|Year : 2018 | Volume
| Issue : 10 | Page : 556-564
Prognostic value of NM23 in patients with gastric cancer: A systematic review and meta-analysis
Qing-hua Wang1, Wei Han2, Min-bin Chen3, Jie Bao1, Bing-fang Wang1
1 Department of Digestive, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan Jiangsu, 215300, PR China
2 Department of General Surgery, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan Jiangsu, 215300, PR China
3 Department of Radiotherapy and Oncology, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan Jiangsu, 215300, PR China
|Date of Web Publication||24-Sep-2018|
Department of Digestive, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan Jiangsu, 215300
Source of Support: None, Conflict of Interest: None
Aim of Study: NM23, as a possible biomarker of prognosis in malignant tumors, has generated remarkable interest in this critical period of the high morbidity and mortality of malignancies. Thus, we launched this meta-analysis to investigate the predictive value of NM23 expression in patients with gastric cancer.
Materials and Methods: We searched PubMed, Embase, and Web of Science for relevant articles. The pooled odds ratios (ORs) and corresponding 95% confidence interval (CI) were calculated to evaluate the prognostic value of NM23 expression in patients with gastric cancer and the association between NM23 expression and clinicopathological factors. We also performed subgroup analyses to find the source of heterogeneity.
Results: Exactly, 2674 patients were pooled from 19 available studies in total. The incorporative OR combined by 11 studies with overall survival (OS) showed no significance (OR = 0.90, 95% CI: 0.51–1.58, P = 0.71). Although we failed to find any significance in N status and tumor node metastasis (TNM) staging (P = 0.23 and P = 0.74, respectively), elevated NM23 expression was related to well tumor differentiation (OR = 0.62, 95% CI: 0.41–0.95, P = 0.03). However, in the subgroup analyses, we could not find any potential source of heterogeneity.
Conclusion: The results showed that statistically significant association was found between NM23 expression and the tumor differentiation of patients with gastric cancer, but no significance was found in OS, N status, and TNM staging. More and further researches should be conducted to reveal the prognostic value of NM23.
Keywords: Clinicopathological factors, gastric cancer, meta-analysis, NM23, nucleoside diphosphate kinase, prognosis, survival
|How to cite this article:|
Wang Qh, Han W, Chen Mb, Bao J, Wang Bf. Prognostic value of NM23 in patients with gastric cancer: A systematic review and meta-analysis. J Can Res Ther 2018;14:556-64
|How to cite this URL:|
Wang Qh, Han W, Chen Mb, Bao J, Wang Bf. Prognostic value of NM23 in patients with gastric cancer: A systematic review and meta-analysis. J Can Res Ther [serial online] 2018 [cited 2018 Dec 11];14:556-64. Available from: http://www.cancerjournal.net/text.asp?2018/14/10/556/183188
| > Introduction|| |
Gastric cancer, with the high morbidity and mortality, has become one of the most terrible threats for human beings. In spite of numerous biomarkers involved in gastric cancer, the prognosis remains to be dismal mainly due to local recurrence, lymph node invasion, and distant metastasis. Furthermore, patients at the same status, such as tumor differential grade, lymph node status, and tumor staging, may have diverse clinical outcomes. Thus, it is urgent to develop new reliable prognostic markers to predict the prognosis and supply better and more suitable therapy for patients with gastric cancer.
NM23 (NM23 stands for nonmetastatic clone 23), also known as nucleoside diphosphate kinase (NDPK), has been found that is associated with the development and progression of various neoplasms. After transplanting eight ovarian cancer cell lines subcutaneously into the flank of nude mice, the expression of NM23 mRNA and protein in human ovarian cancer cells is inversely related to metastatic behavior in experimental animals (r = 0.96, P = 0.0001). Transfection into melanoma cell lines also inhibited invasion, motility, colonization, differentiation, and liver metastasis. Boissan discovered that at early stages of the invasive program, NM23 could control the cell-cell adhesion and cell migration. After silencing NM23 expression in human hepatoma and colon carcinoma cells, cellular scattering, motility, and extracellular matrix invasion were all promoted. In gastric cancer, NM23 also plays a critical role in many respects. NM23 expression in the cytoplasm was more strictly related to age, tumor location, and its histological structure than that in the nucleus in patients with gastric cancer. Moreover, NM23 acted as a molecular switch between the free-floating and adherent states of gastric cancer cells. However, Wang failed to detect any significant difference in NM23 immunoreactivity between primary and metastatic gastric cancer.
