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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 8  |  Page : 54-59

Elevated expression of matrix metalloproteinase-9 is associated with bladder cancer pathogenesis


1 Department of Urology, Lanzhou University Second Hospital, Chengguan District, Lanzhou 730030, P.R. China
2 The Third Affiliated Hospital of Liaoning Medical University, Changchun 130021, P.R. China

Date of Web Publication26-Mar-2018

Correspondence Address:
Zhong-Jin Yue
Department of Urology, Lanzhou University Second Hospital, No. 82, Cuiyingmen, Chengguan District, Lanzhou 730030
P.R. China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.163761

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 > Abstract 


Objective: This study investigated the association between abnormal matrix metalloproteinase-9 (MMP-9) expression and bladder cancer (BC) development.
Materials and Methods: In a retrospective analysis, this study used tissue samples derived from 92 patients pathologically diagnosed with BC (experimental group), who were hospitalized between September 2012 and June 2014 at the Urinary Surgery of Department of Urology, Lanzhou University Second Hospital. As controls (control group), 63 normal pericancerous bladder mucosal tissues (3 cm distant form edge of BC foci) with confirmed pathology were selected from the same time period. Immunohistochemistry was employed to detect MMP-9 protein expression in the tissues and enzyme-linked immunosorbent assay was performed to measure MMP-9 protein levels in tissue samples of patients and control subjects. Finally, a meta-analysis was conducted to understand the overall impact of MMP-9 on BC pathogenesis. STATA 12.0 software (Stata Corp, College Station, TX, USA) was used for all statistical analyses.
Results: The MMP-9 positive expression rate in tissue samples and MMP-9 levels were significantly greater in the experimental group compared to the control group (both P < 0.001). The frequency of MMP-9 positive status showed statistically significant differences between G1 (low-grade) and G3 (high-grade) (P < 0.001), between G2 and G3 (P < 0.05), and between G1/G2 and G3 (P = 0.001). Our meta-analysis findings provided further evidence that MMP-9 positive expression status and MMP-9 levels in the experimental group were significantly higher than the control group (positive expressions: Odds ratio [OR] = 18.59, 95% confidence interval [95% CI] = 11.63–29.71, P < 0.001; expression levels: Standard mean difference = 1.51, 95%CI = 0.63–2.39, P = 0.001). The positive expression status of MMP-9 was notably lower in G1/G2 compared to G3 (OR = 0.24, 95%CI = 0.15–0.36, P < 0.001).
Conclusion: Our study demonstrated that both positive expression status in tumor tissue and expression levels of MMP-9 are significantly elevated in BC patients and correlate with disease progression. Thus, MMP-9 can serve as a biomarker to determine the degree of BC malignancy.

Keywords: Bladder cancer, cohort-control report, matrix metalloproteinase-9, meta-analysis, retrospective analysis


How to cite this article:
Wu GJ, Bao JS, Yue ZJ, Zeng FC, Cen S, Tang ZY, Kang XL. Elevated expression of matrix metalloproteinase-9 is associated with bladder cancer pathogenesis. J Can Res Ther 2018;14, Suppl S1:54-9

How to cite this URL:
Wu GJ, Bao JS, Yue ZJ, Zeng FC, Cen S, Tang ZY, Kang XL. Elevated expression of matrix metalloproteinase-9 is associated with bladder cancer pathogenesis. J Can Res Ther [serial online] 2018 [cited 2019 Jun 17];14:54-9. Available from: http://www.cancerjournal.net/text.asp?2018/14/8/54/163761




 > Introduction Top


Bladder cancer (BC) is the most commonly diagnosed malignancy of the urinary system, with delayed incidence after exposure to risk factors and high recurrence rates after treatment.[1],[2] An estimated 429,800 individuals developed BC, with more than 165,100 deaths, across the world in the year 2012.[3] Interestingly, BC incidence increases with age, especially in men, with approximately 10-fold higher incidence rates reported in men compared to women worldwide.[4] Tobacco smoking is the most well-established factor influencing geographical prevalence of BC and other environmental factors contributing to BC risk include chronic inflammation, radiation exposure and occupational exposure to aromatic amines.[4],[5] The majority of BC patients without muscle invasion at diagnosis still develop at least one incidence of recurrence in the next 5 years after transurethral resection, and might even progress to muscle invasive BC or worse.[2],[6] Therefore, current treatment and management for BC are not adequate for disease-free clinical outcomes. Previous studies reported identification of multiple biomarkers that may be critical for determining the degree of malignancy in BC.[7],[8]

Matrix metalloproteinases (MMPs) are a large family of zinc-dependent proteolytic enzymes mainly involved in the degradation of protein targets that are components of the extracellular matrix (ECM).[9] MMPs play diverse and critical roles in normal physiological processes such as tissue remodeling, embryonic development, and reproduction.[10] The MMP family consists of at least 28 members and all MMPs contain two conserved domains, a catalytic domain and a prodomain that are crucial for their activity and substrate specificity.[11],[12] MMP-9 belongs to the gelatinase subfamily and is the most complex member of the MMP family, with proteolytic activity against type IV collagen.[13] Under normal conditions, MMP-9 expression is tightly regulated and is highly tissue-restricted. However, abnormal expression and up-regulated levels of MMP-9 are observed in various human cancers such as breast cancer, esophageal cancer, and gastric cancer.[14] A few previous studies also described a role for MMP-9 in the development and progression of BC.[15],[16] Nevertheless, the results of relevant published cohort-control studies remain controversial rather than definitive.[17],[18] Therefore, we performed a cohort-control study combined with a meta-analysis to further investigate the correlation between MMP-9 and the development of BC.


