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Eur J Cardiothorac Surg 2004;26:419-424
© 2004 Elsevier Science NL

Prognostic significance of nm23-H1 expression in esophageal squamous cell carcinoma

Liang-Shun Wanga*, Kuan-Chih Chowc, Yung-Chang Liena, Kuang-Tai Kuoa, Wing-Yin Lib

a Division of Thoracic Surgery, Department of Surgery, Taipei-Veterans General Hospital and National Yang-Ming University, 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan, ROC
b Department of Pathology, Taipei-Veterans General Hospital and National Yang-Ming University, Taipei, Taiwan, ROC
c Department of Medical Research, China Medical College Hospital, and Institute of Medical Research, China Medical College, Taichung, Taiwan, ROC

Received 3 February 2004; received in revised form 15 March 2004; accepted 22 March 2004.

* Corresponding author. Tel.: +886-2-2875-7546; fax: +886-2-2873-1488
e-mail: lswang{at}vghtpe.gov.tw


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Objectives: Tumor recurrence and metastasis are major causes of treatment failure in esophageal squamous cell carcinoma (ESCC). Recently, nm23, originally considered to be an anti-metastatic gene, has been reported to associate with various roles in different human cancers. We therefore investigated the clinical significance of nm23-H1 expression in ESCC. Methods: Pathological sections were immunohistochemically stained with monoclonal antibody that was specific to nm23-H1. Expression of positive nm23-H1 staining was further confirmed by Western blot and reverse transcription-polymerase chain reaction (RT-PCR). The relationship between nm23-H1 expression and clinicopathological variables was examined by statistical analysis. Except for 11 (7%) surgical morality, the remaining 145 patients entered the prognostic analysis. The cisplatin-based chemotherapy was established for the patients with tumor stages at or beyond IIb, or with tumor recurrence. Survival difference between groups was compared by log rank test. Results: Immunohistochemically, nm23-H1 expression was detected in 39.3% (57/145) of the pathological sections. It was positively correlated with tumor stage (P=0.002), evident lymphovascular invasion (P<0.001) and tumor recurrence (P=0.02). Survival of nm23-H1 positive group was statistically superior to nm23-H1 negative group (P<0.0001). By multivariate survival analysis, tumor stage, the number of lymph node metastasis and expression of nm23-H1 were the independent prognostic factors for ESCC patients. Conclusions: Our study demonstrated that nm23-H1 expression was associated with disease progression in ESCC. However, survival of nm23-H1 positive group was superior to nm23-H1 negative group. This paradoxical result could suppose that nm23-H1 expression might increase cisplatin chemosensitivity and hence improve survival. Screening for nm23-H1 expression in tumor cells may be a potential therapeutic strategy in ESCC patients.

Key Words: nm23 • Esophageal carcinoma • Chemosensitivity


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 References
 
Esophageal squamous cell carcinoma (ESCC) occurs rather frequently among the Chinese. It has been suggested that curative surgery of ESCC, particularly for early stage tumors, may provide an increased chance of long-term survival. However, rapid tumor growth with early lymphatic and hematogensus spreading discourages the efforts of multiple therapeutic modalities for ESCC patients. More than half of the patients with resectable ESCC have locoregional disease at diagnosis, and most of them die of tumor recurrence within 1–2 years after surgical resection [1]. Nevertheless, that patients at an early stage could have rapid tumor recurrence and distant metastasis after surgery, and that patients at a late stage could survive for a long period of time after treatment suggest the possible role of intrinsic factor(s) in making such a difference. Therefore, a method for identifying cancer cell proliferation and spreading, and factors affecting chemoradiosensitivity are important to commence the effective treatment and to improve survival for ESCC patients.

