Japanese Journal of Clinical Oncology 33:173-179 (2003)
© 2003 Foundation for Promotion of Cancer Research
Prognostic Significance of p53, nm23, PCNA and c-erbB-2 in Gastric Cancer
1 Department of Surgery and 2 Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, 3 Department of Surgery, Inje University College of Medicine, Seoul and 4 Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTREFERENCES |
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Background: Although the TNM stage is the most important prognostic factor for gastric cancer, there is a need for new prognostic and predictive factors, because the prognosis varies among patients of the same stage. The purpose of this study was to clarify the relationship of p53, nm23, proliferating cell nuclear antigen (PCNA) and c-erbB-2 with the clinicopathological parameters and the survival results.
Methods: For 841 patients who had undergone gastrectomy for gastric cancer at Seoul National University Hospital from July 1996 to December 1997, the expression levels of p53, nm23, PCNA and c-erbB-2 in gastric cancer tissues were examined immunohistochemically. Also, the clinicopathological parameters such as gender, age, operation type, TNM stage and size of the tumor, histology and Lauren classification were analyzed retrospectively.
Results: There were 568 males and 273 females (2.07:1) with a mean age of 56 years (range:25–82 years). The percentages of positive expression of p53, nm23 and c-erbB-2 were 43, 74 and 17%, respectively; 59% of tumors expressed PCNA index ≥50. p53 expression was associated with age, gender, tumor size, histology, Lauren classification, stage, nm23 expression, PCNA index ≥50 and c-erbB-2 expression. nm23 expression was associated with age, tumor size, Borrmann type, histology, Lauren classification and stage. PCNA index ≥50 was associated with age, gender, tumor size, Borrmann type, histology, Lauren classification and c-erbB-2 expression. c-erbB-2 expression was associated with gender, Borrmann type, histology and Lauren classification. p53 and nm23 were related with poor prognosis in univariate analysis. nm23 was related with poor prognosis of stage III and diffuse-type gastric cancer in univariate subgroup analysis. However, in a multivariate study, these prognostic impacts were not maintained.
Conclusion: The expression of p53 and nm23 seems to be related with poor prognosis of gastric cancer patients who have undergone gastrectomy. However, the prognostic significance was not revealed by a multivariate analysis.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTREFERENCES |
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Although the incidence of gastric cancer is decreasing worldwide, it is still the second in cancer-related mortality next to lung cancer (1). In Korea, where the incidence rate of gastric cancer is high, it is the most common cancer and the second leading cause of cancer-related death (2,3). It is essential to predict precisely the risk of recurrence in order to minimize adverse effects and to maximize the therapeutic effect in the treatment of cancer patients. Among the prognostic factors now available for gastric cancer, the most important factor is UICC TNM stage determined by the depth of invasion, the involvement of the lymph nodes and distant metastasis. However, in fact, the prognosis varies among patients of the same stage, hence it is necessary to have new prognostic and predictive factors other than the TNM stage.
The advances in molecular biology have transformed clinical oncology with respect to the prevention, diagnosis and treatment of cancer. Oncogenes and tumor-suppressor genes, growth factors and their receptors, adhesion molecules and angiogenic molecules have been studied in relation to tumor genesis, growth, invasion and metastasis. Many studies are directed towards the development of new prognostic factors with these molecular markers. There are several methods for detecting molecular alterations in cancer, including DNA sequencing, polymerase chain reaction (PCR), immunoblot and immunohistochemistry. Immunohistochemistry can be applied to relatively small specimens, is simple and fast and is consistent with other methodologies. Therefore, the immunohistochemistry method has been widely used for searching for molecular markers of cancer.
In this study, the relationships of the immunohistochemical expressions of p53, nm23, proliferating cell nuclear antigen (PCNA) and c-erbB-2 in gastric cancer specimens with clinicopathological parameters and survival were studied in gastric cancer patients who had undergone gastrectomy.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTREFERENCES |
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Patients
Retrospective analysis was performed on gastric cancer patients who had undergone gastrectomy from July 1996 to December 1997 in Seoul National University Hospital. Gastric cancer specimens were stained immunohistochemically after operation with routine histological examination. Age, gender, operation, tumor size, gross morphology of tumor, histological classification, UICC TNM stage and Lauren’s classification were reviewed. The end-point of the follow-up was May 2002 and median follow-up period was 54.8 months.
