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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 8  |  Page : 159-166

Overexpression of S100A4 protein may be associated with the development and progression of pancreatic cancer


1 Department of General Surgery, The Second Hospital of Shandong University, Jinan 250033, P.R. China
2 Department of Medical Imaging, The Second Hospital of Shandong University, Jinan 250033, P.R. China
3 Department of Traditional Chinese Medicine, The Second Hospital of Shandong University, Jinan 250033, P.R. China
4 Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan 250012, P.R. China

Date of Web Publication26-Mar-2018

Correspondence Address:
Qifeng Yang
Department of Breast Surgery, Qilu Hospital of Shandong University, No. 44, Culture West Road, Lixia District, Jinan 250012
P.R. China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.172582

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 > Abstract 


Aim: Accumulated evidence has suggested a relationship between S100A4 protein expression and the development and progression of pancreatic cancer (PC) while its role in diagnosis and prognosis of PC still keeps inconsistent. To obtain definitive associations between S100A4 and PC, a meta-analysis was conducted.
Materials and Methods: The PubMed and Chinese National Knowledge Infrastructure databases were electronically searched to identify studies reporting an association between S100A4 protein and PC. Statistical analyses were undergone with the utilization of STATA version 12.0 software.
Results: Nine clinical studies with a total of 545 tumor samples were included in the meta-analysis. Results revealed that increased S100A4 expression were associated with the tumor-node-metastasis stages of PC (III-IV vs. I-II: odds ratio [OR] =5.50, 95% confidence interval [95% CI] =3.13–9.67, P < 0.001). Also, compared with 1–2 histologic grade of PC samples, S100A4 protein was expressed more frequently in samples with 3–4 histologic grade (grades 1–2 vs. grades 3–4: OR = 2.57, 95% CI = 1.05–6.24, P = 0.038).
Conclusion: This meta-analysis showed that overexpression of S100A4 seems to be associated with tumor progression and poor prognosis of PC patients.

Keywords: Meta-analysis, pancreatic cancer, S100A4


How to cite this article:
Zhou Y, Li Z, Ding Y, Zhang J, Yang Q, Wu Y. Overexpression of S100A4 protein may be associated with the development and progression of pancreatic cancer. J Can Res Ther 2018;14, Suppl S1:159-66

How to cite this URL:
Zhou Y, Li Z, Ding Y, Zhang J, Yang Q, Wu Y. Overexpression of S100A4 protein may be associated with the development and progression of pancreatic cancer. J Can Res Ther [serial online] 2018 [cited 2019 Nov 16];14:159-66. Available from: http://www.cancerjournal.net/text.asp?2018/14/8/159/172582




 > Introduction Top


Pancreatic cancer (PC) is a malignant neoplasm arising from transformed cells of pancreas forming tissues with a mortality rate nearly equals to its incidence.[1] It is reported to lead to an annually estimated 227,000 deaths in the world and becomes the fourth common cancer following lung carcinoma, colorectal tumor, and breast cancer in America.[2] Moreover, since it is a rapidly devastating disease with a dismal prognosis, among all American patients suffering PC, 26% survive 1-year after diagnosis and only 6% survive 5 years.[3] The interaction between genetic factors and environmental risks such as cigarette smoking, chronic pancreatitis, long-standing history of diabetes mellitus, Helicobacter pylori infection, and heavy alcohol intake may play a considerable role in the pathogenesis of PC.[4],[5] As for the clinical signs and symptoms of PC, abdominal pain, weight loss, and obstructive jaundice, all of which are nonspecific, almost do not manifest until in the late stage of cancer progression.[3],[6] Moreover, due to its resistance to radiation therapy and chemotherapeutic agents, aggressive invasion, as well as metastasis to other organs, the early diagnosis of PC is critical but difficult and the effects of standard therapy are limited.[7] Therefore, to provide the optimal opportunity to improve the prognoses of PC and increase the survival rates, it is crucial to put up with a more effective method for both diagnosis and treatment.[8] To date, several biomarkers including protein S100A4 have been researched on whether they are available to be employed in the clinical practice.[9],[10]

