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Prognostic Value of Nucleolar Protein p120 in Patients With Resected Lung Adenocarcinoma

From the Departments of Respiratory Oncology & Molecular Medicine and Thoracic Surgery, Institute of Development, Aging, and Cancer, Tohoku University, Sendai; Department of Surgery, Miyagi Semine Hospital, Seminecho; Department of Respiratory Medicine, Sendai Kosei Hospital, Sendai; and Divisions of Thoracic Surgery and Epidemiology, Miyagi Cancer Center, Natori, Japan.

Address reprint requests to Yasuo Saijo, MD, PhD, Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer, Tohoku University, 4-1 Seiryomachi Aobaku, Sendai 980-77, Japan; email yasosj{at}idac.tohoku.ac.jp

	ABSTRACT

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PURPOSE: In this study we investigated the prognostic significance of proliferation-associated nucleolar protein p120 in primary resected lung adenocarcinoma because it reflects tumor growth fractions in vitro.

PATIENTS AND METHODS: Expression levels of p120 in tumors were assessed by immunohistochemistry in 74 patients who underwent radical resection. With clinical follow-up data, the prognostic significance of p120 calculated by labeling indices was evaluated using the Cox proportional hazards model.

RESULTS: p120 protein was clearly detected in nucleoli of adenocarcinoma cells. Its expression levels widely varied in each sample from 8.5% to 67.2%, with a mean ± SD of 35.2% ± 15.1%. No significant correlation was found between expression levels of p120 and clinicopathologic factors. However, the expression levels of p120 were negatively correlated with the tumor doubling time calculated with retrospective chest roentgenograms. Using a cutoff value of 35% in the labeling index of p120, patients with high expression of p120 experienced early recurrence and shorter survival compared with those who had low expression of p120. Multivariate analysis showed that p120 served as an independent, as well as the strongest, prognostic factor for resected lung adenocarcinoma.

CONCLUSION: This report provides the first evidence that expression levels of p120 in tumor tissues can be used as an independent and powerful prognostic marker for resected lung adenocarcinoma.

	INTRODUCTION

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LUNG CANCER IS A leading cause of cancer death in men in Japan.¹ Patients with non–small-cell lung cancer (NSCLC) comprise more than 80% of lung cancer cases, with an overall 5-year survival rate of less than 20% and more than 50% of patients dying of recurrence even after radical surgery.² At present, the best predictor of outcome in NSCLC is the tumor-node-metastasis classification. However, although the high recurrence after surgery has prompted a search for new prognostic factors, only a few markers, such as p53 tumor suppressor gene and angiogenesis, have demonstrated convincingly a prognostic value for survival in NSCLC.^3-8

p120, identified as a proliferation-associated nucleolar protein, has been detected in a wide range of human tumors, but not in quiescent cells or normal resting cells.⁹ Although studies of p120 have been performed mainly in vitro using human cell lines, recent studies have increased our knowledge about the role of p120 in human cancers in vivo.^10-12 However, a relation between the expression of p120 and the clinical outcome of patients with cancers was performed only in breast cancer. Patients with high expression of p120 showed a poor prognosis.¹⁰

To assess the role of p120 in human lung cancer, we investigated p120 in human lung cancer cell lines in vitro.¹³ p120 expression was significantly correlated with the proliferation capacity in human lung cancer cells. Preliminary results of our immunohistochemical study of p120 in resected lung cancer tissues showed that the labeling index of p120 in squamous cell carcinoma (67.7%) was significantly higher than that in adenocarcinoma (35.3%).¹³ Because the labeling indices of p120 in adenocarcinoma were distributed in a wider range (5% to 60%) compared with that in squamous cell carcinoma (40% to 85%), we hypothesized that the expression levels of p120, associated with the proliferation of tumor cells in vivo, could affect the clinical outcome of lung adenocarcinoma. In the present study, we examined the expression of p120 by immunohistochemistry and tumor doubling time (DT) in patients with adenocarcinoma. Our results demonstrated that expression levels of p120 reflected the rate of tumor proliferation and that high expression of p120 was an independent prognostic factor for a poor prognosis in patients with lung adenocarcinoma.

	PATIENTS AND METHODS

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Patients and Tissue Samples
We studied 74 patients with lung adenocarcinoma who consecutively underwent surgical resection in the Hospital of the Institute of Development, Aging, and Cancer, Tohoku University, and affiliated hospitals from September 1993 to December 1996. All patients underwent surgery without preoperative treatment. The patient population consisted of 44 men and 30 women whose ages ranged from 35 to 78 years. According to the International System for Staging Lung Cancer,¹⁴ the cases comprised 39 patients with pathologic stage I (pI; pIA, pIB), 16 with pathologic stage II (pII; pIIA, pIIB), and 19 with pathologic stage III (pIII; pIIIA, pIIIB). For the present analysis, the follow-up data were updated in June 1998. During follow-up, 26 patients died of lung cancer. The 48 patients alive at the time of this study had undergone follow-up evaluation for a median of 38.5 months (range, 18 to 62 months). Chemotherapy and/or radiotherapy were administered to 17 patients with stages II and III disease after surgery. For routine histologic studies, tissues fixed with 10% formaldehyde were stained with hematoxylin and eosin.