The expression of NM23 has been reported to be a promising prognostic indicator. Many studies reported that it was associated with a better overall survival (OS) of various cancers, but some showed that NM23 was associated with tumor progression and indicated a poor 5-year survival., In addition, no systematic reviews with meta-analysis have been published. Hence, to clarify this question and explore its prognostic value in patients with gastric cancer, we performed this systematic review of the literature with meta-analysis.
| > Materials and Methods|| |
Database search strategy
We performed systematic literature search of PubMed, Embase, and Web of Science from their incipiency to December 2015. The retrieval strategy was used as follow: (NM23 or [nonmetastasis 23] or [nucleoside diphosphate kinase] or NDPK or NM23-H1 or [nonmetastasis 23-H1] or [nucleoside diphosphate kinase A] or NDPK-A or NME1 or NM23-H2 or [nonmetastasis 23-H2] or [nucleoside diphosphate kinase B] or NDPK-B or NME2) and (gastric or stomach) and (neoplasms or cancer or carcinoma or tumor or tumor or adenocarcinoma or malignant) and (prognosis or prognostic or predict or survival or outcome or prognos * or [clinical variables] or clinicopatholog * or [clinical pathology] or [clinic pathology]). Reference lists of articles and reviews were hand-searched for additional studies. Manuscripts were also manually scanned to obtain potential articles most relevant to this review. Only studies published in peer-reviewed journals were included. The language of all studies was limited to English. All the initially identified articles were scrutinized independently by two reviewers (Qing-hua Wang and Wei Han). For more details and for information, please see our protocol with the registration number: CRD42015029964.
To be eligible for inclusion, the following criteria had to be fulfilled: (a) clinical studies researched patients with gastric cancer, (b) NM23 expression in cytoplasm of tissue specimens of patients with gastric cancer, who received neither chemotherapy nor radiation therapy before surgery, was measured with immunohistochemistry (IHC), (c) studies reported the association between NM23 expression and survival outcome or clinicopathological information, and (d) only the most recent or the most complete report would be enrolled, if the study population was duplicated or overlapping. Disagreement was resolved by discussion between the two reviewers or consultation with a third reviewer (Min-bin Chen).
Exclusion criteria were: (a) literature published as letters, editorials, abstracts, reviews, case reports, and expert opinions; (b) experiment in vitro or in vivo but not based on patients; (c) articles with neither the odds ratios (ORs) with 95% confidence interval (CI) about clinicopathological information nor the Kaplan–Meier survival curves; and (d) repeated and similar studies.
The following information from each article was extracted: (a) general information, including first author, publication year, country (area) of origin, age and gender of the study patients, sample size, and the follow-up duration; (b) clinicopathological characteristics, including differential grade, lymph node metastasis/N status, and tumor node metastasis (TNM) staging; (c) method to determine NM23 expression and number of patients stratified by NM23 expression; and (d) clinical outcomes, including OS and its correlative ORs with 95% CI, which were all estimated from Kaplan–Meier curves.
Two independent reviewers (Qing-hua Wang and Wei Han) assessed the quality of each study with the Newcastle-Ottawa Scale (NOS) which was mainly used in cohort studies. A study with NOS ≥6 was regarded as a high-quality study. Disparity was resolved by discussion or consultation.
Data synthesis and analysis
OS associated with NM23 expression in patients with gastric cancer was the primary outcome. The secondary outcome was the relationship between the clinicopathological factors and the expression of NM23. OR with its 95% CI was used to be the effect measure of interest. Estimates of ORs were weighted and pooled using the Mantel-Haenszel method. A combined OR >1, with its 95% CI did not overlap 1, indicated a worse survival for the group with NM23 expression. The heterogeneity among studies was measured using the Q and I2 test. A random or fixed model was used according to the heterogeneity analysis. A random effect model was applied if I2 ≥50%; the fixed effect model was selected if I2 <50%. There was substantial heterogeneity in studies if an I2 >50% and we would carry out subgroup analysis to find the source of heterogeneity. A P < 0.05 indicates a significant factor contributing to the observed heterogeneity. The latent publication bias was assessed by a funnel plot and Egger's linear regression test, and a value <0.05 indicated an inevitable significant publication bias. All statistical tests were two-tailed and P < 0.05 was considered statistically significant. All the analyses were conducted by Review Manager Software version 5.3 (The Cochrane Collaboration, Copenhagen, 2014) and STATA Statistical Software Package version 12.0 (Stata Corporation, College Station, TX, USA).