The S100 protein family, which is initially isolated from bovine brain with the form of homodimers or heterodimers, is a family of soluble calcium (Ca 2+)-binding proteins consisting of 21 family members and has a low molecular weight of 10–12 kDa.[11],[12] It is structurally characterized by the EF-hand motif and is believed to be largely involved in diverse cellular functions such as cell growth and differentiation, cell motility along with metabolism, cell cycle regulation, and signal transduction.[7] S100A4, a kind of protein belonging to the S100 family localized to the nucleus and the cytoplasm, was primarily described as p9Ka or mts1 and has been classified to be a metastasis-related gene.[7],[13] This functional molecule is primarily secreted by tumor cells and stromal cells including fibroblasts, macrophages, and activated lymphocytes in the tumor microenvironment.[14] It has emerged as multiple roles in the cellular proliferation by binding to and sequestrating the tumor-suppressor-related protein p53, and in the cellular adhesion via interacting with cadherin.[15],[16] In addition, it is reported that overexpression of S100A4 have resulted inside clinical influences in various human cancers including colorectal cancer, ovarian carcinoma, and bladder tumor.[17],[18],[19] Meanwhile, its expression at higher levels along with high levels of some oncogenic proteins has been confirmed in PC.[20] S100A4 is presented to be involved in cancer by up-regulating cell motility and invasion as an angiogenic factor and inducing the remodeling of extracellular matrix, for which S100A4 is suggested to be a mediator of tumor metastasis.[20] Besides, S100A4 has possibly induced the chemoresistance and the inhibition of apoptosis presented in PC and thus, has been significantly associated with tumor invasion and metastasis.[21] A considerable amount of researches have reported the predictive role of S100A4 expression in patients with PC while there were some underpowered studies failing to clearly and reliably resolve this question.[7],[11] To determine the accurate correlation of S100A4 protein as a promising biomarker in PC, we thus performed this meta-analysis based on a series of previous similar studies.


 > Materials and Methods Top


Search strategy

Potential studies reporting the association between S100A4 expression and PC were retrieved by a comprehensive and systematical literature search, which involved in the PubMed and Chinese National Knowledge Infrastructure databases. The search terms were: (“Pancreatic neoplasms” or “PC” or “pancreatic carcinoma” or “pancreatic adenocarcinoma” or “pancreas cancer” or “pancreas carcinoma” or “pancreatic tumor” or “cancer of the pancreas” or “pancreatic neoplasms”) and (“S100A4 protein, human” or “S100A4” or “PEL98” or “18A2” or “metastazin” or “calvasculin” or “CAPL” or “metastasin-1” or “P9KA”). Furthermore, reference lists of pertinent studies identified from the computerized bibliographic databases were searched manually to avoid omission of additional work.

Inclusion and exclusion criteria

A predefined inclusion criteria was set as followed: (1) Subjects of study were human; (2) only those cohort studies investigating the association between S100A4 expression and PC were enrolled into the current meta-analysis; (3) cancer tissues were obtained from PC patients, and the clinical staging for each PC specimen should be based on the tumor-node-metastasis (TNM) system;[22] (4) the article must provide original data with sufficient information about the S100A4 protein expression in diverse clinicopathological stages; and (5) we choose the study with largest number when the study had overlapping data. The leading exclusion criteria: (1) Some publication types, such as abstracts, letters, meta-analysis, reviews and proceedings; (2) duplication publications; (3) study was written in non-Chinese and non-English; and (4) the study did not meet the above inclusion criteria.

Study quality and data extraction

The methodological quality of the trials enrolled in the present meta-analysis was estimated on the basis of the Critical Appraisal Skills Program (available at http://www.phru.nhs.uk/casp/qualitat.htm). Two reviewers utilized a standardized data form to gather the following relevant information: The first author, publication or submission time, country, race, publication language, study design, sample size, cancer type, sample type, detection methods, clinicopathological features, etc.

Statistical analysis

The odds ratio (OR) with 95% confidence interval (95% CI) for S100A4 protein expression in different demographic variables (gender and age) and clinicopathological stages (TNM and histologic grade) were calculated by the use of Z-test. Moreover, the examination for heterogeneity across the included trials for each comparison was undergone by the utilization of the Cochran's Q-statistic and I2 tests.[23] If the Q-test showed evidence of a P < 0.05 or I2 test exhibited more than 50%, suggesting maximal heterogeneity existing across the included studies, we conducted meta-regression analyses under a random-effects model or fixed-effects model to estimate possible sources of heterogeneity.[24],[25] Furthermore, to evaluate the influence of single studies exerting on the overall results, a sensitivity analyses was employed. In addition, Egger's linear regression visualized by funnel plot was employed to check the publication bias risk.[26],[27] Data analyses were undergone with the use of STATA version 12.0 software (Stata Corporation, College Station, TX, USA).


