Clinicopathological and prognostic significance of metastasis-associated in colon cancer-1 in gastric cancer: A meta-analysis
Show all authors
Yan Jin, Kun Zhou, Wenjing Zhao, ...
First Published March 10, 2019 Research Article
https://doi.org/10.1177/1724600818813634
Article information
Open Access Creative Commons Attribution, Non Commercial 4.0 License
Abstract
Background:
The gene metastasis-associated in colon cancer-1 (MACC1) has been reported to be overexpressed in diverse human malignancies, and an increasing amount of evidence suggests that its overexpression is associated with the development and progression of many human tumors. However, the prognostic and clinicopathological value of MACC1 in gastric cancer remains inconclusive. Therefore, we conducted this meta-analysis to investigate the effect of positive MACC1 expression on clinicopathological features and survival outcomes in gastric cancer.
Methods:
Medline, Web of Science, and EMBASE databases were searched for relevant articles published up to 10 April 2018. The correlation of MACC1 expression levels with overall survival and clinicopathological features was analyzed.
Results:
In this meta-analysis, nine studies with a total of 2103 gastric cancer patients were included. Our results showed that high expression of MACC1 was significantly related to a poor overall survival. Moreover, our meta-analysis showed that MACC1 overexpression was significantly linked to distant metastasis and vascular invasion. There were no significant correlations between positive MACC1 expression and gender, localization, tumor-node-metastasis (TNM) stage, tumor extent (T stage) and lymph node involvement (N stage)
Conclusions:
MACC1 expression levels can serve as a novel prognostic factor in gastric cancer patients.
Keywords MACC1, gastric cancer, meta-analysis, prognosis
Introduction
Gastric cancer (GC) is a malignant disease arising from gastric tissue. It is the fifth most common cancer in the world and the second leading cause of cancer-related death globally.1 Although the last decade has witnessed a decrease in the prevalence of GC in some developed countries, it is estimated that 951,600 new stomach cancer cases and 723,100 deaths occurred in 2012.1 Given that the tumorigenesis of GC is attributable to the interactions between environmental and genetic factors, it often demonstrates high morbidity in Asian countries, especially China. Because the mechanism of GC carcinogenesis is still not fully understood, GC has become a major public health problem. Prognosis is usually assessed by tumor-node-metastasis (TNM) staging. However, this approach may be flawed, as prognoses often differ in patients at the same tumor stage.2 Given this fact, it is necessary to identify a specific prognostic biomarker that can accurately identify patients with poor prognosis, allowing health care professionals to preemptively alter their treatment strategy.
The metastasis-associated in colon cancer-1 (MACC1) mRNA is located on chromosome 7 (7p21.1) of the human genome and contains seven exons and six introns. The MACC1 coding sequence contains 2559 nucleotides and is translated to form a MACC1 protein containing 821 amino acids.3,4 The MACC1 protein contains an SH2 domain, an SH3 domain, an Eps15 homology domain, and phosphorylation sites of multiple tyrosine kinases. MACC1 has been shown to be involved in the regulation of related signaling pathways in various tumors,5 and its aberrant expression is often accompanied by the activation of associated signaling pathways, leading to the occurrence and metastasis of tumors. The hepatocyte growth factor (HGF)/c-met signaling pathway is recognized as a signaling pathway that plays an important role in cell growth, epithelial–mesenchymal transition, angiogenesis, invasion, and metastasis. In the initial study of the function of MACC1, the expression of MACC1 was positively correlated with the expression of the HGF receptor c-Met. Increasing or decreasing the expression of MACC1 can promote or inhibit the expression of c-Met.6 MACC1 and c-Met were highly expressed in the nuclei of colorectal cancer metastasis, while in situ tumor tissues MACC1 and c-Met were mainly expressed in the cytoplasm. Further, through electrophoretic mobility shift assay and chip experiments, MACC1 can be combined with SP1 binding sites in the c-Met promoter region to initiate c-Met transcription expression.7 Therefore, MACC1 can promote the activity of HGF/c-met signals by transcription activation of c-Met and participate in the regulation of tumor growth and metastasis. Subsequent studies have verified the positive regulatory effects of MACC1 on the HGF/c-met signaling pathway in GC,8-10 hepatocellular carcinoma,11 and ovarian cancer.12,13
Previous studies found a relationship between the expression of MACC1 and clinicopathological parameters of GC, but the results of these studies have been inconsistent. Guo et al.10 reported that high expression of MACC1 was highly associated with hepatic metastasis and peritoneal metastasis. However, Ge et al.14 suggested that high expression of MACC1 did not correlate with distant metastasis. The results of different studies have varied. Therefore, it is necessary to identify eligible studies and to perform a meta-analysis to investigate the association between MACC1 expression and clinicopathological characteristics, and to re-evaluate the prognostic significance of MACC1 in patients with GC.
Methods
Publication search
The studies related to the relationship between the expression of MACC1 and GC were searched in the databases of MEDLINE, Web of Science, and Embase using the keywords (“MACC1” or “Metastasis-associated in colon cancer-1”) and (“gastric cancer” or “stomach cancer” or “gastric neoplasm” or “stomach neoplasm”) and (“prognosis” or “survival”). The search was limited to English-language papers. Among the studies with the same or overlapping data published by the same investigators, we selected the most recent publications with the largest numbers of subjects.