Immunohistochemical Staining of p120
Fresh tumor samples were embedded in an ornithine carbamyl transferase compound (Tissue-Tek, Elkhart, IN), frozen in liquid nitrogen, and stored at -80°C until use. Cryostat specimens were fixed with 2% formaldehyde and permeabilized with acetone. The samples were then incubated with mouse anti-human p120 monoclonal antibody (Oncogene Science, Cambridge, MA) overnight at 4°C.¹³ Immunohistochemical staining was performed using the streptavidin-biotin procedure with the Histofine SAB PO (M) kit (Nichirei, Tokyo, Japan). The tissues were finally counterstained with Myer-hematoxylin solution.

Two examiners independently observed more than 500 cancer cells in more than 10 randomly selected fields and counted the p120-positive cancer cells.¹³ The labeling index of p120 was defined as the percentage of cancer cells with p120-positive nucleoli in the total number of cancer cells counted. When the difference of the labeling index of p120 was more than 15% between two examiners, the labeling index of p120 was re-evaluated. The results of the assessment for p120 staining were blinded with regard to the clinical data of patients.

Determination of Tumor DT
The tumor DT was calculated in 40 patients whose chest roentgenograms taken at least 2 months before surgery were available and whose tumor shadows were measurable. The maximum diameter of the tumor and the diameter of the right angles were measured from the chest roentgenogram, and DT was determined using the Schwartz formula.¹⁵

Statistical Analysis
All statistical analyses were conducted with SAS version 6.11 (SAS Institute Inc, Cary, NC). The ² test was used to examine the association between the labeling index of p120 and several clinicopathologic factors. Overall survival was calculated from the date of surgery, using death from any causes as the end point. Disease-free survival (DFS) was determined from the day of surgery, using as the end point the initial recurrence of the resected lung cancer assessed by clinical examinations, including local, regional, or distant relapses. Two patients were lost to follow-up at 27.2 and 42.7 months after surgery without relapse. These two patients were therefore considered alive at 27.2 and 42.7 months after surgery. Overall survival and DFS curves were calculated using the Kaplan-Meier method and were analyzed by the log-rank test. The influence of each variable on survival was examined by the Cox proportional hazards model in multivariate regression analyses. Scores were assigned to each variable for regression analysis. Statistical significance was defined as P < .05.

	RESULTS

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Clinicopathologic Factors and Immunohistochemical Staining of p120
Although all tumor tissues showed p120-positive nucleoli in the tumor cells, there were also nucleoli negative for p120 in the tumor cells (Fig 1). The distribution of p120-positive cancer cells was almost uniform with little heterogeneity. When the expression levels of p120 protein were quantified by counting the p120-positive cancer cells in the cancer tissues, the labeling indices of p120 among the cases varied from 8.5% to 67.2%, with a mean ± SD of 35.2% ± 15.1% (Fig 1). The labeling indices of p120 in pI, pII, and pIII were 33.2% ± 14.0%, 33.1% ± 15.5%, and 40.8% ± 16.2%, respectively, with no statistical difference (Table 1). No other clinicopathologic factors, including sex, age, tumor status, node status, and differentiation, were statistically correlated with the labeling index of p120 (Table 1).

View larger version (97K): [in this window] [in a new window]   Fig 1. Immunohistochemical staining of nucleolar protein p120 in resected lung adenocarcinoma. (A) Tumor tissue with high labeling index of p120 ; (B) tumor tissue with moderate labeling index of p120; (C) tumor tissue with low labeling index of p120.

Expression of p120 and Tumor DT
DT could be calculated in 40 of 74 patients with lung adenocarcinoma. The shortest DT was 19 days, and the longest was 1,160 days. The mean DT was 196.5 days (± SD, 224.4 days). When logarithmic conversion of DT was plotted against the labeling index of p120 in each case, there was a significant negative correlation between DT and the labeling index of p120 (r = -.595; P = .0001; Fig 2).

View larger version (19K): [in this window] [in a new window]   Fig 2. Correlation between tumor DT and labeling index of p120. Logarithmic conversion of tumor DT was plotted against the labeling index of p120 in 40 cases.