 > Results Top


Baseline characteristics of included studies

The combination of electronic and manual searches initially hit 69 potentially pertinent studies. After the exception of a duplicate, titles and abstracts of these retrieved studies (n = 68) were browsed to confirm their eligibility. Subsequently, 31 irrelevant articles were removed. Then, the remaining 37 articles were systematically reviewed. After full-text reading, 26 articles were inappropriate, leading to being excluded. Besides, additional two studies were removed owing to lack of complete data. Flow diagram of study selection progress was presented in [Figure 1]. Finally, nine clinical studies published from 2002 to 2013 with 545 PC samples were recruited into this meta-analysis, the sample size of the 9 studies ranged from 20 to 83 specimens.[7],[11],[28],[29],[30],[31],[32],[33],[34] The subjects of two studies were Caucasians (USA [Ligato and Rosty]), and the rest seven studies were from Asian (China [Shang, Liu, Jia, Yang, and Ai] and Japan [Tsukamoto and Oida]). In addition, two studies failed to obtain the age information (Tsukamoto and Rosty), another two studies did not provide the gender information (Yang and Rosty). The methods for the detection of S100A4 protein levels were included with nonstreptavidin-perosidase (SP) (EliVision Plus [Shang], PV-900 [Jia], LAB Vision [Yang], and EnVision [Ligato and Rosty]) and SP (Tsukamoto, Liu, Ai, and Oida). Baseline characteristics of the individual studies were arranged in [Table 1].
Figure 1: Flow diagram of study selection progress. A total of nine clinical studies published from 2002 to 2013 were incorporated into this meta-analysis

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Table 1: Characteristics of included studies focused on protein expression of S100A4

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Quantitative data synthesis

In the meta-analysis, with regard to the correlation of S100A4 expression with clinicopathological features of PC, findings in the current meta-analysis indicated that elevated S100A4 expression were found to be remarkably associated with the TNM stages of PC (III-IV vs. I-II: OR = 5.50, 95% CI = 3.13–9.67, P < 0.001). Moreover, we found that S100A4 protein was expressed more frequently in samples with 3–4 histologic grade of PC in contrast to those with 1–2 histologic grade of PC (grades 1–2 vs. grades 3–4: OR = 2.57, 95% CI = 1.05–6.24, P= 0.038). As for the connection between S100A4 expression and the gender, the results of this study revealed no significant difference in S100A4 expression between male PC cases and female PC cases (male vs. female: OR = 0.96, 95% CI = 0.61–1.53, P= 0.880). Additionally, S100A4 expression did not show a significant correlation with age (older vs. younger: OR = 0.95, 95% CI = 0.60–1.49, P= 0.814) [Figure 2].
Figure 2: Forest plot presented the association between S100A4 expression and clinicopathologic features of pancreatic cancer including gender, age, tumor-node-metastasis, and histologic grade

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Meanwhile, based on the significant heterogeneity that exists across different countries and methods, studies were stratified by country and detection method. In the country-stratified subgroups on the S100A4 expression, the results yielded significant different estimates in S100A4 expression between TNM III-IV and I-II PC in China subgroup (OR = 5.61, 95% CI = 3.13–10.04, P < 0.001), but not in the Japan subgroup (OR = 4.03, 95% CI = 0.40–40.79, P= 0.682). Whereas, we found that S100A4 expression did not differ from the 1–2 histologic grade and the 3–4 histologic grade of PC in the following three subgroups (China: OR = 4.08, 95% CI = 0.98–17.00, P= 0.054; Japan: OR = 1.23, 95% CI = 0.40–3.81, P= 0.718; and USA: OR = 4.22, 95% CI = 0.22–82.45, P= 0.343, respectively). In the method-stratified subgroups, evidence suggested that S100A4 showed more expression in the PC III-IV stage group than the I-II stage group in the non-SP subgroup (OR = 8.35, 95% CI = 3.56–19.59, P < 0.001); similar relation was also presented in the SP subgroup (OR = 3.97, 95% CI = 1.87–8.43, P < 0.001). Further, there was significant difference in S100A4 expression in tumors with histologic grade of 1–2 and 3–4 in non-SP subgroup (OR = 6.59, 95% CI = 1.95–22.25, P= 0.002), while not in the SP subgroup (OR = 1.57, 95% CI = 0.50–4.88, P= 0.439) [Figure 3].
Figure 3: Forest plot presented subgroup analyses based on country and detection methods about the association between S100A4 expression and clinicopathologic features of pancreatic cancer including gender, age, tumor-node-metastasis, and histologic grade

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We further conducted sensitivity analyses to determine whether review conclusions were affected by the choice of single study, the finding suggested that no single study had the effect on the pooled ORs in the current meta-analysis [Figure 4]. Finally, by the Egger's regression test, symmetrical distribution was visualized in the funnel plot for the correlation of S100A4 expression and PC in gender, age, and TNM stage (all P > 0.05), which demonstrated the absence of publication bias; whereas, the funnel plot for the correlation of S100A4 expression and PC in the histologic grade demonstrated the presence of publication bias (P = 0.015) [Figure 5].
Figure 4: Sensitivity analyses about the association between S100A4 expression and clinicopathologic features of pancreatic cancer including gender, age, tumor-node-metastasis, and histologic grade

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Figure 5: Publication bias visualized by funnel plot about the association between S100A4 expression and clinicopathologic features of pancreatic cancer including gender, age, tumor-node-metastasis, and histologic grade