Inclusion criteria
The following inclusion criteria were used for the literature selection in our meta-analysis: (a) the study could be either a prospective or retrospective clinical research; (b) the patients had pathologically confirmed GC; (c) the studies focused on the association of expression of MACC1 with clinical parameters and/or prognosis of patients with GC; and (d) MACC1 expression was examined by immunohistochemistry in GC specimens. For MACC1 staining intensity, sections were scored as 0 (negative), 1 (weak), 2 (medium) or 3 (intense); whereas the staining extent was scored according to the area percentages: 0 (0%), 1 (1%–25%), 2 (26%–50%), 3 (51%–75%), or 4 (76%–100%). The products of the staining intensity and extent scores were the final staining scores (0–12) for MACC1 expression. Tumors of final staining score ⩾3 were considered to be a positive expression.
The exclusion criteria were: (a) letters, reviews, editorials, case reports, or animal trials, and conference abstracts without original data; and (b) repeated articles based on the same database.
Study selection and data extraction
All data were extracted by two independent reviewers (Yan Jin and Kun Zhou). Discrepancies were resolved by discussion and re-evaluation. The following variables were extracted from each study if available: first author’s name, publication year, number of cases, MACC1 detection, MACC1 cut-off, high MACC1 proportion, outcome, hazard ratio (HR). To minimize bias, the HR and 95% confidence interval (CI) were extracted preferentially from multivariable analyses. If not available, HR and 95% CI from Kaplan–Meier curves were retrieved using Engauge Digitizer version 4.1 (http://digitizer.sourceforge.net/).
Assessment of study quality and statistical analysis
The Newcastle–Ottawa Scale (NOS) was used to evaluate the methodological quality of all included studies. A study with an NOS score ⩾6 was an indication of high quality. Discrepancies in the score were resolved through discussion between the authors.
The odds ratio (OR), as a relative risk in case-control retrospective studies, was used to quantitatively determine the association between MACC1 expression and the clinical parameters of GC in our manuscript. The heterogeneity of pooled data was assessed using I2 test. When significant heterogeneity among studies was absent (I2 < 50% or P > 0.05, a fixed-effects model (the Mantel–Haenszel method) was applied. Otherwise, a random-effects model (the DerSimonian and Laird method) was selected (I2 ⩾ 50% or P ⩽ 0.05). Sensitivity analysis was applied to evaluate the stability of the results. Begg’s funnel plot and Egger’s test were used to provide an evaluation of publication bias (linear regression analysis).15 All analyses were performed using STATA 14.0 software (STATA Corporation, College Station, TX, USA). Statistical significance was defined as P-values < 0.05.
Results
Literature retrieval and analysis
A flowchart of the literature retrieval process is shown in Figure 1. Initially, a total of 329 potential studies were found utilizing the electronic database search based on the study’s inclusion and exclusion criteria. After screening the titles and abstracts, nine eligible studies were included in the meta-analysis.9,10,14,16-21 The characteristics of selected studies are summarized in Table 1. All the included studies were performed retrospectively and published between 2011 and 2018. The follow-up period was over a span of 5 years in all eligible studies. It is noteworthy that none of the studies scored less than 6 on the NOS, suggesting that all included studies were of high methodological quality.
figure
Figure 1. Flow diagram of the literature search and selection.
Table
Table 1. Characteristics of nine studies included in the meta-analysis.
Table 1. Characteristics of nine studies included in the meta-analysis.
View larger version
Quantitative synthesis
To identify the clinical significance of MACC1, the association of MACC1 expression with clinicopathological features was investigated in this meta-analysis. Data, including gender, differentiation type, depth of invasion, lymph node metastasis, distant metastasis, and TNM stage were extracted from the included studies for the calculation of pooled ORs.
The results failed to show a correlation between positive expression of MACC1 and gender (OR 1.00; 95% CI 0.82, 1.23; P=0. 0.97; I2= 27.9%), differentiation type (OR 1.27; 95% CI 0.56, 2.88; P= 0.58; I2= 79.8%), depth of invasion (OR 1.74; 95% CI 0.82, 3.71; P= 0.15, I2=23.6%), lymph node metastasis (OR 1.58; 95% CI 0.78, 3.17; P= 0.20; I2=88.7%), and TNM stage (OR 2.05; 95% CI 0.78, 5.36; P= 0.20; I2=88.7%) (Table 2).
Table
Table 2. Meta-analysis results of the associations of high MACC1 expression level with clinicopathological characteristics.
Table 2. Meta-analysis results of the associations of high MACC1 expression level with clinicopathological characteristics.
View larger version
Our meta-analysis indicated that positive expression of MACC1 was significantly associated with distant metastasis (OR 4.68; 95% CI 1.98, 11.06; P <0.001; I2= 59.4%) and vascular invasion (OR 1.63; 95% CI 1.11, 2.38; P = 0.14; I2= 93.8%) (Table 2).
