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Prognostic value of matrix metalloproteinase-2 protein and matrix metalloproteinase-9 protein in colorectal cancer: a meta-analysis

BMC Cancer volume 24, Article number: 1065 (2024) Cite this article

Abstract

Introduction

Matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) are critical components of the extracellular matrix (ECM) in colorectal cancer (CRC). We aimed to evaluate the prognostic value of MMP-2 and MMP-9 in patients with CRC.

Methods

We performed a meta-analysis of cohort studies with available data on the effect of MMP-2 and MMP-9 expression on both disease-free survival (DFS) and overall survival (OS) by the risk ratios (RRs) with their 95% confidence intervals (CIs). Studies were subgrouped based on the different tissue types, including cancer tissue and normal tissue, and the subgroup effect of MMP expression in different tissues was analyzed through meta-regression. To ensure the quality and reduce the risk of bias, the Newcastle‒Ottawa Scale (NOS) was used to assess the included studies. A sensitivity analysis was randomly performed to assess the potential impact of each study on our results.

Results

Eighteen trials were selected (Table 1) and included a total of 3944 patients. According to our primary meta-analysis, the expression of MMP-2 was significantly associated with a decrease in OS (RR = 1.75, 95% CI = 1.34 to 2.29, P < 0.001) and DFS (RR = 2.62, 95% CI = 1.25 to 5.49, P < 0.001), and the expression of MMP-9 was not significantly associated with a decrease in OS (RR = 1.48, 95% CI = 0.97 to 2.24, P = 0.069) or DFS (RR = 1.60, 95% CI = 0.87 to 2.94, P = 0.133). According to the subgroup analysis of MMPs in different tissues, high MMP-2 expression in cancer tissue (RR = 1.90, 95% CI = 1.29 to 2.79) and normal tissue (RR = 1.59, 95% CI = 1.17 to 2.17) were significant indicators of poor OS. High MMP-2 expression in cancer tissue was significant indicator of poor DFS (RR = 2.12, 95% CI = 1.09 to 4.11). MMP-9 expression was also associated with poor OS (RR = 1.40, 95% CI = 0.85 to 2.29), but the difference in OS between the high and low expression groups was not statistically significant.

Conclusions

High MMP-2 expression, especially in cancer tissue, is significantly associated with both poor DFS and poor OS in patients with CRC. High MMP-9 expression tended to indicate a poor prognosis of CRC but the correlation was not significant.

Peer Review reports

Background

Colorectal cancer (CRC), recognized as the second most common cause of cancer mortality worldwide, has become a major global health burden [1]. Although only approximately 20% of patients with CRC are initially diagnosed with metastatic colorectal cancer (mCRC), up to 50% of patients with localized disease will eventually develop metastases [2]. Known for its high morbidity, mortality and distinctive evolution mechanism, mCRC has a poor clinical outcome, with a median overall survival (OS) of only 25–30 months after systemic therapy [3]. Treatment regimens include local resection, downstaging preoperative systemic therapy, extensive surgery, palliative chemotherapy, targeted therapy, and immunotherapy [4]. However, one of the significant challenges in CRC treatment is multidrug resistance (MDR), which refers to the ability of cancer cells to become resistant to a wide range of chemotherapies, making treatment increasingly difficult and often leading to treatment failure [5]. Hence, unraveling the molecular mechanism of colorectal cancer, identifying novel tumor targets, and developing personalized treatments are crucial research goals.

In recent years, the role of the extracellular matrix (ECM) as a possible predictive and prognostic marker in multiple types of malignant tumors, including colorectal cancer, has been explored [6]. A variety of molecules in the ECM, such as collagen, fibronectin, and matrix metalloproteinases (MMPs), have been shown to contribute to the cleavage of protein fibers and tissue remodeling. Among these, MMPs, which are the most important family of proteases, play an essential role in cleaving different components during the reconstruction of the ECM [7]. Furthermore, MMPs also regulate many biological functions by controlling the activity of growth factors, chemokines, and cell receptors [8]. In colorectal cancer, some studies have shown that MMPs are crucial for tumor invasion and metastasis, suggesting their potential role as diagnostic markers [9].

The analysis of MMP-2 and MMP-9 protein expression and its prognostic value in colorectal cancer could therefore be of particular value in the treatment setting. Several studies have revealed that the increased expression of MMP-2 and MMP-9 is closely related to the course of colorectal cancer, suggesting an association between MMP-2 and MMP-9 and poor prognosis in colorectal cancer patients [10, 11]. However, some investigators have reported that the MMP-9 gene inhibits β-catenin activity by stimulating Notch activation to lead to p21WAF1/CIP1 activation, thereby exerting a protective effect on CRC [12, 13]. Therefore, we performed a meta-analysis of available data to confirm these associations and address the heterogeneity of different reports on the prognostic role of MMP-2 and MMP-9 expression in CRC.