Methods
Immunohistochemistry
The sections were deparaffinized in xylene. After hydration, the sections were microwaved twice in 10 mM citrate (pH 6.0) for 5 min and washed three times in distilled water for 5 min. The sections were placed in 3% H2O2 for 10 min to inhibit the endogenous peroxide activity, washed three times with phosphate-buffered saline (PBS) buffer for 5 min and placed in normal horse serum as blocking antibody at room temperature for 30 min.
The primary antibodies used were Do-7 (Dako Diagnostica, Hamburg, Germany, 1:100) for p53, NCL-nm23 (Novocastra Laboratories, Newcastle, UK, 1:100) for nm23, PC10 (Dako Diagnostica, 1:100) for PCNA and NCL-CB11 (Novocastra Laboratories, 1:40) for c-erbB-2. After incubation at 4°C for 24 h, sections were washed three times with PBS buffer for 5 min. Biotinylated anti-mouse immunoglobulin was used as the second antibody. 3,3-Diaminobenzidine tetrahydrochloride (DAB) was used as a chromogen. The sections were counter-stained with hematoxylin.
All slices were evaluated without knowledge of the clinical outcome. Sections were considered positive for p53 when more than 15% of tumor cells were stained by p53. Sections were considered positive for nm23 when more than 30% of tumor cells were stained moderately or strongly in the cell cytoplasm. PCNA index was determined by the percentage of the cells positively stained by PCNA in the nucleus. Sections were considered positive for c-erbB-2 when cells were stained diffusely in the cell membranes (Fig. 1).
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Statistical Analysis
The SPSS 10.0 program for Windows was used for statistical analysis. The chi-squared test was used to compare the immunohistochemical staining and the clinicopathological parameters. Survival was compared by the Kaplan–Meier log-rank test. Multivariate analysis was performed with Cox regression analysis. P values <0.05 were considered significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTREFERENCES |
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General Considerations
The mean age of the patients was 56 years, ranging from 25 to 82 years. There were 568 males and 273 females (2.07:1). Regarding operation method, there were 225 (26.8%) total gastrectomies, 31 (3.7%) extended total gastrectomies, 579 (68.8%) subtotal gastrectomies, six (0.7%) proximal gastrectomies and three (0.4%) wedge resections. There were 289 (34.4%) early gastric cancers and 552 (65.6%) advanced gastric cancers. According to the Borrmann gross classification, 17 (3.1%) were type I, 108 (19.6%) type II, 365 (66.1%) type III and 62 (11.2%) type IV. The mean size of the tumors was 4.87 cm, ranging from 0.2 to 20 cm. According to the UICC (1997) TNM classification, there were 269 (32.0%) stage Ia, 149 (17.7%) stage Ib, 162 (19.3%) stage II, 121 (14.4%) stage IIIa, 72 (8.6%) stage IIIb and 68 (8.0%) stage IV. According to the Lauren classification, there were 333 (39.6%) intestinal type, 377 (44.8%) diffuse type, 47 (5.6%) mixed type and 84 (10.0%) unclassified. According to tumor histology, there were 84 (10.0%) well-differentiated tumors, 275 (32.6%) moderately differentiated tumors, 273 (32.5%) poorly differentiated tumors, 140 (16.6%) signet ring cell tumors, nine (1.1%) undifferentiated tumors, 43 (5.1%) mucinous tumors and 17 (2.0%) unclassified tumors.
p53 Expression
p53 expression was positive in 43.2% of all gastric cancer tissues. Older age, male gender, larger tumor size and well-differentiated histology were positively correlated with p53 expression. Gross Borrmann type had no correlation. According to Lauren classification, intestinal type gastric cancer had more positive p53 expression than diffuse-type gastric cancer (Table 1). As the TNM stage increased, the expression of p53 became more positive. p53 expression had a positive correlation with nm23, PCNA and c-erbB-2.
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nm23 Expression
nm23 expression was positive in 73.9% of all gastric cancer tissues. Younger age, larger tumor size, gross Borrmann type I/II and well-differentiated histology were positively correlated with nm23 expression. There was no correlation with gender. According to the Lauren classification, intestinal-type gastric cancer had more positive nm23 expression than diffuse-type gastric cancer (Table 1). As the TNM stage increased, the expression of nm23 became more positive. nm23 expression had a positive correlation with p53.