Relationship between MACC1 expression and overall survival
All of the included studies reported the results of overall survival (OS) regarding MACC1 expression with 2103 cancer patients. Because the heterogeneity was observed among studies (I2= 84.3%; P=0.000), the random-effects model was applied. The meta-analysis of these studies showed that a positive MACC1 expression level was significantly associated with poor OS in human cancer (HR 1.99; 95% CI 1.29, 3.09; P < 0.001) (Figure 2). A worse OS was observed in patients with a positive MACC1 expression level than that observed in patients with a negative MACC1 expression.
figure
Figure 2. Forest plot for the relationship between MACC1 expression and OS. MACC1: metastasis-associated in colon cancer-1; OS: overall survival.
Publication bias
For the meta-analysis of the relationship between MACC1 expression levels and OS, and Egger’s test was used to assess the publication bias. Egger’s test (Figure 3) showed that there was no significant publication bias observed among those studies (t= 0.10; P > |t|=0.85). However, due to the limited number of studies included, it was difficult to confirm the absence of publication bias in this meta-analysis. In the sensitivity analysis, we sequentially omitted each study while repeating the analysis to assess the impact of individual studies on the pooled HRs calculated for OS. The results of the sensitivity analysis indicated that our meta-analysis of OS was not dominated by any single study; therefore, the conclusions herein demonstrated credibility.
figure
Figure 3. Funnel plot analysis of potential publication bias in the meta-analysis.
Discussion
GC is a leading cause of human cancer mortality that is predominantly induced by tumor invasion, metastasis, and recurrence.1 Current prognostic indicators have been unable to satisfy the need for the accurate prediction of long-term outcomes in patients with GC.
MACC1 expression has been found to have prognostic value in lung cancer, oral squamous cell carcinoma, ovarian cancer, and breast cancer in terms of survival and recurrence rates. However, no previous studies have evaluated the prognostic significance of MACC1 overexpression in GC patients, which was the subject of our investigation. Recently, the expression of MACC1 and the relationship between expression of this gene and the clinicopathological parameters of patients with GC have been studied, with inconsistent findings. We performed a detailed and comprehensive meta-analysis study to investigate the prognostic role of expression of MACC1 in patients with GC. We found that (a) positive expression of MACC1 is not associated with gender, differentiation type, depth of invasion, lymph node metastasis, and TNM stage; and (b) positive expression of MACC1 in primary tumors is associated with distant metastasis and results in a poor prognosis. These results implied that MACC1 was likely to participate in tumor metastasis. Further studies are needed to support this conclusion
Considering that tumor metastasis requires a sufficient blood supply, which, in most cases, is achieved by neovascularization, angiogenesis is a well-recognized hallmark of cancer.22 Some studies indicated that MACC1 overexpression was associated with the vascular invasion of GC. In this meta-analysis, we observed similar results. MACC1 facilitates GC lymph angiogenesis by upregulating extracellular secretion of vascular endothelial growth factor C/D, indicating that MACC1 may be an important player in GC lymphatic dissemination; however, we found that the high expression of MACC1 is not related to lymph node metastasis.23
GC patients with high circulating plasma transcript levels of MACC1 had a significantly shorter survival compared to patients with low levels of MACC1 expression. These results indicate that circulating MACC1 possesses prognostic value in patients with GC. The small molecules lovastatin and rottlerin emerged as the most potent MACC1 transcriptional inhibitors. They remarkably inhibited MACC1 promoter activity and expression, resulting in reduced cell motility. Lovastatin impaired the binding of the transcription factors c-Jun and Sp1 to the MACC1 promoter, thereby inhibiting MACC1 transcription.24
Some limitations of this meta-analysis should be noted. First, some heterogeneity existed among the included studies.25 Second, all of the research institutes at which the included studies were performed were located in Asia, suggesting that the tissue samples were probably all obtained from Asian patients. Third, the HRs with 95% CI were not directly extracted from the studies, so we based our studies on the data extracted from Kaplan–Meier curves, which compromises the precision of the data. Lastly, the majority of the included studies did not use blinding; the lack thereof might have resulted in selection bias.
In conclusion, this study demonstrates the significance of MACC1 as an important clinical indicator for patients with GC. Our meta-analysis provides evidence that positive expression of MACC1 may be associated with distant metastasis, vascular invasion, and OS. Due to the limitations of meta-analyses, larger studies are still needed to more accurately evaluate the association of MACC1 expression with the clinicopathological characteristics of patients with GC.
Author contributions
Yan Jin and Kun Zhou contributed equally to this work as the first authors.
Study conception and design: Yan Jin, Jinfei Chen, Kou Zhou, Wenjing Zhao
Acquisition of data: Yan Jin, Kun Zhou, Wenjing Zhao, Fen Yang, Xinying Huo, Rongbo Han
Analysis and interpretation of data: Yan Jin, Fen Yang, Kun Zhou, Jinfei Chen
Drafting of manuscript: Yan Jin, Fen Yang
Critical revision: Yan Jin, Fen Yang, Jinfei Chen.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
References
1. Torre, L. A, Bray, F, Siegel, R. L. Global cancer statistics, 2012. CA Cancer J Clin 2015; 65: 87–108.
Google Scholar | Medline | ISI
2. Bette, S, Barz, M, Wiestler, B. Prognostic value of tumor volume in glioblastoma patients: size also matters for patients with incomplete resection. Ann Surg Oncol 2018; 25: 558–564.