Nm23 gene, originally identified by differential screening of cDNA libraries constructed from metastatic and nonmetastatic cell lines from K-1735 murine melanoma, was highly expressed in nonmetastatic cells [2]. Further experiments showed that this gene asserted anti-metastatic effect in animal models [3] and in human carcinomas [4]. However, these findings cannot be generalized, and the biological function of nm23 in cancer cells is perplexed. Nm23 displays sequence homology with nucleoside diphosphate (NDP) kinase and shows NDP kinase activity [5]. Increasing evidences have suggested that the nm23 gene is involved in controlling normal development and differentiation, and down-regulation of the nm23 gene inhibits cell proliferation [5,6]. Interestingly, detection frequency of nm23 expression in clinical specimens varied among different cancers, and no consensual result of prognostic analysis was achieved. Some studies showed that nm23 expression was indeed associated with a better prognosis, as its in vitro anti-metastatic effect [7–11]. However, some studies revealed that nm23 might in fact facilitate tumor development and disease progression [12–15], which corresponded well with the findings of nm23 involvement in cell proliferation. It is worth noting that upon examining the cisplatin-resistant mechanism in human ovarian carcinoma cells, Andrews et al. [16] detected that Na+, K+-ATPase expression was associated with the accumulation of cisplatin. Moreover, the facts that nm23 gene transfection increased cisplatin sensitivity, and downregulation of nm23-H1 prevented cisplatin-induced DNA damage in cancer cells further implicated that nm23 could be directly associated with Na+, K+-ATPase [17–19]. Nevertheless, the expression of nm23 in ESCC has not been well investigated and its clinicopathological significance is also not properly defined.

In this study, we used immunohistochemical (IHC) method to determine the expression of nm23-H1 in surgical specimens from ESCC patients. The expression of nm23-H1 in ESCC was further confirmed by western immunoblotting and reverse transcription-polymerase chain reaction (RT-PCR). The correlation between clinicopathological parameters and nm23-H1 expression, and the prognostic significance of nm23-H1 expression in ESCC patients were evaluated.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 References
 
From January 1985 to December 2000, 156 patients with esophageal carcinoma were enrolled for study. All patients had pathologically confirmed ESCC. The mean age of the patients was 63 years (range: 43–75 years), and the male: female ratio was 14.6:1. The preoperative work-up included routine blood tests, biochemistry, chest radiography, upper gastroenteric contrast study, bronchoscopy and esophagoscopy with biopsies, chest computed tomography (CT), sognography of neck and abdomen, and radioisotopic scan of whole body bone. Stage of disease progression was classified according to the Unio International Center Cancer System. En bloc esophagectomy with locoregional lymph node dissection was performed for all of these patients [1]. The surgical mortality rate was 7.0% (11/156), and most of the mortality was caused by pulmonary complications (one patient died of myocardial infarction). Thus, only 145 patients entered the prognosis analysis. For patients at stage IIb or beyond, postoperative adjuvant therapy was commenced within one month if their conditions were suitable. Irradiation was prescribed for 60 Gyr (10 Gyr/5 fractions per week), and concurrent chemotherapy was dispensed for two cycles, in the first and sixth week of irradiation. A combination regimen of chemotherapy consisted of cisplatin (20 mg/m2 per day), 5-fluorouracil (5-FU) (600 mg/m2 per day) and leucovorin (120 mg/m2 per day) for 4 days. Those with tumor recurrence were treated with cisplatin-based chemotherapy, and/or additional local irradiation. After treatment, all patients were followed regularly. Written informed consent was obtained from every patient. Tumor recurrence or metastasis were identified when blood examination, chest radiography, sonography of neck and abdomen, whole body bone radioisotopic scan and CT scan of chest showed any suspected evidence of the lesion.

2.1. Immunohistochemical staining and western blot
IHC staining was performed by an immunoperoxidase method as previously described [1]. All of the samples were routinely fixed in 4% buffered formalin, embedded in paraffin, and cut into 4-µm sections. Monoclonal antibody specific to nm23-H1 was manufactured at Santacruz (CA, USA), and a dilution of 1:50 was applied. Procedures for immunoblotting has also been described previously [20]. Briefly, frozen tissue tumor samples were firstly examined by microscopy to ensure that at least 90% of each sample composed of tumor. Nontumorous specimens were also obtained. They were thawed in ice-cold homogenization buffer, and the lysates were sonicated and centrifuged at 10,000xg for 10 min to sediment the particulate material. Protein samples of 20 µg/ml were prepared for electrophoresis. Electrophoresis was carried out in 10% polyacrylamide gel with 4.5% stacking gel. After electrophoresis, proteins were transferred to a nitrocellulose membrane. The membrane was then probed with nm23-H1 specific antibodies (PG-27, 1:500). The signal was amplified by biotin-labeled goat anti-rabbit IgG (1:3000) and peroxidase conjugated streptavidin (1:5000). Nm23-H1 protein was visualized by exposing the membrane to an X-Omat file (Eastman Kodak, Rochester, NY, USA) with enhanced chemiluminescent reagent (PIERCE, Rockford, IL, USA).

