Abstract
Objective: To evaluate the association of S100A4 levels with the prognosis of lung cancer (LC). Methods: The RevMan 5.0 software was utilized to perform literature retrieval, data collection, and statistical analysis according to its guidelines. Literature-based searching was guided to gather data, and the fixed-effect model was used to pool the hazard ratio (HR) in this study. Results: A total of 10 eligible studies that included 1364 LC patients were analyzed. About 72.6% of patients had positive expression of S100A4 according to the criteria defined by the authors. The HR of positive expression for overall survival (OS) was 1.30 times of that of negative expression in LC patients (HR=1.30, 95% confidence interval: 1.04 to 1.61, p=0.02). Conclusion: Patients with positive expression of S100A4 appear to have a poorer OS compared with those with negative expression of S100A4.
Introduction
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Recently, S100A4, a member of the S100 protein family, was identified to be an independent prognostic factor for LC (Matsubara et al., 2005; Miyazaki et al., 2006; Qi and Xu, 2007; Chen et al., 2008; Lin et al., 2009; Qin et al., 2009; Tsuna et al., 2009; Feng et al., 2012; Zhang et al., 2013a, 2013b). Moore (1965) is the first group to isolate the S100 protein family from bovine brain. In addition, subsequent studies identified 16 members of this family, based on amino acid sequence homology and similar structural properties (Schafer and Heizmann, 1996). S100A4 is highly expressed in many cancers, including gastric cancer (Li et al., 2013; Ling and Li, 2013), LC (Matsubara et al., 2005; Miyazaki et al., 2006; Qi and Xu, 2007; Chen et al., 2008; Lin et al., 2009; Qin et al., 2009; Tsuna et al., 2009; Feng et al., 2012; Zhang et al., 2013a, 2013b), and larynx cancer (Liu et al., 2010; Zhao et al., 2013). However, the prognostic value of S100A4 in patients with LC is still controversial. Feng et al. (2012) did not observe the prognostic value of S100A4 to LC in a Chinese population. However, Tsuna et al. (2009) have reported a positive association of S100A4 expression with prognosis of LC in Japanese. This discrepancy may result from the relatively small sample size for each study. Therefore, we performed this meta-analysis to clarify the association of S100A4 with LC prognosis.
Materials and Methods
Inclusion and exclusion criteria
The inclusion criteria
(1) The clinical research of direct comparison of S100A4 expression status in LC, without any restriction on language or publication year; (2) the research subjects are LC patients regardless of any restriction on age or race; and (3) outcome indicator was presented as overall survival (OS). Studies having no clear follow-up and survival analysis or not providing valid data required for prognostic evaluation of patients with LC were excluded from the analysis.
Literature collection and screening
We conducted a computerized literature search of PubMed, EMbase, Chinese Biomedical Literature Database, Chinese CNKI, and Wanfang database using the terms “S100 calcium binding protein A4” or “S100A4” and “lung cancer” and “prognosis.”
Literature quality assessment and data extraction
Two independent reviewers performed the literature filtering and quality assessment. In the procedure, we excluded articles obviously not meeting the inclusion criteria. If inconsistencies existed, we resolved it through discussion. The Cochrane Handbook 5.0 Quality evaluation criteria were utilized to evaluate the methodological quality of included studies, S100A4 status, sample size, and treatment programs.
Data analysis
In the present study, we utilized RevMan 5.0 software to perform the meta-analysis. We directly used the Q-test and I2 test to examine the heterogeneity between each study. We utilized the hazard ratio (HR) value to evaluate the relationship between the S100A4 status and OS in LC. Using heterogeneity test, if p>0.05, we selected the fixed-effects model, and if p<0.05, we selected the random-effects model to merge the HR. A p<0.05 was considered as a significant difference. Analysis of sensitivity included the difference of point estimation and confidence intervals of the combined effects value to observe whether it changed the result. To test publication bias, we used the RevMan 5.0 statistical software to make the funnel plot.
Results
Literature screening
Seventy-four articles were preliminarily detected, 61 were excluded due to duplicate publication and nonclinical-based research literature. Thirteen articles were fully viewed and three of them were further excluded from the analysis because the data were unavailable to calculate the HR and its 95% confidence intervals (CI). A total of 10 articles, including 1364 LC patients were considered in the present study.