Google Scholar | Medline
3. Stein, U, Walther, W, Arlt, F. MACC1, a newly identified key regulator of HGF-MET signaling, predicts colon cancer metastasis. Nat Med 2009; 15: 59–67.
Google Scholar | Medline
4. Arlt, F, Stein, U. Colon cancer metastasis: MACC1 and Met as metastatic pacemakers. Int J Biochem Cell Biol 2009; 41: 2356–2359.
Google Scholar | Medline
5. Wu, ZZ, Chen, LS, Zhou, R. Metastasis-associated in colon cancer-1 in gastric cancer: Beyond metastasis. World J Gastroenterol 2016; 22: 6629–6637.
Google Scholar | Medline
6. Stein, U, Walther, W, Arlt, F. MACC1, a newly identified key regulator of HGF-MET signaling, predicts colon cancer metastasis. Nat Med 2009; 15: 59–67.
Google Scholar | Medline
7. Stein, U, Smith, J, Walther, W. MACC1 controls Met. What a difference an Sp1 site makes. Cell Cycle 2009; 8: 2467–2469.
Google Scholar | Medline
8. Huang, N, Wu, Z, Lin, L. MiR-338–3p inhibits epithelial-mesenchymal transition in gastric cancer cells by targeting ZEB2 and MACC1/Met/Akt signaling. Oncotarget 2015; 6: 15222–15234.
Google Scholar | Medline
9. Ma, J, Ma, J, Meng, Q. Prognostic value and clinical pathology of MACC-1 and c-MET expression in gastric carcinoma. Pathol Oncol Res 2013; 19: 821–832.
Google Scholar | Medline
10. Guo, T, Yang, J, Yao, J. Expression of MACC1 and c-Met in human gastric cancer and its clinical significance. Canc Cell Int 2013; 13: 121.
Google Scholar | Medline
11. Yao, Y, Dou, C, Lu, Z. MACC1 suppresses cell apoptosis in hepatocellular carcinoma by targeting the HGF/c-MET/AKT pathway. Cell Physiol Biochem 2015; 35: 983–996.
Google Scholar | Medline
12. Li, H, Zhang, H, Zhao, S. Overexpression of MACC1 and the association with hepatocyte growth factor/c-Met in epithelial ovarian cancer. Oncol Lett 2015; 9: 1989–1996.
Google Scholar | Medline
13. Sheng, XJ, Li, Z, Sun, M. MACC1 induces metastasis in ovarian carcinoma by upregulating hepatocyte growth factor receptor c-MET. Oncol Lett 2014; 8: 891–897.
Google Scholar | Medline
14. Ge, SH, Wu, XJ, Wang, XH. Over-expression of metastasis-associated in colon cancer-1 (MACC1) associates with better prognosis of gastric cancer patients. Chin J Canc Res 2011; 23: 153–159.
Google Scholar | Medline
15. Egger, M, Davey Smith, G, Schneider, M. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315: 629–634.
Google Scholar | Medline
16. Lu, G, Zhou, L, Zhang, X. The expression of metastasis-associated in colon cancer-1 and KAI1 in gastric adenocarcinoma and their clinical significance. World J Surg Oncol 2016; 14: 276.
Google Scholar | Medline
17. Koh, YW, Hur, H, Lee, D. Increased MACC1 expression indicates a poor prognosis independent of MET expression in gastric adenocarcinoma. Pathol Res Pract 2016; 212: 93–100.
Google Scholar | Medline
18. Dong, G, Wang, M, Gu, G. MACC1 and HGF are associated with survival in patients with gastric cancer. Oncol Lett 2018; 15: 3207–3213.
Google Scholar | Medline
19. Xie, QP, Xiang, C, Wang, G. MACC1 upregulation promotes gastric cancer tumor cell metastasis and predicts a poor prognosis. J Zhejiang Univ Sci B 2016; 17: 361–366.
Google Scholar | Medline
20. Sun, L, Duan, J, Jiang, Y. Metastasis-associated in colon cancer-1 upregulates vascular endothelial growth factor-C/D to promote lymphangiogenesis in human gastric cancer. Cancer Letters 2015; 357: 242–253.
Google Scholar | Medline
21. Wang, L, Wu, Y, Lin, L. Metastasis-associated in colon cancer-1 upregulation predicts a poor prognosis of gastric cancer, and promotes tumor cell proliferation and invasion. Int J Canc 2013; 133: 1419–1430.
Google Scholar | Medline
22. Hanahan, D, Weinberg, RA. Hallmarks of cancer: the next generation. Cell 2011; 144: 646–674.
Google Scholar | Medline | ISI
23. Sun, L, Duan, J, Jiang, Y. Metastasis-associated in colon cancer-1 upregulates vascular endothelial growth factor-C/D to promote lymphangiogenesis in human gastric cancer. Cancer Lett 2015; 1: 242–253.
Google Scholar
24. Juneja, M, Kobelt, D, Walther, W. Statin and rottlerin small-molecule inhibitors restrict colon cancer progression and metastasis via MACC1. PloS Biol 2017; 15 (6): e2000784.
Google Scholar | Medline
25. Fagoonee, S, Durazzo, M. HOTAIR and gastric cancer: a lesson from two meta-analyses. Panminerva Med 2017; 59 (3): 201–202.