2.2. Slide evaluation of immunohistochemical staining
In each case, normal esophagus tissue served as internal positive control and lymph node from tonsil was used as negative control [11]. Slides were read by two independent observers without clinicopathological knowledge (K.C.C. and W.Y.L.). A specimen was considered positive if more than 20% of cancer cells were positively stained and negative if less than 20% were positively stained [20].

2.3. RNA extraction and gene amplification using RT-PCR
RNA extraction and gene amplification have been described previously [20]. Briefly, following RNA extraction, cDNA was synthesized by oligo dT primer and AMV reverse transcriptase. An aliquot of cDNA was then subjected to 35 cycles of polymerase chain reaction (PCR) using standard procedure denaturing at 94 °C for 1 min, hybridizing at 52 °C for 30 s, and elongating at 72 °C for 1.2 min. The primer sequences for nm23-H1 were 5'-ATGGCCAACTGTGAGCGTACC-3' (human NDK gene, NME1, nt 79–94) and 5'-TTCATAGATCCAGTTCTGAGCACAAGC-3' (human NDK gene, NME3 nt 506–529). The amplified products were resolved in a 2.5% agarose-ethidium bromide gel. Specificity of the 456 bp nm23-H1 fragment was confirmed by DNA sequencing (ABI prism, Perkin–Elmer, Foster City, CA, USA), and the nucleotide sequences were matched with the database listed in GenBank (http://www.ncbi.nlm.nih.gov/blast). A constitutively expressed gene, ß-actin, was used as internal control. The primers for ß-actin were 5'-CAGGGCGTGATGGTGGGCAT-3' (nt 131–150) and 5'-ATGGCCACATACATGGCTGGGGTG-3' (nt 394–417), generating a 287-bp PCR product.

2.4. Statistical analysis
The relationship between nm23-H1 expression and clinicopathological parameters was analyzed by Chi-Square test or t-test, respectively. Survival curves were plotted with Kaplan–Meier method. Statistical difference of survival between different groups was compared by the log rank test. Univariate proportional hazards regression was used to estimate the dependence of survival on each variable. Multivariate analysis was used to test the variable selected by the method stated earlier to have prognostic value. Statistical analysis was performed using NCSS 2000/PASS 2000 statistical software (Boston, MA, USA). Statistical significance was defined as a P value <0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 References
 
3.1. Expression of the nm23-H1 gene and protein
As determined by IHC, 57 (39.3%) of 145 cases were positive for nm23-H1 protein expression in pathological specimens. IHC staining for nm23-H1 protein was predominantly cytoplasmic (Fig. 1) . For further confirming nm23-H1 expression in ESCC, immunoblotting and RT-PCR were performed on 20 pairs of tumors and normal counterparts. The representative examples of immunoblotting and RT-PCR were shown in Fig. 2A and B . Compared to the normal esophageal mucosal samples, nm23-H1 expression in the tumorous specimens were highly variable.



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  		Fig. 1. Immunohistochemical staining for nm23-H1 protein in esophageal squamous cell carcinoma (ESCC). (A) Representative nm23-H1-positive case which demonstrates intense nm23-H1 immunoreactivity in the cytoplasma of tumor cells (original magnification x400). (B) Representative nm23-H1-negative case in which expression in tumor cells is similar to that of the nontumorous tissues (original magnification x400).