PCNA Index
The mean PCNA index was 54.34. The proportion of gastric cancer with PCNA index ≥50 was 59.2%. Older age, male gender, larger tumor size, gross Borrmann type I/II and well-differentiated histology were positively correlated with PCNA index. According to the Lauren classification, intestinal-type gastric cancer had more positive PCNA expression than diffuse-type gastric cancer (Table 1). There was no correlation with the TNM stage. PCNA expression had a positive correlation with p53 and c-erbB-2.
c-erbB-2 Expression
c-erbB-2 expression was positive in 16.9% of all gastric cancer tissues. Older age, male gender, gross Borrmann type I/II and well-differentiated histology were positively correlated with c-erbB-2 expression. There was no correlation with the tumor size. According to the Lauren classification, intestinal-type gastric cancer had more positive c-erbB-2 expression than diffuse-type gastric cancer (Table 1). There was no correlation with the TNM stage. c-erbB-2 expression had a positive correlation with p53 and PCNA.
Survival Analysis
The 5-year survival of the p53-positive group was 64.8% (n = 364) and it was significantly lower than that of p53-negative group, which was 70.4% (n = 477) (P < 0.05) (Fig. 2). The 5-year survival of the nm23-positive group was 64.5% (n = 614) and it was significantly lower than that of the nm23-negative group, which was 79.7% (n = 217) (P < 0.05) (Fig. 3). The 5-year survival of the PCNA index ≥50 group was 69.9% (n = 512) and did not differ significantly from that of PNCA index <50 group, which was 65.0% (n = 329) (P = 0.17) (Fig. 4). The 5-year survival of the c-erbB-2-positive group was 62.9% (n = 138) and it did not differ significantly from that of c-erbB-2-negative group, which was 68.9% (n = 702) (P = 0.22) (Fig. 5).
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For the factors which revealed prognostic significance in univariate analysis, subgroup analysis was conducted for the stage and the Lauren’s classification. p53 showed no prognostic significance in any of the stages. In stage III, the 5-year survival of the nm23-positive group was 41.3% (n = 145) and it was significantly lower than that of the nm23-negative group, which was 61.5% (n = 39) (P < 0.05) (Fig. 6). In stages I, II and IV there was no prognostic significance of nm23 expression. p53 showed no prognostic significance in either type of the Lauren classification. In diffuse-type gastric cancer, the 5-year survival of the nm23-positive group was 59.4% (n = 261) and it was significantly lower than that of the nm23-negative group, which was 78.5% (n = 116) (P < 0.05) (Fig. 7). In intestinal-type gastric cancer, there was no prognostic significance of nm23 expression.
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Multivariate Analysis
Multivariate analysis was conducted including TNM stage, tumor size, gross Borrmann classification, tumor histology, Lauren classification and expression of p53, nm23, PCNA and c-erbB-2. The TNM stage was the only prognostic factor with relative risk 1.632 (P < 0.05). The expressions of p53, nm23, PCNA and c-erbB-2 had no prognostic significance in multivariate analysis (Table 2).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTREFERENCES |
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Nowadays, several molecular factors are studied as prognostic and predictive factors for gastric cancer. Those include oncogenes and tumor suppressor genes, growth factors and receptors, cell adhesion molecules and proteolytic molecules and angiogenic factors.
p53 is a tumor suppressor gene, located on the short arm of chromosome 17, producing a 53 kDa nuclear protein. p53 is associated with many human cancers including breast cancer, colon cancer, ovarian cancer, lung cancer and esophageal cancer (4). p53 gene, through the product p53 protein, controls the cell cycle and prevents genetic mutations for carcinogenesis (5). If the p53 gene mutates, the tumor-suppressing function of p53 is altered and the tumor progresses. To detect mutations of p53, DNA sequencing is the most accurate method but it is time consuming and it cannot detect all kinds of mutations of p53. The mutant p53 protein is biologically more stable and has a longer half-life than the wild-type p53 protein (6). This characteristic of mutant p53 protein allows immunohistochemical detection of mutant p53 protein using monoclonal antibody for mutant p53 protein. Immunohistochemical study has the advantage that it can be used in a short time, without any specialized equipment, for relatively small pieces of tissues and also can detect the location in the tissues.
Immunohistochemical expression of p53 in gastric cancer ranges from 13 to 54% (7–11). It is compatible with the 43.2% found in this study. Ochiai et al. (12) showed that intestinal-type gastric cancer has more p53-positive expression than diffuse-type gastric cancer, but Mönig et al. (11) could not find this difference. In this study, we found that intestinal-type cancer had more positive p53 expression. There are conflicting results in studies of the prognostic significance of p53. In Western countries, positive p53 expression has a poor prognostic effect (8,13), whereas in Japan positive p53 is not related to prognosis in gastric cancer patients (14,15). In this study, positive expression of p53 was related to poor prognosis.