Google Scholar | Medline
View Abstract
Show all authors
Yan Jin, Kun Zhou, Wenjing Zhao, ...
First Published March 10, 2019 Research Article
https://doi.org/10.1177/1724600818813634
Article information
Open Access Creative Commons Attribution, Non Commercial 4.0 License
Abstract
Background:
The gene metastasis-associated in colon cancer-1 (MACC1) has been reported to be overexpressed in diverse human malignancies, and an increasing amount of evidence suggests that its overexpression is associated with the development and progression of many human tumors. However, the prognostic and clinicopathological value of MACC1 in gastric cancer remains inconclusive. Therefore, we conducted this meta-analysis to investigate the effect of positive MACC1 expression on clinicopathological features and survival outcomes in gastric cancer.
Methods:
Medline, Web of Science, and EMBASE databases were searched for relevant articles published up to 10 April 2018. The correlation of MACC1 expression levels with overall survival and clinicopathological features was analyzed.
Results:
In this meta-analysis, nine studies with a total of 2103 gastric cancer patients were included. Our results showed that high expression of MACC1 was significantly related to a poor overall survival. Moreover, our meta-analysis showed that MACC1 overexpression was significantly linked to distant metastasis and vascular invasion. There were no significant correlations between positive MACC1 expression and gender, localization, tumor-node-metastasis (TNM) stage, tumor extent (T stage) and lymph node involvement (N stage)
Conclusions:
MACC1 expression levels can serve as a novel prognostic factor in gastric cancer patients.
Keywords MACC1, gastric cancer, meta-analysis, prognosis
Introduction
Gastric cancer (GC) is a malignant disease arising from gastric tissue. It is the fifth most common cancer in the world and the second leading cause of cancer-related death globally.1 Although the last decade has witnessed a decrease in the prevalence of GC in some developed countries, it is estimated that 951,600 new stomach cancer cases and 723,100 deaths occurred in 2012.1 Given that the tumorigenesis of GC is attributable to the interactions between environmental and genetic factors, it often demonstrates high morbidity in Asian countries, especially China. Because the mechanism of GC carcinogenesis is still not fully understood, GC has become a major public health problem. Prognosis is usually assessed by tumor-node-metastasis (TNM) staging. However, this approach may be flawed, as prognoses often differ in patients at the same tumor stage.2 Given this fact, it is necessary to identify a specific prognostic biomarker that can accurately identify patients with poor prognosis, allowing health care professionals to preemptively alter their treatment strategy.
The metastasis-associated in colon cancer-1 (MACC1) mRNA is located on chromosome 7 (7p21.1) of the human genome and contains seven exons and six introns. The MACC1 coding sequence contains 2559 nucleotides and is translated to form a MACC1 protein containing 821 amino acids.3,4 The MACC1 protein contains an SH2 domain, an SH3 domain, an Eps15 homology domain, and phosphorylation sites of multiple tyrosine kinases. MACC1 has been shown to be involved in the regulation of related signaling pathways in various tumors,5 and its aberrant expression is often accompanied by the activation of associated signaling pathways, leading to the occurrence and metastasis of tumors. The hepatocyte growth factor (HGF)/c-met signaling pathway is recognized as a signaling pathway that plays an important role in cell growth, epithelial–mesenchymal transition, angiogenesis, invasion, and metastasis. In the initial study of the function of MACC1, the expression of MACC1 was positively correlated with the expression of the HGF receptor c-Met. Increasing or decreasing the expression of MACC1 can promote or inhibit the expression of c-Met.6 MACC1 and c-Met were highly expressed in the nuclei of colorectal cancer metastasis, while in situ tumor tissues MACC1 and c-Met were mainly expressed in the cytoplasm. Further, through electrophoretic mobility shift assay and chip experiments, MACC1 can be combined with SP1 binding sites in the c-Met promoter region to initiate c-Met transcription expression.7 Therefore, MACC1 can promote the activity of HGF/c-met signals by transcription activation of c-Met and participate in the regulation of tumor growth and metastasis. Subsequent studies have verified the positive regulatory effects of MACC1 on the HGF/c-met signaling pathway in GC,8-10 hepatocellular carcinoma,11 and ovarian cancer.12,13
Previous studies found a relationship between the expression of MACC1 and clinicopathological parameters of GC, but the results of these studies have been inconsistent. Guo et al.10 reported that high expression of MACC1 was highly associated with hepatic metastasis and peritoneal metastasis. However, Ge et al.14 suggested that high expression of MACC1 did not correlate with distant metastasis. The results of different studies have varied. Therefore, it is necessary to identify eligible studies and to perform a meta-analysis to investigate the association between MACC1 expression and clinicopathological characteristics, and to re-evaluate the prognostic significance of MACC1 in patients with GC.
Methods
Publication search
The studies related to the relationship between the expression of MACC1 and GC were searched in the databases of MEDLINE, Web of Science, and Embase using the keywords (“MACC1” or “Metastasis-associated in colon cancer-1”) and (“gastric cancer” or “stomach cancer” or “gastric neoplasm” or “stomach neoplasm”) and (“prognosis” or “survival”). The search was limited to English-language papers. Among the studies with the same or overlapping data published by the same investigators, we selected the most recent publications with the largest numbers of subjects.