Expression of p120 and Prognosis in All Cases
Postoperative overall survival and DFS curves in all cases according to the labeling indices of p120 are shown in Fig 3. We chose 35% as the optimal cutoff value to analyze an independent cohort of 74 patients with adenocarcinoma for the prognostic significance of p120 expression because this gave a good separation between high (n = 36) and low (n = 38) expression of p120 and was close to the mean of the labeling index of p120 (35.2%) in adenocarcinoma. Patients with high expression of p120 showed a worse prognosis than those with low expression in all cases for overall survival and DFS (P = .001 and .002, respectively; Fig 3). Estimated 2-year overall survival and DFS rates were 87% and 73% in the low-p120-expression group, but were only 58% and 41% in the high-p120-expression group. The associations between survival and prognostic factors, including sex, age, tumor status, nodal status, histologic differentiation, and expression of p120, are summarized in Table 2. Although tumor status, nodal status, and p120 expression were found to be significant independent factors, p120 was the most valuable factor (hazards ratio = 4.78) among all variables. In addition, when the patients were divided into four subgroups (p120 < 25%; 25% to 35%; 35% to 45%; and 45%), the hazards ratio for overall survival in multivariate analysis was increased in accordance with the labeling indices of p120 (1.00, 1.460, 2.492, and 9.279, respectively), although the P value of the trend was .112. Postsurgical treatment did not affect the overall survival and DFS of patients with stage II and III disease.

View larger version (18K): [in this window] [in a new window]   Fig 3. Kaplan-Meier plots for all patients with lung adenocarcinoma. Postoperative overall survival (A) or DFS (B) curves in 74 patients with lung adenocarcinoma were plotted based on a comparison between low (< 35%; 38 cases) and high ( 35%; 36 cases) labeling indices of p120.

Expression of p120 and Prognosis in Stage I and Stage II + III
To assess the role of p120 in a subset of early-stage lung adenocarcinoma, the data from 39 patients with pI were separately analyzed. Patients with high labeling indices for p120 again showed a significantly worse prognosis both in overall survival and DFS (P = .04 and .008, respectively; Fig 4). The associations between four prognostic factors and overall survival in cases with pI were examined (Table 3). Because all cases with pI were N0, and because no female patient had died, these two factors were excluded from the original Cox model. Although no factor was significantly influential in overall survival, a factor of p120 showed the highest hazards ratio of 4.755 and a P value of .066.

View larger version (18K): [in this window] [in a new window]   Fig 4. Kaplan-Meier plots for patients with stage I disease. Postoperative overall survival (A) or DFS (B) curves in 39 patients with stage I disease were plotted based on a comparison between low (< 35%; 22 cases) and high ( 35%; 17 cases) labeling indices of p120.

We further evaluated the hazards ratio of p120 in the subset of stages II and III. The hazards ratio of p120 was consistently highest among the variables in multivariate analysis (Table 4). Furthermore, the results based on stratified analysis according to each variable were consistent with the overall results, and interactions between p120 and other variables were not significant in the detailed analysis (data not shown). It was regarded that these observations confirmed the reliability of our overall results.

	DISCUSSION

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Our current study indicates that the immunohistochemical detection of p120 protein in resected lung adenocarcinoma could be used as an independent prognostic factor. The expression levels of p120 in lung adenocarcinoma were negatively correlated with the DT of the tumor. These results indicate that p120 can serve as a proliferation marker in lung adenocarcinoma.¹⁶

p120, a proliferation-associated nucleolar protein, is closely associated with the proliferative properties of the cells. In our clinical analysis of 74 patients with lung adenocarcinoma, the tumor progression was highly associated with expression of p120. Although the precise physiologic function of p120 in eukaryotic cells remains unclear, the increased expression of p120, along with its unique nucleolar localization, suggested possible roles for p120 in activated ribosomal biogenesis.^17-19 A reduction in the expression of Nop2, a recently identified yeast homolog of human p120, suppressed the growth rate and reduced steady-state levels of large ribosomal subunits in yeast.²⁰ Recently, Hong et al²¹ reported that deletion of the Nop2 gene in yeast resulted in the decreased methylation of specific regions of 27 S ribosomal RNA (rRNA) and blocked the processing of 27 S pre-rRNA to mature 25 S rRNA. p120 protein not only exists in the nucleolus but also interacts with rRNA synthesis. Gustafson et al²² showed that p120 protein binds rRNA through an arginine-rich domain (residues 40 to 57). These results shed light on the function of p120 in ribosomal synthesis in eukaryotic cells.