The nm23 gene was first found in murine melanoma cell lines (16) and is known to have anti-metastatic function in animal studies. nm23 has two isotypes, nm23-H1 and nm23-H2, identical in their amino acid sequence to 92% and identical with nucleoside diphosphate kinase (NDPK) A and NDPK B. NDPK acts as the provider of nucleoside diphosphate to the cells and is related to intracellular signal transduction, but the role in tumor metastasis has not yet been defined. In breast cancer, malignant melanoma, hepatoma and colon cancer, a reduction of expression of nm23 is related to an increase in tumor metastasis and poor prognosis (17–20). On the other hand, in lung cancer and pancreas cancer, an increase in expression of nm23 is related to poor prognosis (21,22). This suggests that the role of nm23 expression is different between different tissues. The relation of nm23 expression and prognosis in gastric cancer varies. Kodera et al. (23) found that a reduction of nm23 expression is related to poor prognosis and Nakayama et al. (24) found that nm23 is reduced in primary gastric cancer tissues and is increased in lymph node metastases and hepatic metastases. These results were contradictory to our results where over-expression of nm23 is related to poor prognosis in gastric cancer patients. Müller et al. (25) also showed that nm23 over-expression is related to poor prognosis. In our study, the relation of nm23 over-expression with poor prognosis was somewhat more marked in diffuse-type gastric cancer.
PCNA is a 34 kDa nuclear protein and acts as cofactor of DNA polymerase in DNA synthesis in S phase of the cell cycle (26–28). PCNA has a very long half-life, so it is expressed in most cell cycles in proliferating cells. Konno et al. (29) and Maeda et al. (30) found that PCNA expression is related to prognosis of human gastric cancer, but He et al. (31) and Mangham et al. (32) found no prognostic significance of PCNA. We found no prognostic significance of PCNA in gastric cancer.
c-erbB-2 protein is an 185 kDa glycoprotein encoded by a gene located in the long arm of chromosome 17. c-erbB-2 protein is related to the EGF receptors having tyrosine kinase activity (33,34). In gastric cancer, the expression of c-erbB-2 ranges from 11 to 19% (35,36), which is consistent with the 16.9% in our study. There are conflicting results in studies of c-erbB-2 regarding the relationship with prognosis in gastric cancer. Jain et al. (35) found that c-erbB-2 over-expression has good prognostic significance, whereas Motojima et al. (37), Yonemura et al. (38) and Uchino et al. (39) found that c-erbB-2 over-expression is related to poor prognosis. Mizutani et al. (40) found that c-erbB-2 over-expression is related with lymph node metastasis in well-differentiated gastric cancer. In our study, c-erbB2 expression was not related to prognosis of gastric cancer.
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ACKNOWLEDGMENT |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTREFERENCES |
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This study was partly supported by a grant from Seoul National University Hospital (02-1997-040-0).
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FOOTNOTES |
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+ For reprints and all correspondence: Han-Kwang Yang, Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul 110–744, Korea. E-mail: hkyang{at}plaza.snu.ac.kr
Abbreviations: DAB = 3,3-diaminobenzidine tetrahydrochloride; DNA = deoxyribonucleic acid; EGF = epidermal growth factor; NDPK = nucleoside diphosphate kinase; PBS = phosphate-buffered saline; PCNA = proliferating cell nuclear antigen; PCR = polymerase chain reaction; TNM = tumor node metastasis; UICC = Union Internationale Contre le Cancer
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTREFERENCES |
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1 Cheung LY, Delcore R. Gastric cancer. In: Townsend CM, editor. Sabiston Textbook of Surgery. 16th ed. Philadelphia: W.B. Saunders 2001;855–65.
2 Annual Report on the Cause of Death Statistics (Based on Vital Registration). Seoul: National Statistical Office 2000.
3 Central Cancer Registry in Korea. Annual Report of the Central Cancer Registry in Korea. Seoul: Ministry of Health and Welfare 2000.
4 Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science 253:49:1991.