Inclusion criteria
The following inclusion criteria were used for the literature selection in our meta-analysis: (a) the study could be either a prospective or retrospective clinical research; (b) the patients had pathologically confirmed GC; (c) the studies focused on the association of expression of MACC1 with clinical parameters and/or prognosis of patients with GC; and (d) MACC1 expression was examined by immunohistochemistry in GC specimens. For MACC1 staining intensity, sections were scored as 0 (negative), 1 (weak), 2 (medium) or 3 (intense); whereas the staining extent was scored according to the area percentages: 0 (0%), 1 (1%–25%), 2 (26%–50%), 3 (51%–75%), or 4 (76%–100%). The products of the staining intensity and extent scores were the final staining scores (0–12) for MACC1 expression. Tumors of final staining score ⩾3 were considered to be a positive expression.
The exclusion criteria were: (a) letters, reviews, editorials, case reports, or animal trials, and conference abstracts without original data; and (b) repeated articles based on the same database.
Study selection and data extraction
All data were extracted by two independent reviewers (Yan Jin and Kun Zhou). Discrepancies were resolved by discussion and re-evaluation. The following variables were extracted from each study if available: first author’s name, publication year, number of cases, MACC1 detection, MACC1 cut-off, high MACC1 proportion, outcome, hazard ratio (HR). To minimize bias, the HR and 95% confidence interval (CI) were extracted preferentially from multivariable analyses. If not available, HR and 95% CI from Kaplan–Meier curves were retrieved using Engauge Digitizer version 4.1 (http://digitizer.sourceforge.net/).
Assessment of study quality and statistical analysis
The Newcastle–Ottawa Scale (NOS) was used to evaluate the methodological quality of all included studies. A study with an NOS score ⩾6 was an indication of high quality. Discrepancies in the score were resolved through discussion between the authors.
The odds ratio (OR), as a relative risk in case-control retrospective studies, was used to quantitatively determine the association between MACC1 expression and the clinical parameters of GC in our manuscript. The heterogeneity of pooled data was assessed using I2 test. When significant heterogeneity among studies was absent (I2 < 50% or P > 0.05, a fixed-effects model (the Mantel–Haenszel method) was applied. Otherwise, a random-effects model (the DerSimonian and Laird method) was selected (I2 ⩾ 50% or P ⩽ 0.05). Sensitivity analysis was applied to evaluate the stability of the results. Begg’s funnel plot and Egger’s test were used to provide an evaluation of publication bias (linear regression analysis).15 All analyses were performed using STATA 14.0 software (STATA Corporation, College Station, TX, USA). Statistical significance was defined as P-values < 0.05.
Results
Literature retrieval and analysis
A flowchart of the literature retrieval process is shown in Figure 1. Initially, a total of 329 potential studies were found utilizing the electronic database search based on the study’s inclusion and exclusion criteria. After screening the titles and abstracts, nine eligible studies were included in the meta-analysis.9,10,14,16-21 The characteristics of selected studies are summarized in Table 1. All the included studies were performed retrospectively and published between 2011 and 2018. The follow-up period was over a span of 5 years in all eligible studies. It is noteworthy that none of the studies scored less than 6 on the NOS, suggesting that all included studies were of high methodological quality.
figure
Figure 1. Flow diagram of the literature search and selection.
Table
Table 1. Characteristics of nine studies included in the meta-analysis.
Table 1. Characteristics of nine studies included in the meta-analysis.
View larger version
Quantitative synthesis
To identify the clinical significance of MACC1, the association of MACC1 expression with clinicopathological features was investigated in this meta-analysis. Data, including gender, differentiation type, depth of invasion, lymph node metastasis, distant metastasis, and TNM stage were extracted from the included studies for the calculation of pooled ORs.
The results failed to show a correlation between positive expression of MACC1 and gender (OR 1.00; 95% CI 0.82, 1.23; P=0. 0.97; I2= 27.9%), differentiation type (OR 1.27; 95% CI 0.56, 2.88; P= 0.58; I2= 79.8%), depth of invasion (OR 1.74; 95% CI 0.82, 3.71; P= 0.15, I2=23.6%), lymph node metastasis (OR 1.58; 95% CI 0.78, 3.17; P= 0.20; I2=88.7%), and TNM stage (OR 2.05; 95% CI 0.78, 5.36; P= 0.20; I2=88.7%) (Table 2).
Table
Table 2. Meta-analysis results of the associations of high MACC1 expression level with clinicopathological characteristics.
Table 2. Meta-analysis results of the associations of high MACC1 expression level with clinicopathological characteristics.
View larger version
Our meta-analysis indicated that positive expression of MACC1 was significantly associated with distant metastasis (OR 4.68; 95% CI 1.98, 11.06; P <0.001; I2= 59.4%) and vascular invasion (OR 1.63; 95% CI 1.11, 2.38; P = 0.14; I2= 93.8%) (Table 2).
Relationship between MACC1 expression and overall survival
All of the included studies reported the results of overall survival (OS) regarding MACC1 expression with 2103 cancer patients. Because the heterogeneity was observed among studies (I2= 84.3%; P=0.000), the random-effects model was applied. The meta-analysis of these studies showed that a positive MACC1 expression level was significantly associated with poor OS in human cancer (HR 1.99; 95% CI 1.29, 3.09; P < 0.001) (Figure 2). A worse OS was observed in patients with a positive MACC1 expression level than that observed in patients with a negative MACC1 expression.
figure
Figure 2. Forest plot for the relationship between MACC1 expression and OS. MACC1: metastasis-associated in colon cancer-1; OS: overall survival.