Methods

Research question

This meta-analysis of cohort trials was performed according to the MOOSE (Preferred Reporting Items for Systematic reviews and Meta-analyses of Observational Studies) recommendations. Ethical approval was not necessary since this study was not a human or animal experiment.

Literature search

We searched PubMed, Embase, and the Cochrane Library (all up to Jan 6, 2024) for published articles related to the expression of MMP-2 and MMP-9 in patients with CRC without any language restriction. The search strategy was designed by integrating the different expression levels of MMP-2 and MMP-9, which are diverse terms of CRC, and the required prognostic indicators. The detailed keywords used in the retrieval are listed in Supplementary Table 1.

Eligibility criteria

The inclusion criteria were as follows: (1) original articles on the association between the expression of MMP-2 and/or MMP-9 and the prognosis of CRC and (2) articles whose full text was available. The main exclusion criterion was the absence of hazard ratios (HRs) and/or risk ratios (RRs) of positive/high vs. negative/low expression for DFS, progression-free survival (PFS) or OS. In addition, reviews, meta-analyses, case reports, conference abstracts, and correspondence letters were excluded. When more than 1 article referring to the same trial was found, the most up-to-date and complete report was selected.

Study selection

Records retrieved via the search were imported in tabular format in a CSV file and screened for potential inclusion by 2 investigators independently in parallel. The full texts of the articles deemed candidates for the meta-analysis were obtained and independently assessed for final inclusion by the 2 investigators in parallel. Discrepancies were resolved by discussion or by a third supervisor investigator.

Data extraction

Hazard ratio or risk ratio and 95% confidence interval (CI) data of MMP-2 and/or MMP-9-positive/high vs. negative/low-expression subgroups for DFS, PFS or OS for each study were independently extracted by 2 investigators. Specifically, DFS was defined as the time from treatment allocation to cancer relapse, death or the last follow-up. PFS was defined as the time from randomization or initiation of treatment to the occurrence of disease progression or death. OS was defined as the time from treatment allocation to death due to any cause or to the last follow-up. Due to the limited number of studies included in our meta-analysis, we decided to combine PFS and DFS to enhance the statistical power and obtain more reliable results. Considering the possible challenge in pooling results among different studies, we decided to use RRs throughout and convert HRs to RRs without exaggerating these results.

The following data were also collected: date of publication, first author, publishing journal, country or area, study design, detection methods, patient characteristics (sample source, number of patients, and sex ratio), median time of follow-up, number of positive/high and negative/low cases, type of Cox regression model for hazard ratio estimation (univariate vs. multivariate), and the aforementioned endpoints. All data were extracted from the eligible studies using a standard data-extraction form and then transferred into an Excel spreadsheet.

Quality assessment

To ensure that all the studies included in our meta-analysis were of high quality, we used a set of predefined criteria based on the Newcastle‒Ottawa Scale (NOS) criteria to evaluate the studies; these evaluations were performed independently by 2 investigators in parallel. The criteria of the NOS include three aspects: (1) selection, 0–4; (2) comparability, 0–2; and (3) clinical outcome, 0–3. Total NOS scores range from 0 (lowest) to 9 (highest). According to the NOS, the included studies were classified into two levels: low-quality research with a score of 0–5 and high-quality research with a score of 6–9. A score of 6 or more was considered the inclusion criterion according to a discussion among all the investigators.

Statistical analysis

To evaluate the associations between the expression levels of MMPs and the survival outcomes of patients with CRC, pooled HRs with 95% CIs were evaluated for OS, PFS and DFS. To determine the associations between tumor tissue and normal tissue MMP-2 and MMP-9 expression and survival outcomes, reflecting their prognostic value in CRC, we conducted subgroup analyses. The heterogeneity and publication bias among the different studies were estimated by the I-squared test and visualized in a funnel plot. I2 > 50% and p < 0.05 were considered indicators of obvious heterogeneity among the studies. For heterogeneity analysis, the random-effects model was utilized if I2 > 50% or p < 0.05; otherwise, the fixed-effects model was used. Publication bias was visualized in a funnel plot and analyzed via Begg’s test [14]. In our study, P values less than 0.05 were considered to indicate statistical significance. Analysis of the effect size of all the data were performed with RevMan 5.0 software, while heterogeneity was analyzed with Stata 12.0 software.

Results

Study selection

The initial search yielded 1610 articles, which were thoroughly reviewed for entry criteria (Fig. 1). Eighteen cohort studies were ultimately identified that met the inclusion criteria [10, 11, 15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30] (Table 1). Overall, a total of 3944 patients were analyzed.

