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10.1245/ASO.2004.10.018
Annals of Surgical Oncology 11:697-704 (2004)
© 2004 Society of Surgical Oncology
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ORIGINAL ARTICLES

Expression Level of Valosin-Containing Protein (p97) Is Correlated With Progression and Prognosis of Non-Small-Cell Lung Carcinoma

Shinji Yamamoto, MD, Yasuhiko Tomita, MD, Yoshihiko Hoshida, MD, Norishige Iizuka, MD, Morito Monden, MD, Satoru Yamamoto, MD, Keiji Iuchi, MD and Katsuyuki Aozasa, MD

From the Departments of Surgery and Clinical Oncology (ShY, MM) and Pathology (YT, YH, NI, KA), Osaka University Graduate School of Medicine, Suita, Japan; and the Divisions of Pathology (SaY) and Surgery (KI), National Kinki Chuo Hospital, Osaka, Japan.

Correspondence: Address correspondence and reprint requests to: Yasuhiko Tomita, MD, Department of Pathology (C3), Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita Osaka 565-0871, Japan; Fax: 81-6-6879-3719; E-mail: yt{at}molpath.med.osaka-u.ac.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Valosin-containing protein (VCP; also known as p97) was shown to be associated with antiapoptosis and metastasis via activation of a nuclear factor-{kappa}B signaling pathway. Our previous study showed that the VCP expression level correlated with the disease recurrence rate and prognosis of patients with hepatocellular carcinoma and gastric carcinoma. This study was designed to evaluate the prognostic significance of VCP expression in non-small-cell lung carcinoma (NSCLC).

Methods: VCP expression in 207 patients with NSCLC (133 men and 74 women) aged 35 to 78 years (median, 62 years) was examined by immunohistochemistry, in which staining intensity in tumor cells was categorized as weaker than (level 1) or equal to or stronger than (level 2) that in endothelial cells.

Results: Sixty-nine (33.8%) cases showed level 1 and 135 (66.2%) showed level 2 VCP expression. The frequency of the following was higher in patients with level 2 expression than in those with level 1 expression: male sex (P < .01), histological subtype of squamous cell carcinoma (P < .05), and smoking (P < .05). Patients with level 2 expression had poorer disease-free and overall survival rates (P < .05 and P < .01, respectively) than those with level 1 expression. Multivariate analysis revealed VCP expression and pathologic T (pT) and pN classifications to be independent prognostic factors for both disease-free and overall survival and showed vascular invasion to be an independent prognostic factor for overall survival. VCP level was a prognosticator for overall survival in both the early (pT1) and advanced (pT2–3) group of the pT classification (P < .05 for both).

Conclusions: The prognostic significance of VCP expression in NSCLC was demonstrated.

Key Words: Valosin-containing protein • Prognosis • Non-small-cell lung carcinoma • Survival


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Lung carcinoma is one of the most frequent causes of cancer-related death, and its incidence is rapidly increasing worldwide.1,2 From the standpoint of clinical features, especially responsiveness to adjuvant therapies, lung cancer is basically divided into small-cell and non-small-cell lung carcinoma (NSCLC). Although innovations in diagnostic radiological technology (including helical computed tomography) have enabled the detection of lung carcinoma at an earlier stage,3 local recurrence or systemic dissemination are frequently observed even among patients who receive curative surgery.2 These patients are hypothesized to have occult micrometastases at the time of surgery, from which cancer cells begin to proliferate and disseminate to other organs.4 Therefore, a precise evaluation of metastatic potential is essential to provide appropriate therapeutic modalities for patients with lung carcinoma.

Several clinicopathologic factors are reported to be prognosticators for surgically resected NSCLC. Among them, tumor size and lymph node metastasis are the main factors for patient survival2,5,6 and, together with distant metastasis, are included in the pathologic tumor-node-metastasis staging for lung carcinoma.7 In practice, however, the prognosis of patients with NSCLC in the same pathologic tumor-node-metastasis stage varies; therefore, additional prognostic factors that could further characterize the malignant potential of the tumors are needed to establish appropriate therapeutic modalities.