Publication bias
For the meta-analysis of the relationship between MACC1 expression levels and OS, and Egger’s test was used to assess the publication bias. Egger’s test (Figure 3) showed that there was no significant publication bias observed among those studies (t= 0.10; P > |t|=0.85). However, due to the limited number of studies included, it was difficult to confirm the absence of publication bias in this meta-analysis. In the sensitivity analysis, we sequentially omitted each study while repeating the analysis to assess the impact of individual studies on the pooled HRs calculated for OS. The results of the sensitivity analysis indicated that our meta-analysis of OS was not dominated by any single study; therefore, the conclusions herein demonstrated credibility.
figure
Figure 3. Funnel plot analysis of potential publication bias in the meta-analysis.
Discussion
GC is a leading cause of human cancer mortality that is predominantly induced by tumor invasion, metastasis, and recurrence.1 Current prognostic indicators have been unable to satisfy the need for the accurate prediction of long-term outcomes in patients with GC.
MACC1 expression has been found to have prognostic value in lung cancer, oral squamous cell carcinoma, ovarian cancer, and breast cancer in terms of survival and recurrence rates. However, no previous studies have evaluated the prognostic significance of MACC1 overexpression in GC patients, which was the subject of our investigation. Recently, the expression of MACC1 and the relationship between expression of this gene and the clinicopathological parameters of patients with GC have been studied, with inconsistent findings. We performed a detailed and comprehensive meta-analysis study to investigate the prognostic role of expression of MACC1 in patients with GC. We found that (a) positive expression of MACC1 is not associated with gender, differentiation type, depth of invasion, lymph node metastasis, and TNM stage; and (b) positive expression of MACC1 in primary tumors is associated with distant metastasis and results in a poor prognosis. These results implied that MACC1 was likely to participate in tumor metastasis. Further studies are needed to support this conclusion
Considering that tumor metastasis requires a sufficient blood supply, which, in most cases, is achieved by neovascularization, angiogenesis is a well-recognized hallmark of cancer.22 Some studies indicated that MACC1 overexpression was associated with the vascular invasion of GC. In this meta-analysis, we observed similar results. MACC1 facilitates GC lymph angiogenesis by upregulating extracellular secretion of vascular endothelial growth factor C/D, indicating that MACC1 may be an important player in GC lymphatic dissemination; however, we found that the high expression of MACC1 is not related to lymph node metastasis.23
GC patients with high circulating plasma transcript levels of MACC1 had a significantly shorter survival compared to patients with low levels of MACC1 expression. These results indicate that circulating MACC1 possesses prognostic value in patients with GC. The small molecules lovastatin and rottlerin emerged as the most potent MACC1 transcriptional inhibitors. They remarkably inhibited MACC1 promoter activity and expression, resulting in reduced cell motility. Lovastatin impaired the binding of the transcription factors c-Jun and Sp1 to the MACC1 promoter, thereby inhibiting MACC1 transcription.24
Some limitations of this meta-analysis should be noted. First, some heterogeneity existed among the included studies.25 Second, all of the research institutes at which the included studies were performed were located in Asia, suggesting that the tissue samples were probably all obtained from Asian patients. Third, the HRs with 95% CI were not directly extracted from the studies, so we based our studies on the data extracted from Kaplan–Meier curves, which compromises the precision of the data. Lastly, the majority of the included studies did not use blinding; the lack thereof might have resulted in selection bias.
In conclusion, this study demonstrates the significance of MACC1 as an important clinical indicator for patients with GC. Our meta-analysis provides evidence that positive expression of MACC1 may be associated with distant metastasis, vascular invasion, and OS. Due to the limitations of meta-analyses, larger studies are still needed to more accurately evaluate the association of MACC1 expression with the clinicopathological characteristics of patients with GC.
Author contributions
Yan Jin and Kun Zhou contributed equally to this work as the first authors.
Study conception and design: Yan Jin, Jinfei Chen, Kou Zhou, Wenjing Zhao
Acquisition of data: Yan Jin, Kun Zhou, Wenjing Zhao, Fen Yang, Xinying Huo, Rongbo Han
Analysis and interpretation of data: Yan Jin, Fen Yang, Kun Zhou, Jinfei Chen
Drafting of manuscript: Yan Jin, Fen Yang
Critical revision: Yan Jin, Fen Yang, Jinfei Chen.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
References
1. Torre, L. A, Bray, F, Siegel, R. L. Global cancer statistics, 2012. CA Cancer J Clin 2015; 65: 87–108.
Google Scholar | Medline | ISI
2. Bette, S, Barz, M, Wiestler, B. Prognostic value of tumor volume in glioblastoma patients: size also matters for patients with incomplete resection. Ann Surg Oncol 2018; 25: 558–564.
Google Scholar | Medline
3. Stein, U, Walther, W, Arlt, F. MACC1, a newly identified key regulator of HGF-MET signaling, predicts colon cancer metastasis. Nat Med 2009; 15: 59–67.