| > Results|| |
A total of 224 articles were retrieved in the initial search of databases. In addition, five records were yielded by manual searching. After removing 102 duplicates, we read the titles and abstracts of the 127 studies left. About eighty citations were excluded from analysis based on abstracts or titles, leaving 47 studies for further full-text review. After meticulously reading, 28 studies were excluded: 26 studies, including reviews or letters, were excluded for no or insufficient survival data; another one was removed in that this study investigated the expression of NM23 mRNA, using polymerase chain reaction; and the left one was excluded because of its wrong data., As a result, 19 eligible studies with 2674 patients in total were enrolled in this meta-analysis [Figure 1].,,,,,,,,,,,,,,,,,,
Study characteristics and quality assessment
The basic characteristics of the 19 studies, published ranging from 1993 to 2008, are summarized in [Table 1].,,,,,,,,,,,,,,,,,, Briefly, study sample sizes ranged from 23 to 831; 16 studies were conducted in Asian populations, while the remaining used Caucasian populations; all studies measured the expression of NM23 in cytoplasm of tissue specimens with IHC, and all patients did not receive any preoperative chemotherapy or radiation therapy, as we had written before; all of the primary antibodies were anti-NM23 antibodies, including polyclonal and monoclonal antibodies. Except one article, all studies reported their cutoff of NM23 expression, most of which identified more than about 30–50% staining cancer cells as high expression. Two studies used normal gastric mucosa as a positive control., Although the cutoffs of these two studies were different from those of other studies, the effect, to some extent, is similar to more than 30%. However, the cutoffs of another two studies might be too low as compared with others.,
|Table 1: Main characteristics of all the studies included in the meta-analysis|
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The study quality scores based on the NOS, ranged from 5 to 8, with a mean of 6.95. Only one of these 19 studies gained a NOS = 5 (<6), suggesting that only this study had low quality, and the other had high levels of methodological quality in this meta-analysis [Table 1].
NM23 and overall survival
In this meta-analysis, 11 studies reported the data concerning the association between NM23 expression and OS of the patients. With heterogeneity (I2 = 78%, pH < 0.00001), the pooled OR being 0.90 (95% CI: 0.51–1.58, P = 0.71). [Figure 2] showed that there was no significance between the expression of NM23 and OS.
|Figure 2: Forest plot of odds ratio for the association between NM23 overexpression and overall survival in patients with gastric cancer with random effects model|
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NM23 and clinicopathology features
There were 16, 15, and 7 cohorts reporting ORs for the relationship between NM23 over-expression and differential grade, N status and TNM staging, respectively. Though with heterogeneity (I2 = 67%, pH < 0.0001), we found a pooled estimate with statistical significance in differential grade (OR = 0.62, 95% CI: 0.41-0.95, P = 0.03, [Figure 3]). However, we could not gain any significance in statistics, when evaluating the pooled ORs of N status and TNM staging (P = 0.23 and P = 0.74, respectively, [Figure 3]).
|Figure 3: Forest plot of odds ratio for the association between NM23 overexpression and clinicopathological features in patients with gastric cancer with random effects model. (a) Differential grade, (b) lymph node metastasis/N status, and (c) TNM staging|
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NM23 and subgroup analyses
In view of the heterogeneity, we conducted the subgroup analyses, presented in [Table 2] and [Table 3] by stratifying the pooled data according to study region (Asian vs. Caucasian), sample size (<100 vs. ≥100), years (≤2000 vs. >2000), antibody type (NM23 vs. NM23-H1), and cutoff (NC vs. low vs. moderate vs. high). From these [Table 2] and [Table 3], only “Caucasian” of “study region” in OS and in N status, “>2000” of “years” in TNM staging, and “high” of “cutoff” in TNM staging had a I2 <50%, so we failed to find any potential source of heterogeneity.
|Table 3: Subgroup analyses of N status and tumor node metastasis staging|
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To test the stabilization of our results, we deleted one individual cohort each time and calculated the pooled ORs of the studies left. In OS, N status and TNM staging, no significant differences were observed between the corresponding results and the overall results (data not shown), including the study which had a NOS = 5. However, in differential grade, there were eight new results different from the old result.,,,,,,, Then, we deleted these eight studies, and produced a new pooled estimate with no significance and no heterogeneity (OR = 1.23, 95% CI: 0.88–1.73, P = 0.22, I2 = 46%, pH = 0.07, [Figure 4]a). These deleted studies were also pooled and we gained a new OR being 0.31 (95% CI: 0.19–0.52, P < 0.0001, [Figure 4]b) still with heterogeneity (I2 = 57%, pH = 0.02).
|Figure 4: Forest plot of odds ratio for sensitive analysis about the association between NM23 overexpression and differential grade in patients with gastric cancer. (a) Results without these eight studies, (b) Results only with these eight studies|
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We carried out the publication bias assessment of the 19 eligible studies. There was no obvious asymmetry in these funnel plots [Figure 5]. Moreover, no evident publication bias was found, with the P value of Egger's test (P = 0.129, P = 0.714, P = 0.529, and P = 0.982, respectively, in [Supplementary Data]).
|Figure 5: Funnel plot for NM23 expression and overall survival, differential grade, N status, and tumor node metastasis staging. (a) overall survival, (b) differential grade, (c) N status, and (d) tumor node metastasis staging|
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| > Discussion|| |
As mentioned previously, NM23, as an indicator of good prognosis in malignant tumors, has generated remarkable interest in this crucial period of the high morbidity and mortality of malignancies. Liu found that NM23-H1 expression was an independent prognostic influence on OS in pathologic Stage I nonsmall cell lung cancer. Youn et al. also reported that NM23 was a prognostic biomarker with poor clinical outcomes in ovarian serous carcinoma. In gastric cancer, many studies have investigated the prognostic value of NM23, in spite of small sample sizes and controversial reports. In addition, no meta-analyses have formerly been published on the prognostic value of NM23 in gastric cancer. Hence, we conducted this systematic review to clarify this question and explore its role in the prognosis of gastric cancer.
