anti-sense, 0.4 µl of acceptor probe, 0.8 µl of donor probe and 1 µl of template cDNA in a LightCycler capillary. For PTTG1 amplification, 95°C (30 s) for initial denaturation was followed by 50 rounds of amplification at 95°C (0 s) for denaturation, 60°C (10 s) for annealing and 72°C (6 s) for extension, with a temperature slope of 20°C/s performed in the LightCycler. Real-time RT-PCR monitoring was achieved by measuring the fluorescence signal at the end of the annealing phase for each cycle. For GAPDH amplification, the same temperature profile was used except for the annealing step, which was 55°C for 10 s. External standards for PTTG1 and GAPDH mRNA were prepared by the serial dilutions (1:1 to 1:512) of cDNA from TE8 esophageal carcinoma cell line. Each run consisted of 10 external standards, a negative control without a template and patients’ samples with unknown mRNA concentrations. Quantitation of mRNA in each sample was then performed automatically by reference to the standard curve constructed each time according to the LightCycler software.
Statistical Analysis
The relative mRNA expression levels (PTTG1/GAPDH) were calculated from quantified data. The statistical software package StatView 5.0 was used. The prevalence of PTTG1 mRNA expression in cancers and normal tissues was compared using Student’s paired t-test. Association between PTTG1 expression in tumors and various clinicopathological variables was examined using the Mann–Whitney U-test. A P value <0.05 indicated statistical significance.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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The Specificity of the Primer to PTTG1
The human PTTG family consists of at least three homologues. The PTTG1 gene consists of five exons and four introns, spans over 10 kb and has been localized 5q35.1. PTTG2 and PTTG3 are intronless genes and localized 4p15.1 and 8q13.1. The primers used were specific to PTTG1. We confirmed that PTTG1 was amplified only when cDNA was used as a template and not amplified when genomic DNA was used as a template. Representative data for PTTG1 mRNA expression with the aid of RT-PCR are shown in Fig. 1.
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Generation of LightCycler Standard Curve
Quantitation of messages by the LightCycler was assessed by determination of the crossover point (Ct), marking the cycle when fluorescence of a given sample rose above the background level to give the maximum slope by log-linear amplification. A standard curve was constructed by plotting the log number of the serially diluted samples prepared from TE8 cells against the respective Cts. PTTG1 mRNA values for patients samples with unknown concentration were calculated by reference to this calibration curve.
Correlation Between PTTG1 mRNA Expression and Clinicopathological Characteristics in Esophageal Cancer
Using real-time RT-PCR, we studied 48 esophageal tumor samples and paired normal epithelial tissues for mRNA expression of PTTG1. The relative level of PTTG1 mRNA expression was shown as the ratio of the mRNA of PTTG1 to that of GAPDH. Of the samples from 48 esophageal cancer patients studied, all tumor samples and paired normal samples expressed PTTG1 mRNA. Tumor tissue expressed a significantly higher level of PTTG1 mRNA than the corresponding normal tissue (0.105 ± 0.068 vs 0.048 ± 0.041, P < 0.0001, Student’s paired t-test; Fig. 2). Thirty-seven of 48 tumors expressed PTTG1 mRNA at a higher level than the corresponding normal tissue.
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We examined the relationship between PTTG1 expression in the cancer tissue and clinicopathological characteristics in esophageal cancer patients. There was no significant correlation between the PTTG1 mRNA expression and patients’ age at surgery, gender, histological subtype, lymphatic invasion or venous invasion. However, PTTG1 mRNA expression was significantly higher in tumors with higher pathological stage (IV vs 0–III, P = 0.0442) or more extensive lymph node metastasis (pN factor; N4 vs N0–3, P = 0.003) (Table 2).
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Kaplan–Meier curves for patients with esophageal cancer categorized according to PTTG1 expression are shown in Fig. 3. The patients were divided into two groups by the cutoff of 0.113 for PTTG1 expression relative to GAPDH. The median survival period for patients with high PTTG1 expression (8.5 months) was less than that for patients with low PTTG1 expression (Fig. 3, 14.0 months, P = 0.039, log-rank test). Using univariate analysis, PTTG1 expression (P = 0.0480), pathological stage (P < 0.0001), tumor factor (P = 0.0002), nodal factor (P = 0.0014) and vein invasion (P = 0.0344) were the significant predictors of survival of esophageal cancer patients (Table 3). However, using multivariate analysis, only stage was an independent prognostic factor (data not shown).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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It is now widely accepted that cancer results from the accumulation of mutation in the genes that directly control cell birth or cell death. It has been argued that an underlying genetic instability is required for generation of multiple mutations that lead to cancer (15,16). Alterations in chromosome number involve losses or gains of whole chromosomes (aneuploidy) and are found in nearly all major human tumor types, including esophageal cancer (4,5). Selective growth advantage may be acquired by the loss of the wild-type allele of tumor suppressor genes or an increase in the gene dosage of growth-promoting genes (6,7). We have previously provided direct evidence that chromosome instability (CIN) is a common feature in lung cancer cell lines in consistent association with the presence of aneuploidy (17).
Regarding possible mechanisms that might make cancer cells susceptible to CIN, there are a large number of potential targets (6). The finding that PTTG1 codes for a securin involved in regulating chromatid separation during cell division suggests that abundance of the protein product would disrupt cell division, generate chromosomal instability and thereby increase cell susceptibility to acquisition of further mutations during subsequent division (8). In this paper, we have reported that PTTG is highly expressed in esophageal cancer compared with normal mucosa, as reported in pituitary tumors and other neoplasms.