Fig. 1
figure 1

Study selection flow diagram

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Table 1 Characteristics of the included studies
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Effect of MMP-2 expression on DFS and OS

Thirteen studies evaluated whether the expression of MMP-2 influences survival outcomes of patients with CRC. Nine studies were included for the OS analysis based on MMP-2 expression. Five studies were included for DFS analysis based on MMP-2 expression. Among them, we found that more than one cohort was analyzed in several studies, which were then analyzed separately. High MMP-2 expression was associated with a statistically significant decrease in OS in CRC patients (RR = 1.75, 95% CI = 1.34 to 2.29, P < 0.001; Fig. 2A). Correspondingly, high MMP-2 expression was associated with significantly poorer DFS in CRC patients (RR = 2.62, 95% CI = 1.25 to 5.49, P < 0.001; Fig. 2B). However, substantial heterogeneity was detected in the pooled HRs for both OS (I2 = 60.4%, P = 0.007) and DFS (I2 = 71.6%, P = 0.004).

Fig. 2
figure 2

Effect of MMP-2 expression on the DFS and OS of CRC patients

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Effect of MMP-9 expression on DFS and OS

We further evaluated the correlation between the expression of MMP-9 and the prognosis of CRC since its molecular structure and function are similar to those of MMP-2. Data for a total of 11 studies on cohorts meeting the criteria were extracted; 7 studies reported OS and 5 studies reported DFS. However, our analysis revealed no statistically significant associations between MMP-9 and OS (RR = 1.48, 95% CI = 0.97 to 2.24, P = 0.069; Fig. 3A) or DFS (RR = 1.60, 95% CI = 0.87 to 2.94, P = 0.133; Fig. 3B). The results also showed a high degree of study heterogeneity for OS (I2 = 78.9%, P < 0.001) and DFS (I2 = 81.3%, P < 0.001).

Fig. 3
figure 3

Effect of MMP-9 expression on the DFS and OS of CRC patients

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Effect of MMP-2 expression in different tissues on DFS and OS

To further evaluate the association between MMP-2 expression in different tissues and the clinical outcomes of CRC patients, we performed subgroup analyses of patients stratified according to MMP-2 expression in cancer tissue and normal tissue. The analysis revealed that MMP-2 expression in both cancer tissue (RR = 1.90, 95% CI = 1.29 to 2.79; Fig. 4A) and normal tissue (RR = 1.59, 95% CI = 1.17 to 2.17; Fig. 4A) significantly predicts poor OS in CRC patients. Moreover, we also independently evaluated the association between MMP-2 expression in cancer tissue and DFS (RR = 2.12, 95% CI = 1.09 to 4.11; Fig. 4B). The test for heterogeneity revealed positive associations of tissue MMP-2 expression with OS and DFS except for the normal tissue MMP-2 expression and OS (I2 = 0.0%, P = 0.825). However, there were not enough studies to analyze the effect of MMP-2 expression in normal tissue on DFS.

Effect of MMP-9 expression in cancer tissue on OS

According to the subgroup analysis, the expression of MMP-9 in cancer tissue was also associated with inferior OS, but this difference was not statistically significant (RR = 1.40, 95% CI = 0.85 to 2.29; Fig. 4C). A high degree of study heterogeneity was observed for this analysis (I2 = 82%, P = 0.000). However, few studies have analyzed the effect of MMP-9 expression in normal tissue on OS, and no study has reported the effect of MMP-9 expression in normal tissue on DFS.

Fig. 4
figure 4

Effect of MMP-2 and MMP-9 expression in different tissues on the DFS and OS of CRC patients

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Publication bias analysis and study quality assessment

All included studies were assessed for bias risk according to the NOS criteria, and all studies received an independent assessment and discussion score of 6 by 2 investigators, which further confirmed that the results were stable. Furthermore, a sensitivity analysis was randomly performed to assess the potential impact of each study on our results. The results indicated that some studies significantly influenced the observed association between the expression of MMP-2 and MMP-9 and poor survival outcomes (Fig. 5). Notably, one study had opposite results compared to all other included studies, which led to a negative change in overall statistical significance for the MMP-9-related analysis. According to this article, high MMP-9 expression in primary tumors indicates a better prognosis in patients with CRC, especially after resection of colorectal liver metastases. Through comparison, we found that the patients enrolled had both primary colorectal tumors and liver metastases, which implies that liver metastasis and surgery may change the expression of MMP-9 in the extracellular matrix. Similarly, the subgroup sensitivity analysis showed that the pooled RR for MMP-9 was influenced the most by this study. When this study was excluded from the analysis, MMP-9 was a significant biomarker for poor outcomes in CRC patients (Supplementary Fig. 1).