A previous study of p120 in human cancer tissues was conducted in patients with breast cancer.¹⁰ Using specimens from 114 patients, the immunopositivity of p120 was correlated with patient survival, nodal status, estrogen receptor levels, and number of mitoses. This study concluded that patients with p120-positive tumor tissue had a poor prognosis, and p120 was thus shown to be an independent and strongest prognostic marker in resected breast cancer by multivariate analysis. The expression of p120 has been studied in colorectal cancer and prostate cancer.^11,12 Although the expression of p120 could serve as a marker for cells with high proliferative potential and could be linked to tumor progression, neither of these two studies evaluated the prognostic significance of p120 in these tumors.

In our immunohistochemical study of p120 in lung adenocarcinoma, the p120 protein was detected clearly in the nucleoli of cancer cells, and its positivity widely varied from sample to sample. This wide distribution of p120 positivity was not reported in any previous studies.^10-12 The expression level of p120 was negatively correlated with the tumor DT determined by retrospective radiographic calculation. The mean DT in the present study was 196 days, which is close to that of our previous report.²³ None of the proliferation markers demonstrated a direct correlation with DT in vivo.^6,24 Patients with a high labeling index for p120 had a high risk of early recurrence, resulting in a poor prognosis. In the multivariate analysis, p120 was recognized as an independent prognostic factor. We have shown previously that the expression of p120 was associated with growth fractions in human lung cancer cell lines in vitro.¹³ Taken together, p120 could predict the clinical outcome of the patients with resected lung adenocarcinoma by reflecting the tumor growth fractions in vivo.

We also examined the expression of p120 in 31 tumor tissues of squamous cell carcinoma. The labeling index of p120 in squamous cell carcinoma was 67.8% ± 17.6%, and the intensity of p120 staining was stronger than that in adenocarcinoma. This high expression of p120 in squamous cell carcinoma may be caused, in part, by the shorter DT and high S-phase fraction.²⁵ This difference of p120 expression between adenocarcinoma and squamous cell carcinoma needs to be elucidated. No correlation between p120 and the prognosis was found in patients with squamous cell carcinoma, in contrast to the results with lung adenocarcinoma. The characteristics of lung adenocarcinoma, from poor to good differentiation in histology and the wide distribution of DT from 19 to 1,160 days, also supported matched p120 as a prognostic marker.

Other nuclear proliferation markers studied in human tumor tissues are PCNA, Ki67, and silver-stained nucleolar organizer region (Ag-NOR). Both PCNA and Ki-67 are predominantly localized in the nucleus, whereas p120 and Ag-NOR are localized in the nucleolus. Although both PCNA and Ki67 were well characterized as proliferation markers, the prognostic significance of these markers in NSCLC has not been established convincingly, although some studies suggested that the high expression of these markers predict a poor prognosis in lung cancer.^6,24,26 Because most of the studies on these proliferation markers evaluated NSCLC as a combined group, re-evaluation in the histologic subsets of NSCLC may lead to clinical applications.²⁷

As a nucleolar marker, Ag-NOR is of particular interest when compared with the characteristics of p120. Although Ag-NOR has been studied, its exact nature is still unclear. Ag-NOR is a complex of several proteins; among them, C23 and B23 have been shown to be the two major proteins.²⁸ Because it can be detected in almost all the nucleoli of cancer cells, the number of Ag-NOR stainings per nucleus has been evaluated. Studies on Ag-NOR in NSCLC have indicated that patients with early-stage disease and a high number of Ag-NOR markers had a poor prognosis.^24,29,30

p53, a tumor suppresser gene, is greatly mutated and is a key gene for molecular pathogenesis in NSCLC.³¹ p53 is one of the few markers that can demonstrate a prognostic value consistently in NSCLC, particularly in lung adenocarcinoma.^3-5 The relation between p53 mutations and the expression of PCNA suggested that tumor cells gained high-growth properties by the p53 mutation.³ Although we tried p53 staining in a small number of patients with lung adenocarcinoma, no prognostic value or relation with p120 positivity could be found (data not shown). In this study, a relatively small number of samples (74) was studied because p120 can be reliably stained only in cryostat specimens but not in paraffin-embedded specimens. Although the intrinsic heterogeneity of lung adenocarcinoma, the inclusion of various stages and treatments, and the short follow-up duration may reduce the reliability of the results of this study, the high hazards ratio of p120 in the different stages suggested that it is a possible prognostic factor in lung adenocarcinoma. Because only one recent report described the availability of p120 monoclonal antibody for the paraffin-embedded tissues using microwave-oven heating,³² the prognostic significance of p120 and its relation with other prognostic markers in NSCLC, particularly in adenocarcinoma, should be evaluated further in a large number of tumor samples.

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Submitted December 2, 1998; accepted May 21, 1999.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sato, G. Articles by Nukiwa, T. Search for Related Content PubMed PubMed Citation Articles by Sato, G. Articles by Nukiwa, T. Social Bookmarking                            What's this?