This meta-analysis, with 19 articles and 2674 patients, evaluated the prognostic value of the expression of NM23 in patients with gastric cancer. Among them, there were 11 studies reporting the association between NM23 expression and OS, and the pooled estimate showed no significance (P = 0.71). Thus, it was difficult for us to identify whether high expression of NM23 is associated with better survival. We also failed to obtain any statistical significance, when pooling ORs of N status and TNM staging (P > 0.05). Fortunately, we found that elevated NM23 expression was related to well differentiation in patients with gastric cancer. Hence, the association between NM23 overexpression and better clinicopathological outcome could be proven partly through this meta-analysis.
In our subgroup analysis, to find the source of heterogeneity, we stratified the pooled data according to study region, sample size, years, antibody type, and cutoff. However, we failed to find any possible source of heterogeneity in OS, differential grade, N status, and TNM staging. In the following sensitivity analysis, except in differential grade, others all had no significant differences between the new results and the old results. In differential grade, we deleted the eight studies whose new results were different from the old one and produced a new pooled estimate still with no significance but without heterogeneity (P = 0.22, I2 = 46%, pH = 0.07).,,,,,,, Finally, according to our funnel plots, without any obvious asymmetry and Egger's test, without any P < 0.05, we could say, there was no obvious publication bias in our meta-analysis.
Two independent genetic pathways of NM23, loss of heterozygosity (LOH), and microsatellite instability (MSI) were crucial mechanisms in the development and progression of gastric cancer. LOH mostly arose in the late period of sporadic colon cancer and endowed it with high aggressive and poor prognosis, while MSI was an early stage molecule marker in gallbladder carcinoma., In addition, the LOH rate of NM23 in cancer with lymph node or distant metastasis (42.86%) was significantly higher than that in lung cancer without metastasis (8.33%) (P < 0.01). Regulating the Ras-MAPK pathway is another key molecular function of NM23., Upregulation of NM23 inhibited KSHV-induced Ras-BRaf-MAPK pathway activation, and overexpression of NM23 by 5-aza-2'-deoxycytidine reduced KSHV-induced cell invasiveness. Li used an adeno-associated virus (AAV) to transfer NM23 gene into the mice and led to the 60% reduction in the number of animals developing liver metastasis. Furthermore, members of the CDC42 signaling cascade was identified, using Fisher's exact test (P < 0.014), including ARPC5 L, CDC42, CDC42EP2, FNBP1 L, HLA-DOA, HLA-F, HLA-G, ITGB1, JUN, MYL7, MYL10, MYL12A, and RASA1, all of which were regulated by NME1, and linked to metastasis and outcome of patients with melanoma and breast carcinoma. However, few clinically relevant therapeutic targets had been developed from these known substrates of NM23.
Admittedly, our meta-analysis is subject to a few limitations. First, some antibodies recognized both NM23-H1 and NM23-H2 but some only recognized NM23-H1. Despite NM23-H1 and NM23-H2 encoded, respectively, the A and B subunits of NDPK, which possessed 88% identity in their amino acid sequences, these articles could cause some selection bias or else. Second, all of the enrolled studies were nonrandomized controlled trial, and some bias, such as selection bias, misclassification bias, and information bias, might be present in this meta-analysis. Third, the ORs of OS were all estimated from the Kaplan–Meier curves in this meta-analysis. This estimate could also produce some bias. Fourth, all cohorts we included was investigated by IHC. Maybe other methods could also indicate the prognostic value of NM23 expression. In addition, though with a total of 19 cohorts, which reported patients with gastric cancer, further studies were still required to be carried out in the future. Besides, we only adopted articles written in English. This could lose some available studies in other languages. Moreover, some unpublished studies could also be ignored. The last but not least, in this meta-analysis, our results, especially in OS, failed to reveal its good prognostic value in patients with gastric cancer. Fortunately, we discovered that elevated NM23 expression might be related to well tumor differentiation. Hence, we will continue searching articles in the following years and make updates immediately. In a word, our results might be flawed to some extent.
| > Conclusion|| |
Our meta-analysis showed that statistically significant association was detected between high NM23 expression and well differentiation of patients with gastric cancer, but no significance was found in OS, N status, and TNM staging. More and further researches should be conducted to reveal the prognostic value of NM23.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3]