Through the heterogeneity test, we chose random effect models if I2 > 50%. The publication bias in our study was assessed by Begg’s test and funnel plots, all of which were generated with Stata software [31]. Funnel plots were used to assess publication bias for the main outcome, which was the effect of MMP-2 expression on DFS and OS, and the secondary outcome, which was the effect of MMP-9 expression on DFS and OS in our meta-analysis (Supplementary Fig. 2). The same was true for the subgroup analysis, which involved assessment of the correlation of MMP-2 and MMP-9 expression in different tissues and the clinical outcomes of patients with CRC (Supplementary Fig. 3). The relatively significant asymmetry for both MMP-2 and MMP-9 was shown by Begg’s test, with an overall p value greater than 0.151. Regarding subgroup analysis, Begg’s test also indicated that no publication bias existed in the pooled analysis.

Fig. 5
figure 5

Sensitivity plots of studies included in the meta-analysis

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Discussion

In 2020, there were an estimated 1,148,515 new colorectal cancer (including anal cancer) diagnoses and 576,858 related deaths worldwide, making it the second most common cause of death among malignancies [1]. Unfortunately, disease recurrence and metastases after curative surgery with or without adjuvant chemotherapy contribute to many of these mortalities. Biomarkers that can predict local recurrence or distant metastasis should be identified, and drug targets should be explored to guide more personalized treatment. In addition, understanding the roles of these molecules in processes such as tumor growth, local invasion, and distant metastasis may help to elucidate the pathogenesis of CRC. MMP-2 and MMP-9, which are known as gelatinases, can digest type IV collagen and gelatin in the ECM. Previous studies have shown a positive correlation between the expression of MMP-2 and MMP-9 and tumor invasion and metastasis in CRC. To increase the likelihood of high-quality assessments of MMP-2 and MMP-9 in CRC, we searched for cohort studies with survival data and found 18 studies in which the effects of the expression of these MMPs on DFS, PFS, and/or OS were investigated.

MMP-2 plays a significant role in angiogenesis and affects cell adhesion by enhancing tumor invasion and distant metastasis through the degradation of collagen type IV in the ECM [17]. High MMP-2 expression is related to high-grade tumor stage, lymph node metastasis, and poor survival in CRC patients [19, 32, 33]. Similarly, the detrimental effect of MMP-2 expression on DFS and OS was evident in our study. Increased MMP-2 expression in both cancer and normal tissues was observed to be associated with worse outcomes CRC patients, highlighting its role as a potential prognostic biomarker for CRC. However, the relationship between MMP-2 expression and DFS in normal tissues was not analyzed because of the lack of studies. Overall, according to the RR, MMP-2 in cancer tissue may be a better index for predicting survival in CRC patients.

As a member of the MMP family with complex domains, MMP-9 is capable of degrading a variety of components in the ECM, such as decorin, fibrillin, and collagen [34]. The overexpression of MMP-9 has been found to be a biomarker predictive of poor prognosis in various malignancies, including colorectal cancer. In contrast, several studies have reported that MMP-9 can suppress β-catenin, reduce reactive oxygen species (ROS) levels, and decrease DNA damage, suggesting its protective role in CRC [12, 13, 35]. In our study, although there was a poor prognosis in MMP-9-positive CRC patients, the difference in prognosis between these patients and MMP-9-negative patients was not statistically significant. Specifically, we observed that one study had opposite results compared to all other included studies. Therefore, the negative results may be related to the findings of the outlier study or to the protective role of MMP-9, which has been previously reported. This indicates the need for more studies. Generally, MMP-9 had no statistically significant effect on the clinical outcomes of CRC patients, which may indicate that the expression of MMP-2 is a better prognostic biomarker than the expression of MMP-9.

As MMPs are widely expressed in the ECM, MMP-2 and MMP-9 may have different characteristics and functions according to their location and relative expression. In our subgroup analysis, we analyzed the effect of MMPs, including MMP-2 and MMP-9, in normal tissue and cancer tissue on the prognosis of CRC. Notably, cancer tissue was inferred to be a more appropriate sample source for the detection of MMPs since the expression levels were more closely related to prognosis. However, MMP-9 expression in tumor tissue was not significantly associated with poor OS in CRC patients. The effect of MMP-9 in normal tissue on the prognosis of CRC was not assessed due to insufficient data in the included studies. Based on these limited results, we can infer that the expression of MMP-2 in tumor tissues has prognostic value and that the prognostic value of MMP-9 expression in different tissues cannot be confirmed. Overall, our study has shown that high expression of MMP-2 and MMP-9 tend to be associated with poor prognosis in CRC patients. Exploring related inhibitors may be a promising treatment for CRC. Recent advances have highlighted the ability of natural small molecules to inhibit tumor growth through various mechanisms, including the modulation of signaling pathways and inhibition of MMPs [36]. For instance, berberine and apigenin derivatives inhibit the activity and expression of MMP-2 and MMP-9 and demonstrate significant promise in cancer treatment [37, 38]. Future research should focus on the application of MMPs inhibitors in CRC treatment.