5 Milner J, Watson JV. Addition of fresh medium induces cell cycle and conformational changes in p53, a tumor suppressor protein. Oncogene 1990;5:1683–90.[Web of Science][Medline]
6 Finlay CA, Hinds PW, Tan TH, Eliyahu D, Oren M, Levine AJ. Activating mutations for transformation by p53 produced a gene product that forms an HSP70–p53 complex with an altered half-life. Mol Cell Biol 1988;8:531–9.
7 Renault B, van den Broek M, Fodde R, Wijnen J, Pellegata NS, Amadori D, et al. Base transitions are the most frequent genetic changes at p53 in gastric cancer. Cancer Res 1993;53:2614–7.
8 Starzynska T, Bromley M, Ghosh A, Stern PL. Prognostic significance of p53 expression in gastric and colorectal carcinoma. Br J Cancer 1992;66:558–62.[Web of Science][Medline]
9 Kakeji Y, Korenaga D, Tsujitani S, Baba H, Anai H, Maehara Y, et al. Gastric cancer with p53 overexpression has high potential for metastasizing to lymph nodes. Br J Cancer 1993;67:589–93.[Web of Science][Medline]
10 Seruca R, David L, Holm R, Nesland JM, Fangan BM, Castedo S, et al. p53 mutations in gastric carcinomas. Br J Cancer 1992;65:708–10.[Web of Science][Medline]
11 Mönig SP, Eidt S, Zirbes TK, Stippel D, Baldus SE, Pichlmaier H. p53 expression in gastric cancer: clinicopathological correlation and prognostic significance. Dig Dis Sci 1997;42:2463–7.[CrossRef][Web of Science][Medline]
12 Ochiai A, Yamauchi Y, Hirohashi S. p53 mutations in the non-neoplastic mucosa of the human stomach showing intestinal metaplasia. Int J Cancer 1996;69:28–33.[CrossRef][Web of Science][Medline]
13 Martin HM, Filipe MI, Morris RW, Lane DP, Silvestre F. p53 expression and prognosis in gastric carcinoma. Int J Cancer 1992;50:859–62.[Web of Science][Medline]
14 Shun CT, Wu MS, Lin JT, Chen SY, Wang HP, Lee WJ, et al. Relationship of p53 and c-erbB-2 expression to histopathological features, Helicobacter pylori infection and prognosis in gastric cancer. Hepato-Gastroenterology 1997;44:604–9.[Medline]
15 Sasano H, Date F, Imatani A, Asaki S, Nagura H. Double immunostaining for c-erbB2 and p53 in human stomach cancer cells. Hum Pathol 1993;24:584–9.[CrossRef][Web of Science][Medline]
16 Steeg PS, Bevilacqua G, Kopper L, Thorgeirsson UP, Talmadge JE, Liotta LA, et al. Evidence for a novel gene associated with low tumor-metastatic potential. J Natl Cancer Inst 1988;80:200–3.
17 Barnes R, Masood S, Barker E, Rosengard AM, Coggin DL, Crowell T, et al. Low nm23/NDP kinase protein expression in infiltrating ductal breast carcinomas correlates with reduced patient survival. Am J Pathol 1991;139:245–50.[Abstract]
18 Florenes VA, Aamdal S, Myklebost O, Maelandsmo GM, Bruland OS, Fodstad O. Levels of nm23 messenger RNA in metastatic malignant melanomas: inverse correlation to disease progression. Cancer Res 1992;52:6088–91.
19 Nakayama T, Ohtsuru A, Nakao K, Shima M, Nakata K, Watanabe K, et al. Expression in human hepatocellular carcinoma of nucleoside diphosphate kinase, a homologue of the nm23 gene product. J Natl Cancer Inst 1992;84:1349–54.
20 Ayhan A, Yasui W, Yolozaki H, Kitadai Y, Tahara E. Reduced expression of nm23 protein is associated with advanced tumor stage and distant metastases in human colorectal carcinomas. Virchows Arch B Cell Pathol 1993;63:213–8.[Web of Science][Medline]
21 Ozeki Y, Takishima K, Mamiya G. Immunohistochemical analysis of nm23/NDP kinase expression in human lung adenocarcinoma: association with tumor progression in Clara cell type. Jpn J Cancer 1994;85:840–6.
22 Nakamori S, Ishikawa O, Ohhigashi H, Kameyama M, Furukawa H, Sasaki Y, et al. Expression of nucleoside diphosphate kinase/nm23 gene product in human pancreatic cancer: an association with lymph node metastasis and tumor invasion. Clin Exp Metastasis 1993;11:151–8.[CrossRef][Web of Science][Medline]
23 Kodera Y, Isobe K, Yamauchi M, Kondoh K, Kimura N, Akiyama S, et al. Expression of nm23-H1 RNA levels in human gastric cancer tissues. Cancer 1993;73:259–65.