Google Scholar | Medline
4. Arlt, F, Stein, U. Colon cancer metastasis: MACC1 and Met as metastatic pacemakers. Int J Biochem Cell Biol 2009; 41: 2356–2359.
Google Scholar | Medline
5. Wu, ZZ, Chen, LS, Zhou, R. Metastasis-associated in colon cancer-1 in gastric cancer: Beyond metastasis. World J Gastroenterol 2016; 22: 6629–6637.
Google Scholar | Medline
6. Stein, U, Walther, W, Arlt, F. MACC1, a newly identified key regulator of HGF-MET signaling, predicts colon cancer metastasis. Nat Med 2009; 15: 59–67.
Google Scholar | Medline
7. Stein, U, Smith, J, Walther, W. MACC1 controls Met. What a difference an Sp1 site makes. Cell Cycle 2009; 8: 2467–2469.
Google Scholar | Medline
8. Huang, N, Wu, Z, Lin, L. MiR-338–3p inhibits epithelial-mesenchymal transition in gastric cancer cells by targeting ZEB2 and MACC1/Met/Akt signaling. Oncotarget 2015; 6: 15222–15234.
Google Scholar | Medline
9. Ma, J, Ma, J, Meng, Q. Prognostic value and clinical pathology of MACC-1 and c-MET expression in gastric carcinoma. Pathol Oncol Res 2013; 19: 821–832.
Google Scholar | Medline
10. Guo, T, Yang, J, Yao, J. Expression of MACC1 and c-Met in human gastric cancer and its clinical significance. Canc Cell Int 2013; 13: 121.
Google Scholar | Medline
11. Yao, Y, Dou, C, Lu, Z. MACC1 suppresses cell apoptosis in hepatocellular carcinoma by targeting the HGF/c-MET/AKT pathway. Cell Physiol Biochem 2015; 35: 983–996.
Google Scholar | Medline
12. Li, H, Zhang, H, Zhao, S. Overexpression of MACC1 and the association with hepatocyte growth factor/c-Met in epithelial ovarian cancer. Oncol Lett 2015; 9: 1989–1996.
Google Scholar | Medline
13. Sheng, XJ, Li, Z, Sun, M. MACC1 induces metastasis in ovarian carcinoma by upregulating hepatocyte growth factor receptor c-MET. Oncol Lett 2014; 8: 891–897.
Google Scholar | Medline
14. Ge, SH, Wu, XJ, Wang, XH. Over-expression of metastasis-associated in colon cancer-1 (MACC1) associates with better prognosis of gastric cancer patients. Chin J Canc Res 2011; 23: 153–159.
Google Scholar | Medline
15. Egger, M, Davey Smith, G, Schneider, M. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315: 629–634.
Google Scholar | Medline
16. Lu, G, Zhou, L, Zhang, X. The expression of metastasis-associated in colon cancer-1 and KAI1 in gastric adenocarcinoma and their clinical significance. World J Surg Oncol 2016; 14: 276.
Google Scholar | Medline
17. Koh, YW, Hur, H, Lee, D. Increased MACC1 expression indicates a poor prognosis independent of MET expression in gastric adenocarcinoma. Pathol Res Pract 2016; 212: 93–100.
Google Scholar | Medline
18. Dong, G, Wang, M, Gu, G. MACC1 and HGF are associated with survival in patients with gastric cancer. Oncol Lett 2018; 15: 3207–3213.
Google Scholar | Medline
19. Xie, QP, Xiang, C, Wang, G. MACC1 upregulation promotes gastric cancer tumor cell metastasis and predicts a poor prognosis. J Zhejiang Univ Sci B 2016; 17: 361–366.
Google Scholar | Medline
20. Sun, L, Duan, J, Jiang, Y. Metastasis-associated in colon cancer-1 upregulates vascular endothelial growth factor-C/D to promote lymphangiogenesis in human gastric cancer. Cancer Letters 2015; 357: 242–253.
Google Scholar | Medline
21. Wang, L, Wu, Y, Lin, L. Metastasis-associated in colon cancer-1 upregulation predicts a poor prognosis of gastric cancer, and promotes tumor cell proliferation and invasion. Int J Canc 2013; 133: 1419–1430.
Google Scholar | Medline
22. Hanahan, D, Weinberg, RA. Hallmarks of cancer: the next generation. Cell 2011; 144: 646–674.
Google Scholar | Medline | ISI
23. Sun, L, Duan, J, Jiang, Y. Metastasis-associated in colon cancer-1 upregulates vascular endothelial growth factor-C/D to promote lymphangiogenesis in human gastric cancer. Cancer Lett 2015; 1: 242–253.
Google Scholar
24. Juneja, M, Kobelt, D, Walther, W. Statin and rottlerin small-molecule inhibitors restrict colon cancer progression and metastasis via MACC1. PloS Biol 2017; 15 (6): e2000784.
Google Scholar | Medline
25. Fagoonee, S, Durazzo, M. HOTAIR and gastric cancer: a lesson from two meta-analyses. Panminerva Med 2017; 59 (3): 201–202.
Google Scholar | Medline
View Abstract
Δεν υπάρχουν σχόλια:
Δημοσίευση σχολίου