Several limitations of the present meta-analysis should be discussed. Given the relatively moderate number of included studies, the conclusion that MMP-2 is a prognostic indicator of cancer should be recognized with caution. In addition, given its retrospective nature, the grade of evidence was inferior to that of randomized controlled trials. Furthermore, the reason for the high heterogeneity may include the following factors. First, patient characteristics, including age, sex, tumor grade, complications and treatment regimens, were not taken into consideration. Second, the detection methods used for IHC among different laboratories and the cutoff values used vary. Third, there are not enough studies to demonstrate the relationship between the expression of MMP-9 and its expression in different tissues and the prognosis of colorectal cancer patients. Similarly, there is a lack of studies exploring the effect of MMP-2 in normal tissue on prognosis. Moreover, not only do MMP-2 and MMP-9 have prognostic value in CRC, but other MMPs, such as matrix metalloprotein-1 (MMP-1), matrix metalloprotein-7 (MMP-7), matrix metalloprotein-8 (MMP-8) and matrix metalloprotein-13 (MMP-13), are also potential prognostic markers [39,40,41,42].

Conclusions

The present meta-analysis demonstrated a significant association between high MMP-2 expression and a poor prognosis in CRC patients, especially in cancer tissue. Although we expected to that MMP-9 would have the same predictive effect, we only observed a nonsignificant trend. Considering the paucity of studies included, larger samples and well-designed prospective confirmation studies of these findings are warranted.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

CRC:

Colorectal cancer

CI:

Confidence interval

DFS:

Disease-free survival

ECM:

Extracellular matrix

HR:

Hazard ratio

IHC:

Immunohistochemistry

mCRC:

Metastatic colorectal cancer

MMPs:

Matrix metalloproteins

MDR:

Multidrug resistance

NOS:

Newcastle‒Ottawa Scale

NA:

Not available

OS:

Overall survival

PFS:

Progression-free survival

ROS:

Reactive oxygen species

RR:

Risk ratio

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer statistics 2020: GLOBOCAN estimates of incidence and Mortality Worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49. https://doi.org/10.3322/caac.21660.

    Article  CAS  PubMed  Google Scholar 

  2. Ciardiello F, Ciardiello D, Martini G, Napolitano S, Tabernero J, Cervantes A. Clinical management of metastatic colorectal cancer in the era of precision medicine. CA Cancer J Clin. 2022;72(4):372–401. https://doi.org/10.3322/caac.21728.

    Article  PubMed  Google Scholar 

  3. Weng J, Li S, Zhu Z, Liu Q, Zhang R, Yang Y, Li X. Exploring immunotherapy in colorectal cancer. J Hematol Oncol. 2022;15(1):95. https://doi.org/10.1186/s13045-022-01294-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet. 2019;394(10207):1467–80. https://doi.org/10.1016/s0140-6736(19)32319-0.

    Article  PubMed  Google Scholar 

  5. Emran TB, Shahriar A, Mahmud AR, Rahman T, Abir MH, Siddiquee MF, Ahmed H, Rahman N, Nainu F, Wahyudin E, et al. Multidrug Resistance in Cancer: understanding Molecular mechanisms, Immunoprevention and therapeutic approaches. Front Oncol. 2022;12:891652. https://doi.org/10.3389/fonc.2022.891652.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Karlsson S, Nyström H. The extracellular matrix in colorectal cancer and its metastatic settling - alterations and biological implications. Crit Rev Oncol Hematol. 2022;175:103712. https://doi.org/10.1016/j.critrevonc.2022.103712.

    Article  CAS  PubMed  Google Scholar 

  7. Zhong Y, Lu YT, Sun Y, Shi ZH, Li NG, Tang YP, Duan JA. Recent opportunities in matrix metalloproteinase inhibitor drug design for cancer. Expert Opin Drug Discov. 2018;13(1):75–87. https://doi.org/10.1080/17460441.2018.1398732.

    Article  CAS  PubMed  Google Scholar 

  8. Baker AH, Edwards DR, Murphy G. Metalloproteinase inhibitors: biological actions and therapeutic opportunities. J Cell Sci. 2002;115(Pt 19):3719–27. https://doi.org/10.1242/jcs.00063.