Recently, we showed that the gene that encodes valosin-containing protein (VCP; also known as p97) was associated with metastasis of a murine osteosarcoma cell line, by using a messenger RNA subtraction technique.8 VCP, a member of the adenosine triphosphatases associated with various cellular activities superfamily, is known to be involved in the ubiquitin-dependent proteasome degradation pathway of inhibitor {kappa}B{alpha}, an inhibitor of nuclear factor-{kappa}B (NF-{kappa}B).9 Cell lines transfected with VCP showed a constant activation of NF-{kappa}B, rapid degradation of phosphorylated inhibitor {kappa}B{alpha}, decreased rates of apoptosis after treatment with tumor necrosis factor-{alpha}, and increased metastatic potential.8 These findings suggest that the expression level of VCP could be used for predicting the metastatic potential of tumors and, thus, the prognosis of patients with cancer. Indeed, our previous study showed that the VCP expression level correlated with the recurrence rate and prognosis of patients with hepatocellular carcinoma, in which hematogenous metastasis is considered the principal pattern of cancer spread,10 and of patients with gastric carcinoma, in which lymphatic metastasis is considered the principal pattern of cancer spread.11 Metastasis via lymphatic vessels is regarded as the main route for NSCLC recurrence and spread.2,6,12

To verify whether VCP levels could be used for the prediction of recurrence and prognosis, VCP expression was analyzed in 207 patients with NSCLC, and its correlation with clinicopathologic features and patient prognosis was evaluated.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients and Tissue Samples
Two hundred seven patients who underwent curative surgery for NSCLC at the Division of Surgery, National Kinki Chuo Hospital, from April 1990 to December 1995 were enrolled onto this study. There were 133 men and 74 women aged 35 to 78 years (median, 62 years).

Operations were left lower lobectomy in 22 patients, left upper lobectomy in 41, left pneumonectomy in 7, left lower segmentectomy in 1, right upper lobectomy in 76, right lower lobectomy in 28, right middle lobectomy in 16, right middle and lower lobectomy in 8, and right pneumonectomy in 8. Resected lung specimens were macroscopically examined to determine the location and size of the tumor. The size of the main tumor ranged from 7 to 110 mm (median, 29 mm). Samples obtained from the lung lesions and dissected lymph nodes were fixed in 10% formalin and routinely processed for paraffin embedding. Histological sections cut at 4 µm were stained with hematoxylin and eosin and immunoperoxidase procedures (avidin-biotin complex method). Histological sections were reviewed by Y.H. to define the extent and mode of cancer invasion, lymph node metastasis, and histological subtype of NSCLC based on the World Health Organization classification.13 Stage of disease was determined on the basis of the pathologic tumor-node-metastasis classification.7

After surgery, all patients were followed up with laboratory examinations such as routine peripheral blood cell counts at 1- to 6-month intervals; chest roentgenogram; computed tomographic scan of the chest; and endoscopic examinations of the bronchus at 6- to 12-month intervals. Adjuvant therapy was performed in 33 patients at a high risk of tumor recurrence, i.e., with lymph node metastasis, a huge tumor (diameter > 5 cm), and tumor invasion to the visceral pleura. The protocols were as follows: preoperative chemotherapy with cis-platinum, vindesine, and mitomycin C in 2 patients; postoperative chemotherapy with cis-platinum and vindesine in 5; a 5-fluorouracil derivative (uracil + 1,2-tetrahydrofuranyl-fluorouracil) alone in 18; postoperative immunotherapy with bestatin in 7, and OK-432 in 1. The follow-up period for survivors ranged from 45.4 to 150.3 months (median, 101.7 months).

Immunohistochemistry
The immunoperoxidase procedure (avidin-biotin complex method) for detection of VCP was performed on paraffin-embedded sections as previously described. Briefly, antigen retrieval was performed by heating the sections in 10 mM of citrate buffer for 5 minutes. Mouse monoclonal anti-VCP (p97) antibody (Progen Biotechnik, Heidelberg, Germany) was used as the primary antibody at a dilution of 1/3000. Sections were lightly counterstained with methylgreen. Positive staining in endothelial cells was used as an internal positive control. For negative controls, nonimmunized mouse immunoglobulin G serum (Vector Laboratories, Burlingame, CA) was used as the primary antibody and gave uniformly negative results. Stained sections were evaluated in a blinded manner without prior knowledge of the clinicopathologic parameters. Endothelial cells showed positive staining with a constant intensity; thus, the staining intensity in the cytoplasm of the tumor cells was shown in comparison to that of endothelial cells and was categorized as weaker than (VCP expression of level 1) or equal to or stronger than (level 2) that in endothelial cells. Samples that showed combined level 1 and 2 staining in different areas of the tumor were classified as having level 2 expression.