 


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  		Fig. 2. Representative examples of detection of nm23-H1 expression in ESCC by Western blot and RT-PCR. (A) Western blot of nm23-H1 protein in ESCC. Except for one tumorous sample showing very weakly expression of nm23-H1, all the other samples demonstrate the positive expression of 23 kDa nm23-H1. (B) Expression of nm23-H1 mRNA is confirmed by RT-PCR in 8 samples. N: normal esophageal mucosa. T: tumor fraction of surgical resections.

 
3.2. Relationship between nm23-H1 expression and clinicopathological variables
The relationship between nm23-H1 expression and clinicopathological variables was examined according to the positive and negative groups (Table 1). No statistical difference between two groups was found with respect to age, gender, habit of cigarette smoking, mitotic index, number of metastatic lymph nodes and cell differentiation (P>0.05). However, nm23-H1 expression was correlated to tumor stage (P=0.002), evident lymphovascular invasion (P<0.001) and tumor recurrence (P=0.02). Among 57 patients with positive nm23-H1 expression, 39 patients (68.4%) were with advanced tumor stages (stages III and IV). In contrast, the nm23-H1 negative group had significantly lower incidence in advanced tumor stages (35/88, or 39.8%) (P=0.002). Histopathologically, evident lymphovascular invasion was found in 47.4% of nm23-H1 positive group, but a markedly lower rate (14.8%) in nm23-H1 negative group was detected (P<0.001). Interestingly, the rate of tumor recurrence was also significantly higher in nm23-H1 positive group than in nm23-H1 negative group (positive group=47.4%; negative group=28.4%) (P=0.02). These results indicated that the expression of nm23-H1 in ESCC was associated with disease progression.


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  		Table 1. Correlation of nm23 expression with clinicopathological parameters

 
3.3. Survival analysis
The cumulative survival curves for patients with positive or negative nm23-H1 expression are shown in Fig. 3 . The overall 1-, 3- and 5-year survival rates of nm23-H1 positive group were 80, 51 and 22%, respectively. In contrast, those of nm23-H1 negative group were 35, 12 and 0%, respectively. Statistically, the nm23-H1 positive group had significantly better survival than the nm23-H1 negative group (P<0.0001). This result was in sharp contrast to the abovementioned analysis that tumor recurrence rate was notably higher in the nm23-H1 positive group than in the nm23-H1 negative group. In our opinions, the major factor of this discrepancy is chemotherapy following the diagnosis of advanced stages or tumor recurrence. In order to verify our viewpoints, we further divided the patients into four groups: (1) early staged (stages I and II) tumors with positive nm23-H1 expression (group A, n=18); (2) early staged tumors with negative nm23-H1 expression (group B, n=53); (3) late-staged (stages III and IV) tumors with positive nm23-H1 expression (group C, n=39), and (4) late-staged tumors with negative nm23-H1 expression (group D, n=35). As shown in Fig. 4 , no survival difference was identified between groups A and C (P>0.05), but significant difference was found between groups A and B (P<0.001), groups C and D (P<0.001), and groups B and D (P<0.001). It should be emphasized that the group C had even a better survival than group B (P<0.001), though group C had more advanced tumors than those of group B.



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  		Fig. 3. Overall survival curves of patients with ESCC according to the status of nm23-H1 expression. The nm23-H1 positive group had significantly better survival than the nm23-H1 negative group (P<0.0001).

 


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  		Fig. 4. Overall survival curves of patients with ESCC according to tumor stages and the status of nm23-H1 expression. Group A: early staged (stages I+II) tumors with nm23-H1 positive expression (n=18), group B: early staged (stages I and II) tumors with nm23-H1 negative expression (n=53), group C: late-staged (stages III and IV) tumors with nm23-H1 positive expression, group D: late-staged (stages III and IV) tumors with nm23-H1 negative expression. P-values: groups A vs. B, P<0.01; groups A vs. C, P<0.05; groups C vs. D, P<0.001; groups B vs. C, P<0.01.