    Article  CAS  PubMed  Google Scholar 

  9. Mustafa S, Koran S, AlOmair L. Insights into the role of Matrix metalloproteinases in Cancer and its various therapeutic aspects: a review. Front Mol Biosci. 2022;9:896099. https://doi.org/10.3389/fmolb.2022.896099.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Langers AM, Verspaget HW, Hawinkels LJ, Kubben FJ, van Duijn W, van der Reijden JJ, Hardwick JC, Hommes DW, Sier CF. MMP-2 and MMP-9 in normal mucosa are independently associated with outcome of colorectal cancer patients. Br J Cancer. 2012;106(9):1495–8. https://doi.org/10.1038/bjc.2012.80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Araújo RF Jr., Lira GA, Vilaça JA, Guedes HG, Leitão MC, Lucena HF, Ramos CC. Prognostic and diagnostic implications of MMP-2, MMP-9, and VEGF-α expressions in colorectal cancer. Pathol Res Pract. 2015;211(1):71–7. https://doi.org/10.1016/j.prp.2014.09.007.

    Article  CAS  PubMed  Google Scholar 

  12. Garg P, Jeppsson S, Dalmasso G, Ghaleb AM, McConnell BB, Yang VW, Gewirtz AT, Merlin D, Sitaraman SV. Notch1 regulates the effects of matrix metalloproteinase-9 on colitis-associated cancer in mice. Gastroenterology. 2011;141(4):1381–92. https://doi.org/10.1053/j.gastro.2011.06.056.

    Article  CAS  PubMed  Google Scholar 

  13. Garg P, Sarma D, Jeppsson S, Patel NR, Gewirtz AT, Merlin D, Sitaraman SV. Matrix metalloproteinase-9 functions as a tumor suppressor in colitis-associated cancer. Cancer Res. 2010;70(2):792–801. https://doi.org/10.1158/0008-5472.Can-09-3166.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–34. https://doi.org/10.1136/bmj.315.7109.629.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Buhmeida A, Bendardaf R, Hilska M, Collan Y, Laato M, Syrjänen S, Syrjänen K, Pyrhönen S. Prognostic significance of matrix metalloproteinase-9 (MMP-9) in stage II colorectal carcinoma. J Gastrointest Cancer. 2009;40(3–4):91–7. https://doi.org/10.1007/s12029-009-9091-x.

    Article  CAS  PubMed  Google Scholar 

  16. Cho YB, Lee WY, Song SY, Shin HJ, Yun SH, Chun HK. Matrix metalloproteinase-9 activity is associated with poor prognosis in T3-T4 node-negative colorectal cancer. Hum Pathol. 2007;38(11):1603–10. https://doi.org/10.1016/j.humpath.2007.03.018.

    Article  CAS  PubMed  Google Scholar 

  17. Deng J, Chen W, Du Y, Wang W, Zhang G, Tang Y, Qian Z, Xu P, Cao Z, Zhou Y. Synergistic efficacy of Cullin1 and MMP-2 expressions in diagnosis and prognosis of colorectal cancer. Cancer Biomark. 2017;19(1):57–64. https://doi.org/10.3233/cbm-160341.

    Article  CAS  PubMed  Google Scholar 

  18. Dong W, Li H, Zhang Y, Yang H, Guo M, Li L, Liu T. Matrix metalloproteinase 2 promotes cell growth and invasion in colorectal cancer. Acta Biochim Biophys Sin (Shanghai). 2011;43(11):840–8. https://doi.org/10.1093/abbs/gmr085.

    Article  CAS  PubMed  Google Scholar 

  19. Hilska M, Roberts PJ, Collan YU, Laine VJ, Kössi J, Hirsimäki P, Rahkonen O, Laato M. Prognostic significance of matrix metalloproteinases-1, -2, -7 and – 13 and tissue inhibitors of metalloproteinases-1, -2, -3 and – 4 in colorectal cancer. Int J Cancer. 2007;121(4):714–23. https://doi.org/10.1002/ijc.22747.

    Article  CAS  PubMed  Google Scholar 

  20. Inafuku Y, Furuhata T, Tayama M, Okita K, Nishidate T, Mizuguchi T, Kimura Y, Hirata K. Matrix metalloproteinase-2 expression in stromal tissues is a consistent prognostic factor in stage II colon cancer. Cancer Sci. 2009;100(5):852–8. https://doi.org/10.1111/j.1349-7006.2009.01116.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Langers AM, Sier CF, Hawinkels LJ, Kubben FJ, van Duijn W, van der Reijden JJ, Lamers CB, Hommes DW, Verspaget HW. MMP-2 geno-phenotype is prognostic for colorectal cancer survival, whereas MMP-9 is not. Br J Cancer. 2008;98(11):1820–3. https://doi.org/10.1038/sj.bjc.6604380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Li M, Li JY, Zhao AL, He JS, Zhou LX, Li YA, Gu J. Survival stratification panel of colorectal carcinoma with combined expression of carcinoembryonic antigen, matrix metalloproteinases-2, and p27 kip1. Dis Colon Rectum. 2007;50(11):1887–98. https://doi.org/10.1007/s10350-007-9053-y.