We also investigated the correlation between the PTTG1 expression and clinicopathological factors in esophageal cancer. Higher PTTG1 expression significantly correlated with pathological stage and lymph node metastasis. In colorectal cancer, Heaney et al. reported that high PTTG1 expression was correlated with extension to the bowel wall, metastasis, vascularity and Dukes’ staging (18). These findings suggested that PTTG1 may be a marker of invasive cancer including esophageal cancer.
Pei recently showed that PTTG binds to c-myc promoter near the transcription initiation site and activates c-myc transcription in transfected cells. These findings suggest that PTTG may act as a transcription activator and be involved in cellular transformation and tumorigenesis through activation of c-myc oncogene in the cancers without c-myc amplification (19). Furthermore, PTTG induces an angiogenesis, which is a key determinant and rate-limiting step in tumor progression and metastatic spread, through basic fibroblast growth factor. Poor prognosis in the patients with high PTTG mRNA expression may be due to an angiogenic phenotype in addition to the acquisition of chromosome instability (13,20).
The prognosis of esophageal cancer even after curative operation is poor. Several conventional chemotherapeutic agents have been tried, but the results are generally disappointing. We suggest that PTTG1 may be a marker of metastatic esophageal carcinoma and may be a prognostic marker. Detection of high PTTG1 expression in surgically excised esophagus tumor tissues might help to identify patients with aggressive disease who require adjuvant therapy.
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Acknowledgments |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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The authors thank Ms Makino for her excellent technical assistance. This work was supported in part by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science and Culture of Japan.
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FOOTNOTES |
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+ For reprints and all correspondence: Nobuhiro Haruki, Department of Surgery II, Nagoya City University Medical School, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. E-mail: haruki@med.nagoya-cu.ac.jp
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REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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1 Nishihira T, Hashimoto Y, Katayama M, Mori S, Kuroki T. Molecular and cellular features of esophageal cancer cells. J Cancer Res Clin Oncol 1993;119:441–9.[ISI][Medline]
2 Sugimachi K. Advances in the surgical treatment of oesophageal cancer. Br J Surg 1998;85:289–90.[ISI][Medline]
3 Montesano R, Hollstein M, Hainaut P. Genetic alterations in esophageal cancer and their relevance to etiology and pathogenesis: a review. Int J Cancer 1996;69:225–35.[ISI][Medline]
4 Watanabe M, Kuwano H, Tanaka S, Toh Y, Sadanaga N, Sugimachi K. Flow cytometric DNA analysis is useful in detecting multiple genetic alterations in squamous cell carcinoma of the esophagus. Cancer 1999;85:2322–8.[Medline]
5 Choma D, Daures JP, Quantin X, Pujol JL. Aneuploidy and prognosis of non-small-cell lung cancer: a meta-analysis of published data. Br J Cancer 2001;85:14–22.[ISI][Medline]
6 Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature 1998;396:643–9.[Medline]
7 Sen S. Current Opinion in Oncology, vol. 12. Houston: Lippincott Williams & Wilkins 2000.
8 Zou H, McGarry TJ, Bernal T, Kirschner MW. Identification of a vertebrate sister-chromatid separation inhibitor involved in transformation and tumorigenesis. Science 1999;285:418–22.
9 Dominguez A, Ramos-Morales F, Romero F, Rios RM, Dreyfus F, Tortolero M, et al. hpttg, a human homologue of rat pttg, is overexpressed in hematopoietic neoplasms. Evidence for a transcriptional activation function of hPTTG. Oncogene 1998;17:2187–93.[ISI][Medline]
10 Kakar SS. Molecular cloning, genomic organization and identification of the promoter for the human pituitary tumor transforming gene (PTTG). Gene 1999;240:317–24.[ISI][Medline]
11 Zhang X, Horwitz GA, Prezant TR, Valentini A, Nakashima M, Bronstein MD, et al. Structure, expression and function of human pituitary tumor-transforming gene (PTTG). Mol Endocrinol 1999;13:156–66.
12 Lee IA, Seong C, Choe IS. Cloning and expression of human cDNA encoding human homologue of pituitary tumor transforming gene. Biochem Mol Biol Int 1999;47:891–7.[Medline]
13 Pei L, Melmed S. Isolation and characterization of a pituitary tumor-transforming gene (PTTG). Mol Endocrinol 1997;11:433–41.
14 Japanese Society for Esophageal Diseases. Guidelines for the Clinical and Pathological Studies on Carcinoma of the Esophagus, 9th ed. Tokyo: Kanehara 1999.
15 Loeb LA. Mutator phenotype may be required for multistage carcinogenesis. Cancer Res 1991;51:3075–9.
16 Hartwell L. Defects in a cell cycle checkpoint may be responsible for the genomic instability of cancer cells. Cell 1992;71:543–6.[ISI][Medline]
17 Haruki N, Harano T, Masuda A, Kiyono T, Takahashi T, Tatematsu Y, et al. Persistent increase in chromosome instability in lung cancer: possible indirect involvement of p53 inactivation. Am J Pathol 2001;159:1345–52.
18 Heaney AP, Singson R, McCabe CJ, Nelson V, Nakashima M, Melmed S. Expression of pituitary-tumour transforming gene in colorectal tumours. Lancet 2000;355:716–9.[ISI][Medline]
19 Pei L. Identification of c-myc as a down-stream target for pituitary tumor-transforming gene. J Biol Chem 2001;276:8484–91.
20 Zetter BR. Angiogenesis and tumor metastasis. Annu Rev Med 1998;49:407–24.[ISI][Medline]
Received January 18, 2002; accepted April 1, 2002
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