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 > Discussion Top


This meta-analysis was to explore the level of S100A4 expression in PC and its association with pathological features of PC. In this meta-analysis, we found that high S100A4 expression was associated with TNM stage and histological differentiation in PC, but there was no significant statistical difference in S100A4 expression between gender and age. The results revealed that the expression of S100A4 was positively associated with the tumor metastasis, and high expression of S100A4 was obviously associated with poor survival of patients with PC, that is to say, S100A4 expression may be used as a helpful predictor in evaluating the metastatic potential of PC. Nevertheless, the specific mechanism by which S100A4 expression affect the TNM stage, and histological differentiation of PC is still not totally understood. As we all known, invasion and metastasis were the major biological characteristics of various malignancies, which may result in the treatment failure and even death of patients with malignancies.[35] In the past few decades, an increasing number of studies have revealed that S100A4 exert functions on tumor invasion and metastasis, and also overexpressed in different cancers.[36],[37] Meanwhile, S100A4 was considered to be implicated in the process of metastasis in PC and was strongly linked to the neoplasm invasion, metastasis and unfavorable prognosis in patients with PC.[29] S100A4 participates in a variety of biological functions including inhibition of the tumor cell apoptosis, promotion of cell proliferation and angiogenesis, as well as cell motility.[38] It has also been reported that S100A4 may affect the expression and activity of matrix metalloproteinase, accelerate the degradation of basement membrane and promoting the neovascularization that would inhibit the adhesion of tumor cells and increase the motility of tumor cells.[8] In this study, S100A4 protein expression in patients with TNM III-IV PC was demonstrated to be significantly higher than patients with TNM I-II PC, revealing that S100A4 protein expression positively involved in the tumor invasion, as well as metastasis. In line with our study results, Ai et al. have suggested that pancreatic tumors at III-IV stage had a higher S100A4 expression than those at I-II stage, and the S100A4 protein expression can be used as a biomarker to predict the prognosis and survival of PC patients.[11] Furthermore, we also observed that the frequency of S100A4 protein positivity in poorly differentiated group (groups 3–4) was obviously higher than that in high differentiated group (groups 1–2), suggesting that the expression of S100A4 was significantly associated with the histological differentiation of PC. A previous study performed by Tsukamoto et al. has showed that the S100A4 is highly expressed in PC and is strongly associated with the tumor invasion, which can predict a poor prognosis of PC patients.[7]

In this study, the stratified analysis was performed to investigate whether country and detection methods were not factors that reduced the validity of our overall results. The results from country subgroup analysis have demonstrated that the level of S100A4 expression was significantly higher in patients with TNM III-IV PC than that in TNM I-II stage among China, but not among Japan population, suggesting that country differences may be one of the potential heterogeneity sources of this outcome. The differences may cause the changes in environment, genetic backgrounds, and risk factors relating to lifestyle. Further subgroup analysis based on detection method has showed that S100A4 had higher expression in the poorly differentiated tumors when compared with the high differentiated tumors in the non-SP subgroup, however, similar relationship was not presented in the SP subgroup, implying that different detection methods may influence this result and may be a potential heterogeneity source. In addition, no matter in non-SP subgroup or SP subgroup, S100A4 expression was positively connected with the TNM stage of PC. In one word, our study results indicate that S100A4 protein expression was elevated in PC patients, and the high-expression of S100A4 was obviously connected with the development and progression of PC, hence the detection of the S100A4 protein level may be helpful in predicting the prognosis of PC patients.

These data at present available on S100A4 protein expression and PC are somewhat promising, nevertheless, these results should be further confirmed by a relatively larger prospective publishes for several reasons as follows. The first limitation in the current analysis may be that it was different with regard to the cut-off values of S100A4, high or low expression. Clearly, different cut-off value of S100A4 between studies may have an impact on the present results and responsible for the inconclusive outcome. Most importantly, it was hard to provide an accurate definition for the “high” or “low” expression considering that detection method of S100A4 expression which differed from each other. Secondly, though significance did not change, some publication bias was still observed especially in the histologic grade, after adjusting by the trim-and-fill method. Finally, stratified analyses cannot be singly continued by TMN or histologic stages, significantly due to the apparent heterogeneity of PC stages among varieties types of studies. Given the above limitations listed, our statistical analysis results must be interpreted with caution sincerely.


 > Conclusion Top


Our meta-analysis demonstrated that overexpression of S100A4 protein may be associated with the development and progression of PC. S100A4 has the potential to be a predictive biomarker for PC. Our conclusions, however, need to be confirmed considering the limitations of the present analysis, further studies focusing on this topic should be more accurate and precise using the same S100A4 detection method to increase the strength and reduce bias to the greatest extent.

Acknowledgment

This project was supported by the Shandong Provincial Bureau of Traditional Chinese Medicine 2013-175. The authors wish to express their gratitude to reviewers for their critical comments.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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