Statistical Analysis
Statistical analyses were performed with JMP software (SAS Institute Inc., Cary, NC). The {chi}2 test and Fisher’s exact probability test were used to analyze the correlation between VCP expression and clinicopathologic features of NSCLC. Kaplan-Meier methods with the log-rank test were used to calculate survival rates and differences in survival curves.14 Cox’s proportional hazards regression model with a stepwise manner was used to analyze the independent prognostic factors.15 P values of <.05 were considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Histological Findings
Histologically, 71 tumors were squamous cell carcinoma (29 well differentiated, 23 moderately differentiated, and 19 poorly differentiated), 130 were adenocarcinoma (62 well differentiated, 40 moderately differentiated, and 28 poorly differentiated), 4 were large-cell carcinoma, and 2 were adenosquamous carcinoma. The resected main tumor was ≤3 cm in greatest dimension (pathologic T1 [pT1]) in 96 patients; was >3 cm or showed invasion of the main bronchus or visceral pleura (pT2) in 105 patients; and had invasion of the chest wall, diaphragm, pericardium, or mediastinal pleura (pT3) in 3 patients.

Patient Outcomes
The 5-year disease-free and overall survival rates were 67.6% and 73.8%, respectively. Seventy-nine patients showed tumor recurrence: lung in 23, lymph node in 9, liver in 11, bone in 12, brain in 17, chest wall in 4, and other organs in 14. Seventy-one patients died as a result of the tumor.

VCP Expression and Clinicopathologic Factors in NSCLC
Three (.9%) of 207 samples that did not show endothelial staining were regarded as having poor antigen preservation and were excluded from further analyses. The remaining 204 samples that showed endothelial staining were evaluated for VCP expression. Cancer cells in 69 (33.8%) and 132 (64.7%) samples showed constant level 1 and level 2 VCP expression, respectively, in every area of the specimens. Three samples that showed combined level 1 and 2 staining were regarded as having level 2 VCP expression. In total, 135 cases (66.1%) were judged as having level 2 VCP expression (Fig. 1). Nontumorous lung epithelium showed level 1 VCP expression.



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  		FIG. 1. (A and B) Valosin-containing protein (VCP) level 1 non-small-cell lung carcinoma (NSCLC) of the well-differentiated subtype. Tumor cells exhibited weak VCP staining in the cytoplasm. (C and D) VCP level 2 NSCLC of the well-differentiated subtype. Tumor cells exhibited strong cytoplasmic VCP staining (original magnification, x50). A and C, hematoxylin and eosin staining; B and D, VCP immunohistochemistry.

 
Univariate and Multivariate Analysis of Prognostic Factors in NSCLC Patients
The correlation between VCP expression and clinical factors is listed in Table 1. The frequency of the following was higher in NSCLC with level 2 expression than with level 1 expression: male sex (P < .01), histological subtype of squamous cell carcinoma (P < .05), and smoking (P < .05). Patients with level 1 NSCLC showed better 5-year survival rates than those with level 2 NSCLC (disease-free: 76.8% vs. 62.7%, P < .05; overall: 85.3% vs. 67.2%, P < .01; Table 2; Fig. 2).


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  		TABLE 1. TABLE 1.Relationship between VCP expression and clinicopathologic factors of 204 NSCLC patients
 


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  		FIG. 2. Disease-free (A) and overall (B) survival of patients with valosin-containing protein (VCP) level 1 and 2 non-small-cell lung carcinoma. A significant difference was observed between groups.

 
Univariate analysis revealed VCP expression, tumor size, histological differentiation, visceral pleural invasion, pT and pN classifications, and tumor stage to be significant for both disease-free and overall survival (Table 2). Microscopic vascular invasion significantly affected overall survival but not disease-free survival. Multivariate analysis with factors proven to be significant in the univariate analysis revealed that VCP expression and pT and pN classifications were independent prognostic factors for both disease-free and overall survivals and showed vascular invasion to be significant for overall survival (Table 3).


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  		TABLE 2. TABLE 2.Univariate analysis of clinicopathologic factors for disease-free and overall survival of 204 NSCLC patients
 

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  		TABLE 3. TABLE 3.Multivariate analysis of clinicopathologic factors for disease-free and overall survival of 204 NSCLC patients
 
Prognostic Significance of VCP Expression in pT Classification
The prognostic significance of VCP expression was further analyzed in patients with NSCLC according to the pT classification. There was a significant difference in overall survival between patients with level 1 and 2 VCP expression in both early (pT1) and advanced (pT2–3) groups (P < .05 for both; Fig. 3).