 
By univariate analysis, clinicopathological variables that were significantly correlated with survival were tumor stage, number of metastatic lymph nodes, cell differentiation, evident lymphovascular invasion and expression of nm23-H1 (Table 2). Moreover, multiunivariate survival analysis revealed that in addition to tumor stage and number of lymph node metastasis, expression of nm23-H1 was also an independent prognostic factor in the current series.


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  		Table 2. Distribution of prognostic features (N=145)

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
References
 
Since the discovery of nm23 gene, six different isoforms of nm23 genes have been found in humans [21]. Nm23-H1 and H2 are most widely studied, which are 88% identical in sequence and map 4 kb apart on chromosome 17q 21–22 [22]. In tumors, in particular as the tumors become more malignant, nm23-H1 expression increases more remarkably than that of nm23-H2 [23]. It was then suggested that the level of nm23-H1 could be a more reliable marker for assessing disease progression. In the present study, we used IHC, RT-PCR and Western blot to detect nm23-H1 gene and protein in the ESCC cells, respectively. Our results showed that 39.3% of 145 cases were stained positively with nm23-H1 protein in pathological sections, and most of nm23-H1 protein was expressed in the cytoplasm of cancer cells.

It is worth noting that nm23 protein is related to multiple cellular reactions [6]. However, the biological function of nm23-H1 seems to be organ- and tissue-specific, especially in human cancers. For instance, unlike malignant melanoma [8], hepatocellular carcinoma [9], or colorectal cancer [10], in which reduced nm23-H1expression was correlated with tumor metastasis and mortality, overexpression of nm23 detected in thyroid cancer [13], gastric cancer [14], head and neck cancer [15] and lung cancer [24] was closely associated with tumor aggressiveness and disease progression. Additionally, an elegant study conducted by Ferguson et al. [17] showed that sensitivity to cisplatin could be increased by nm23-transfected tumor cell lines. Interestingly, there is a paradox in our results that the patients with nm23H1 positive tumors were associated with a more advanced tumor stage and an increased tumorous recurrence, but their survival was significantly better. Herein, we would repeatedly emphasize that in this series, the patients at stage IIb or beyond, or those with tumor recurrence, were treated with cisplatin-based chemotherapy, and/or additional local irradiation. Then, the paradoxical results in survival might strongly suggest a close relationship between nm23-H1 expression and cisplatin-based chemosensitivity. In fact, Iizuka et al. [18] had demonstrated similar results, in which nm23-H1 overexpression was most accountable for the increased survival of ESCC patients receiving cisplatin-based chemotherapy. Furthermore, the in vitro abrogation of nm23-H1 expression by anti-sense RNA could increase cisplatin resistance. Based on these data, they proposed that in addition to NDP kinase activity, nm23-H1 expression is related to Na+, K+-ATPase function, which in turn is responsible for the increase of intracellular accumulation of cisplatin and subsequent drug sensitivity [19]. On the other hand, the cytotoxic effect of cisplatin is most potent during S to G2 phases [25], the period of cell cycle that nm23-H1 is preferentially expressed [6]. It should be noted that if nm23-H1 positive cancer cells are more malignant, but also more sensitive to cisplatin toxicity. Then following ablative chemotherapy, the residual cancer cells, if there is any, would be potentially less malignant. Then, it is reasonable to suppose that the nm-23 H1 positive patients could live with cancer cells of lesser vice, and potentially improved their survivals. However, the real mechanisms contributing to these results remain to be further clarified.

In conclusion, our results showed that nm23-H1 overexpression in ESCC was significantly correlated with disease progression. However, survival of nm23-H1 positive group was superior to nm23-H1 negative group. Our analysis imply that the patients with nm23-H1 expression in tumor cells were more responsive to chemotherapeutic regimens containing cisplatin, and subsequently resulted in an improvement of survival. Although, further studies are required for determining the pathophysiological role of nm23 in tumors, using tumorous nm23-H1 expression as a clinical reference for monitoring chemotherapeutic responses for ESCC patients should be considered in the prospective therapeutic strategy.


   Acknowledgments
 
This study was supported in part, by Taipei-Veterans General Hospital (VGH-296), and, in parts, by Lite-on Cultural Foundation (LF2002MD01), Taiwan.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 

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