24 Nakayama H, Yasui W, Yokozaki H, Tahara E. Reduced expression of nm23 protein is associated with metastasis of human gastric carcinomas. Jpn J Cancer Res 1993;84:184–90.[CrossRef][Web of Science]
25 Müller W, Schneiders A, Hommel G, Gabbert H. Expression of nm23 in gastric carcinoma. Association with tumor progression and poor prognosis. Cancer 1998;83:2481–7.[CrossRef][Web of Science][Medline]
26 Waseen NH, Lane DP. Monoclonal antibody analysis of the proliferating cell nuclear antigen (PCNA). Structural conservation and the detection of a nucleolar form. J Cell Sci 1990;96:121–9.
27 Lee SH, Hurwitz J. Mechanism of elongation of primed DNA by DNA polymerase delta, proliferating cell nuclear antigen and activator 1. Proc Natl Acad Sci USA 1990;87:5672–6.
28 Shivji KK, Kenny MK, Wood RD. Proliferating cell nuclear antigen is required for DNA excision repair. Cell 1992;69:367–74.[CrossRef][Web of Science][Medline]
29 Konno S, Takebayashi Y, Aiba M, Akiyama S, Ogawa K. Clinicopathological and prognostic significance of thymidine phosphorylase and proliferating cell nuclear antigen in gastric cancer. Cancer Lett 2001;166:103–11.[CrossRef][Web of Science][Medline]
30 Maeda K, Chung YS, Takatsuka S, Ogawa Y, Onoda N, Sawada T, et al. Tumor angiogenesis and tumor cell proliferation as prognostic indicators in gastric carcinoma. Br J Cancer 1995;72:319–23.[Web of Science][Medline]
31 He XB, Ii K, Muguruma N, Hayashi S, Ito S. Expression of proliferating cell nuclear antigen in biopsy and autopsy specimens of gastric carcinoma. J Med Invest 1998;44:149–53.[Medline]
32 Mangham DC, Rowlands DC, Newbold KM, Reynolds GM, Fielding JW, Hallissey MT. Expression of proliferating cell nuclear antigen in gastric carcinoma: no evidence for prognostic value. J Clin Pathol 1994;47:473–4.
33 Akiyama T, Sudo C, Ogawara H, Toyoshima K, Yamamoto T. The product of the human c-erbB-2 gene: a 185-kilodalton glycoprotein with tyrosine kinase activity. Science 1986;232:1644–6.
34 Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, et al. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 1985;230:1132–9.
35 Jain S, Filipe MI, Gullick WJ, Linehan J, Moris RW. c-erbB-2 protooncogene expression and its relationship to survival in gastric carcinoma: an immunohistochemical study on archive material. Int J Cancer 1991;48:668–71.[Web of Science][Medline]
36 Falck VG, Gullick WJ. c-erbB-2 oncogene product staining in gastric adenocarcinoma. An immunohistochemical study. J Pathol 1989;159:107–11.[CrossRef][Web of Science][Medline]
37 Motojima K, Furui J, Kohara N, Izawa K, Kanematsu T, Shiku H. erbB2 expression in well-differentiated adenocarcinoma of the stomach predicts shorter survival after curative resection. Surgery 1994;115:349–54.[Web of Science][Medline]
38 Yonemura Y, Ninomiya I, Yamaguchi A, Fushida S, Kimura H, Ohoyama S, et al. Evaluation of immunoreactivity for erbB2 protein as a marker of poor short term prognosis in gastric cancer. Cancer Res 1991;51:1034–8.
39 Uchino S, Tsuda H, Maruyama K, Kinoshita T, Sasako M, Saito T, et al. Overexpression of c-erbB-2 protein in gastric cancer: its correlation with long-term survival of patients. Cancer 1993;72:3179–84.[CrossRef][Web of Science][Medline]
40 Mizutani T, Onda M, Tokunaga A, Yamanaka N, Sugisaki Y. Relationship of c-erbB-2 protein expression and gene amplification to invasion and metastasis in human gastric cancer. Cancer 1993;72:2083–8.[CrossRef][Web of Science][Medline]
Received November 20, 2002; accepted March 20, 2003
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