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  		FIG. 3. Overall survival of patients with valosin-containing protein (VCP) level 1 and 2 non-small-cell lung carcinoma according to the pT classification. A significant difference was observed between level 1 and 2 patients in both the pT1 (A) and pT2–3 (B) groups (P < .05 for both analyses).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In general, a conventional tumor-node-metastasis staging system is useful for predicting the prognosis of patients with NSCLC,2,6,16 but prognoses vary even among patients with the same stage of disease. Therefore, much effort has been made to discern molecular alterations in lung cancer17,18: alternations in the p53–p21 pathway, which controls G1/S transition; increase proliferative activity, as revealed by the Ki-67 labeling index, DNA ploidy pattern, S-phase fraction, and proliferating cell nuclear antigen expression; K-ras oncogene activation due to gene mutation; and overexpression of proteins involved in angiogenesis, such as vascular endothelial growth factor.17,18 However, none of these factors has proven to be useful in the establishment of therapeutic modalities for NSCLC. The aim of this study was to evaluate whether VCP expression could be a new prognostic factor for NSCLC.

VCP is involved in regulating the activation of NF-{kappa}B,8,9 which is a transcription factor whose expression is correlated with various cellular activities, including antiapoptosis, cell proliferation, and invasion.19 NF-{kappa}B activates matrix metalloprotainase-9 and its activator urokinase-like plasminogen activator, and both are necessary for intravasation and extravasation of cancer cells during metastasis.20 Therefore, it is postulated that VCP plays a crucial role in tumor invasion and metastasis through activation of NF-{kappa}B. Indeed, a blockade of the NF-{kappa}B signal was reported to inhibit intravasation of tumor cells, as well as spontaneous metastasis.20 These findings suggest a fundamental role for NF-{kappa}B signaling in the progression and metastasis of cancers.

VCP is involved in the ubiquitin/proteasome-dependent protein-degradation pathway, which plays an essential role in controlling the levels of various cellular proteins and thus regulates basic cellular processes such as cell-cycle progression, signal transduction, and cell transformation.21–23 Inhibition of VCP function leads to reduced proliferation and induction of apoptosis in yeast24 and nontumorous zebra fish cells25 exposed to low temperature and in HeLa cells in culture.26 Thus, it is supposed that VCP is also involved in the proliferation and antiapoptosis of lung cancer cells.

In this study, the VCP expression level was examined immunohistochemically. A clear correlation in VCP expression between the messenger RNA and protein levels has been reported by us10 in cases of hepatocellular carcinoma and by Muller et al.27 in murine nontumoral tissue, by reverse transcriptase-polymerase chain reaction and immunohistochemistry and by in situ hybridization and immunohistochemistry, respectively. This shows the reliability of immunohistochemical methods for the evaluation of VCP expression.

The patients’ characteristics, such as sex, age, and 5-year survival rates, in this series were similar to those of NSCLC in previous reports from Japan2,12 and Western countries.16 These findings indicate that the results obtained from this study on early and advanced NSCLC are applicable to NSCLC in other countries.

The present univariate and multivariate analyses revealed the VCP expression level to be an independent prognosticator for recurrence and survival in NSCLC. These findings are consistent with our previous reports showing the correlation of VCP overexpression with increased metastatic potential of tumor cells in an experimental metastasis model8 and with an increased recurrence rate and poor prognosis of hepatocellular carcinoma and gastric carcinoma in clinical analyses.10,11 In addition, the VCP expression level proved to be useful for predicting the overall survival rate in NSCLC patients in both the early (pT1) and advanced (pT2–3) pT classifications.

These results show that the analysis of VCP expression, along with the pT classification, could be a useful guide in the stratification for NSCLC patients. The outcome of patients with pT1 NSCLC expressing level 1 VCP might be favorable. Because a higher risk of tumor recurrence and metastasis is supposed in patients with pT1/level 2 and pT2–3/level 1 tumors, a watchful follow-up is necessary for these patients. Patients with pT2–3 NSCLC with level 2 VCP expression belong to the highest-risk group for tumor recurrence; therefore, intensive follow-up is necessary for these patients.

In conclusion, VCP expression, as determined by immunohistochemistry, could be used as a new prognosticator for NSCLC. Stratification of NSCLC patients based on the pT classification and VCP expression level would be a useful tool for predicting tumor recurrence and patient prognosis. This system might provide a novel way to explore effective treatment modalities for NSCLC.


   ACKNOWLEDGMENTS
 
The acknowledgments are available online in the full-text version at www.annalssurgicaloncology.org. They are not available in the PDF version.


   FOOTNOTES
 
Valosin-containing protein (VCP) expression in 207 patients with non-small-lung cell carcinoma (133 men and 74 women) was examined immunohistochemically. Univariate and multivariate analysis revealed VCP expression to be an independent prognostic factor for both disease-free and overall survival.

Received for publication October 17, 2003. Accepted for publication March 17, 2004.


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 ABSTRACT
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 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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