    Article  PubMed  Google Scholar 

  23. Ogata Y, Matono K, Sasatomi T, Ishibashi N, Ohkita A, Mizobe T, Ogo S, Ikeda S, Ozasa H, Shirouzu K. The MMP-9 expression determined the efficacy of postoperative adjuvant chemotherapy using oral fluoropyrimidines in stage II or III colorectal cancer. Cancer Chemother Pharmacol. 2006;57(5):577–83. https://doi.org/10.1007/s00280-005-0081-9.

    Article  CAS  PubMed  Google Scholar 

  24. Peltonen R, Hagström J, Tervahartiala T, Sorsa T, Haglund C, Isoniemi H. High expression of MMP-9 in primary tumors and High Preoperative MPO in serum predict Improved Prognosis in Colorectal Cancer with Operable Liver metastases. Oncology. 2021;99(3):144–60. https://doi.org/10.1159/000510609.

    Article  CAS  PubMed  Google Scholar 

  25. Salem N, Kamal I, Al-Maghrabi J, Abuzenadah A, Peer-Zada AA, Qari Y, Al-Ahwal M, Al-Qahtani M, Buhmeida A. High expression of matrix metalloproteinases: MMP-2 and MMP-9 predicts poor survival outcome in colorectal carcinoma. Future Oncol. 2016;12(3):323–31. https://doi.org/10.2217/fon.15.325.

    Article  CAS  PubMed  Google Scholar 

  26. Sundov Z, Tomić S, Vilović K, Kunac N, Kalebić M, Bezić J. Immunohistochemically detected high expression of matrix metalloproteinase-2 as predictor of poor prognosis in Duke’s B colon cancer. Croat Med J. 2008;49(5):636–42. https://doi.org/10.3325/cmj.2008.5.636.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Wang W, Li D, Xiang L, Lv M, Tao L, Ni T, Deng J, Gu X, Masatara S, Liu Y, et al. TIMP-2 inhibits metastasis and predicts prognosis of colorectal cancer via regulating MMP-9. Cell Adh Migr. 2019;13(1):273–84. https://doi.org/10.1080/19336918.2019.1639303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yang XZ, Cui SZ, Zeng LS, Cheng TT, Li XX, Chi J, Wang R, Zheng XF, Wang HY. Overexpression of Rab1B and MMP9 predicts poor survival and good response to chemotherapy in patients with colorectal cancer. Aging. 2017;9(3):914–31. https://doi.org/10.18632/aging.101200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhang Y, Guan XY, Dong B, Zhao M, Wu JH, Tian XY, Hao CY. Expression of MMP-9 and WAVE3 in colorectal cancer and its relationship to clinicopathological features. J Cancer Res Clin Oncol. 2012;138(12):2035–44. https://doi.org/10.1007/s00432-012-1274-3.

    Article  CAS  PubMed  Google Scholar 

  30. Zhou ZG, Wu XJ, Li LR, Peng ZH, Ding PR, Wang RJ, Pan ZZ. A multivariate analysis of prognostic determinants for stages II and III colorectal cancer in 141 patients. Chin Med J (Engl). 2011;124(14):2132–5.

    CAS  PubMed  Google Scholar 

  31. Li HC, Cao DC, Liu Y, Hou YF, Wu J, Lu JS, Di GH, Liu G, Li FM, Ou ZL, et al. Prognostic value of matrix metalloproteinases (MMP-2 and MMP-9) in patients with lymph node-negative breast carcinoma. Breast Cancer Res Treat. 2004;88(1):75–85. https://doi.org/10.1007/s10549-004-1200-8.

    Article  CAS  PubMed  Google Scholar 

  32. Chan CC, Menges M, Orzechowski HD, Orendain N, Pistorius G, Feifel G, Zeitz M, Stallmach A. Increased matrix metalloproteinase 2 concentration and transcript expression in advanced colorectal carcinomas. Int J Colorectal Dis. 2001;16(3):133–40. https://doi.org/10.1007/s003840100287.

    Article  CAS  PubMed  Google Scholar 

  33. Langenskiöld M, Holmdahl L, Falk P, Ivarsson ML. Increased plasma MMP-2 protein expression in lymph node-positive patients with colorectal cancer. Int J Colorectal Dis. 2005;20(3):245–52. https://doi.org/10.1007/s00384-004-0667-4.