The characteristics and treatment of these studies
In these 10 studies, there were 6 studies in which chemotherapy was used; 4 studies reported that the majority of patients were treated with chemotherapy and some patients with both radiotherapy and chemotherapy.
Methodology assessment of S100A4 expression detection
S100A4 expression detection methods in these included studies were all immunohistochemistry. Therefore, these included studies were homogeneous in methodology.
S100A4 expression and prognosis
In these 10 studies, there were 5 articles from which can be extracted the HR values and their 95% CIs directly used for the evaluation of the value of S100A4 expression and the prognosis. Although another five articles did not provide the HR values, we can calculate the HR values and their 95% CIs according to the survival curves provided by the authors. There was better homogeneity between each study in our analysis (p=1.00, I2=0%). The HR for OS of the patients with S100A4-positive expression was 1.30 times as much as the patients with S100A4-negative expression (HR=1.30, 95% CI: 1.04 to 1.61, p=0.02, Fig. 1).
Forest plot of prognosis of lung cancer (LC) and S100A4 expression. The horizontal lines correspond to the study-specific hazard ratio (HR) and 95% confidence intervals (CIs), respectively. The area of the squares reflects the study-specific weight. The diamond represents the pooled results of HR and 95% CI. In this analysis, the fixed-effects model was used.
Publication bias analysis
We made a funnel plot using RevMan 5.0 software to analyze the publication bias. As shown in Figure 2, the points were evenly distributed, symmetrical, and most of the points are within the 95% confidence interval. It indicates that there is no publication bias, and the result of the study is credible.
Begg's funnel plot for publication bias test. Each point represents a separate study for the indicated association. Log HR represents the natural logarithm of HR. The vertical line represents the mean effect size.
Discussion
In the present study, we found that S100A4 is an independent prognosis factor of LC by a meta-analysis method. To the best of our knowledge, this is the first meta-analysis to reveal the prognostic value of S100A4 in LC.
S100A4 is a member of the S100 family of calcium binding proteins. It is localized in the cytoplasm, nucleus, and extracellular space and has multiple biological functions, including regulation of angiogenesis and stimulation of motility and invasion (Wang and Griffin, 2013). S100A4 promotes metastasis in several experimental animal models and is associated with patient outcome in a variety of cancer types, including LC (Dmytriyeva et al., 2012).
Several studies have investigated S100A4 protein expression in LC, with the percentage of positive cases ranging from 20% to 84% (Matsubara et al., 2005; Miyazaki et al., 2006; Qi and Xu, 2007; Chen et al., 2008; Lin et al., 2009; Qin et al., 2009; Tsuna et al., 2009; Feng et al., 2012; Zhang et al., 2013a, 2013b). In general, S100A4 is not expressed in normal lung epithelium (Wolf et al., 2011), whereas a variety of cells in the tumor microenvironment are S100A4 positive, including lymphocytes, fibroblasts, and smooth muscle cells (Rygiel et al., 2008; Yadav et al., 2010). In some examinations, S100A4 expression has been shown to be associated with poor patient outcome (Miyazaki et al., 2006; Qi and Xu, 2007; Chen et al., 2008), while other studies have failed to demonstrate a prognostic role for S100A4 in LC (Tsuna et al., 2009).
In the meta-analysis, we enrolled 10 studies that were of clear diagnostic criteria, inclusion criteria, and exclusion criteria. In addition, the patients were grouped according to S100A4 status, and the OS was the main outcome. The HR value was a statistical indicator to assess the impact of different status of S100A4 expression for OS of patients with LC. In the present study, we included both English and Chinese literature that had the full texts available. Because the baseline data and the detailed therapy were not available in some articles, the method to select the articles may influence the result of the study.
In the present study, no significant heterogeneity was found among the included studies. Sensitivity analysis also showed that omission of any single study did not have a significant impact on the combined odds ratios. Furthermore, a funnel plot did not reflect obvious asymmetry, and the Egger's test further indicated no considerable publication bias in this meta-analysis. This made the results of this meta-study more reliable to some extent.
In conclusion, this meta-analysis of 10 studies showed that the S100A4 is a prognostic factor of LC patients. The patients with S100A4-positive expression had a poorer prognosis compared to those with negative expression of S100A4.
Footnotes
Author Disclosure Statement
No competing financial interests exist.