    Article  PubMed  Google Scholar 

  34. Westermarck J, Kähäri VM. Regulation of matrix metalloproteinase expression in tumor invasion. Faseb j. 1999;13(8):781–92.

    Article  CAS  PubMed  Google Scholar 

  35. Walter L, Canup B, Pujada A, Bui TA, Arbasi B, Laroui H, Merlin D, Garg P. Matrix metalloproteinase 9 (MMP9) limits reactive oxygen species (ROS) accumulation and DNA damage in colitis-associated cancer. Cell Death Dis. 2020;11(9):767. https://doi.org/10.1038/s41419-020-02959-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Islam MR, Islam F, Nafady MH, Akter M, Mitra S, Das R, Urmee H, Shohag S, Akter A, Chidambaram K, et al. Natural small molecules in breast Cancer Treatment: understandings from a therapeutic viewpoint. Molecules. 2022;27(7). https://doi.org/10.3390/molecules27072165.

  37. Rauf A, Abu-Izneid T, Khalil AA, Imran M, Shah ZA, Emran TB, Mitra S, Khan Z, Alhumaydhi FA, Aljohani ASM, et al. Berberine as Potential Anticancer Agent: Compr Rev Molecules. 2021;26(23). https://doi.org/10.3390/molecules26237368.

  38. Akash S, Bayıl I, Hossain MS, Islam MR, Hosen ME, Mekonnen AB, Nafidi HA, Bin Jardan YA, Bourhia M, Bin Emran T. Novel computational and drug design strategies for inhibition of human papillomavirus-associated cervical cancer and DNA polymerase theta receptor by apigenin derivatives. Sci Rep. 2023;13(1):16565. https://doi.org/10.1038/s41598-023-43175-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Liang Y, Lv Z, Huang G, Qin J, Li H, Nong F, Wen B. Prognostic significance of abnormal matrix collagen remodeling in colorectal cancer based on histologic and bioinformatics analysis. Oncol Rep. 2020;44(4):1671–85. https://doi.org/10.3892/or.2020.7729.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sunami E, Tsuno N, Osada T, Saito S, Kitayama J, Tomozawa S, Tsuruo T, Shibata Y, Muto T, Nagawa H. MMP-1 is a prognostic marker for hematogenous metastasis of colorectal cancer. Oncologist. 2000;5(2):108–14. https://doi.org/10.1634/theoncologist.5-2-108.

    Article  CAS  PubMed  Google Scholar 

  41. Leeman MF, McKay JA, Murray GI. Matrix metalloproteinase 13 activity is associated with poor prognosis in colorectal cancer. J Clin Pathol. 2002;55(10):758–62. https://doi.org/10.1136/jcp.55.10.758.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Yan Q, Yuan Y, Yankui L, Jingjie F, Linfang J, Yong P, Dong H, Xiaowei Q. The expression and significance of CXCR5 and MMP-13 in Colorectal Cancer. Cell Biochem Biophys. 2015;73(1):253–9. https://doi.org/10.1007/s12013-015-0624-6.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are grateful to all the authors of the studies included in the present study and their study participants.

Funding

There is no funding to declare related to the present project.

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Author notes

  1. Yusha Wang, Yuhao Wei and Jing Huang contributed equally to this work.

Authors and Affiliations

  1. Department of Biotherapy, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    Yusha Wang, Yuhao Wei & Xuelei Ma

  2. Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    Yusha Wang & Li Wang

  3. Department of Medical Ultrasound, West China Hospital of Sichuan University, 37 Guoxue Lane, Wuhou District, Chengdu, Sichuan, 610041, China

    Jing Huang

  4. West China Clinical Medical College of Sichuan University, Chengdu, Sichuan, China

    Xinke Li

  5. Department of Hematology, School of Medicine UESTC, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China

    Diqing You

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Contributions

Yuhao Wei and Yusha Wang established the retrieval criteria. Jing Huang and Diqing You completed the data curation. Yuhao Wei, Yusha Wang, and Jing Huang performed the methodology. Yusha Wang, Yuhao Wei, and Jing Huang wrote the original manuscript. Xuelei Ma and Li Wang corrected the original draft. Yusha Wang, Yuhao Wei, and Xinke Li revised the manuscript. All authors have read and agreed to the published version of the manuscript.

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Wang, Y., Wei, Y., Huang, J. et al. Prognostic value of matrix metalloproteinase-2 protein and matrix metalloproteinase-9 protein in colorectal cancer: a meta-analysis. BMC Cancer 24, 1065 (2024). https://doi.org/10.1186/s12885-024-12775-9

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BMC Cancer

ISSN: 1471-2407

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