 > Materials and Methods Top


Ethics statement

The study was approved by the Ethics Committee of Department of Urology, Lanzhou University Second Hospital, and written informed consents were signed by all participants. All the experimental procedures in this study conformed to the guidelines of Declaration of Helsinki.[19]

Recruitment of subject

In this retrospective analysis study, we included 92 BC tissues from patients pathologically diagnosed as BC, who were hospitalized between September 2012 and June 2014 at the Urinary Surgery of Department of Urology, Lanzhou University Second Hospital. These 92 patients' tissues consisted of the experimental group. Additionally, 63 normal bladder mucosa tissues from pericancerous region (3 cm distant form edge of BC foci) was confirmed for normal pathology and selected as the control group during the same period. The 92 BC patients (73 males and 19 females) showed mean age of 56.17 ± 15.00 (range from 32 to 81 years) and the control group consisted of 49 males and 14 females with mean age of 60.13 ± 14.94 (range from 31 to 83 years). All subjects were diagnosed as BC by ultrasound, computed tomography (CT) or magnetic resonance imaging. Diagnostic criteria for BC were: (1) Patients with indolent macroscopic hematuria; (2) prior history of the disease, family history of patients and physical examination including urine routine, exfoliative urinary cytology, tumor markers in urine, abdomen and pelvic cavity examination by B-mode ultrasound; (3) cystoscopy, intravenous urography, pelvic CT or pelvic MRI was performed based on above examination results.[20] Exclusion criteria were: (1) Renal cancer patients clinically presenting hypertension, anemia, weight loss, cachexia, fever, polycythemia, abnormal liver function, hypercalcemia, galactorrhea; (2) patients with cystitis glandularis clinically presenting recurrently refractory urinary frequency and urgency, odynuria, hematuria, suprapubic and perineal discomfort, abdominal bulge, urinary incontinence; (3) urolithiasis patients with hematuria frequently followed by colic or severe pain due to heavy exercise.[21] All patients were histologically graded as G1 (n = 23), G2 (n = 49), and G3 (n = 20) based on the WHO classification of 1974.[22] Clinical stage was determined according to the Union for International Cancer Control-Tumor Node Metastasis (UICC-TNM) criteria,[23] with 55 cases of Tis-T1 (superficial) and 37 of T2 ~ T4 (invasive).

Immunohistochemical staining

The paraffin sections prepared from BC tissues (4–5 μm thickness) were dewaxed and rehydrated, and subjected to antigen retrieval for 1–2 min using microwave and washed with phosphate-buffered solution (PBS). The tissues were incubated with 3% H2O2 at 36°C for 13 min, washed with PBS again, blocked in normal goat serum and incubated again in PBS without goat serum (no washing). Anti-MMP-9 antibody was used as the primary antibody (Fuzhou Maxim Biotechnology Co., Ltd, China) and incubated at 36°C for 2 h (negative control was PBS instead of the primary antibody). After a brief wash with PBS, biotinylated secondary antibody (Beijing Zhongshan Biotechnology Co., Ltd, China) was added and incubated at 36°C for 45 min. Subsequently, streptavidin labeled horseradish peroxidase (HRP) was added and incubated again at 36°C for 15 min, followed by PBS wash. Chromogenic development was performed by immersion of the tissue sections in 3, 3'-diaminobenzidine. The slides were counterstained with Mayer's hematoxylin and immersed into muriatic acid and ethyl alcohol. The dehydrated samples were mounted with a coverslip, and the results were observed and recorded using a microscope fitted with a camera. MMP-9 positive staining was observed in the tumors as brown to yellow color pattern. The staining color intensity and the extent of staining in the tissue section represented the level of expression and were used for semiquantitative measurement of MMP-9 expression. No color and color <30% were considered negative (-), and ≥30% were positive (+).

Enzyme-linked immunosorbent assay

Matrix metalloproteinase-9 protein expression level in the tissue was measured using enzyme-linked immunosorbent assay (ELISA) kit components (R and D Systems, Inc., Minneapolis, MN, USA) with Luminex Bioanalyzer (Luminex Corp., Austin, TX, USA) in strict accordance with the supplier's instructions. Each sample was in duplicates with 1:100 dilutions. HRP-labeled rabbit polyclonal antibody against human MMP-9 was used in this assay, and optical density of MMP-9 ELISA result was measured at 490 nm.

Observation indices

Positive expressions of MMP-9 protein in experimental and control groups, and between histologically different grades were detected by immunohistochemistry staining. Additionally, MMP-9 expression levels in experimental and control groups were analyzed by ELISA.

Statistical analysis

Statistical analysis was performed using SPSS 18.0 software (SPSS Inc., Chicago, IL, USA). Continuous data were measured as mean ± standard deviation (x̄ ± s), and t-test was performed to examine inter-group comparison. Categorical data were tested using χ2 test. The level of significance was set at P < 0.05. Additionally, a meta-analysis was performed using the STATA 12.0 software (Stata Corp, College Station, TX, USA). We undertook a literature search of articles archived in the databases of PubMed, Ovid and China National Knowledge Infrastructure. The following retrieved keywords were used: MMP, BC, urinary bladder neoplasms, neoplasms, bladder, and malignant tumor of urinary bladder, cancer of bladder, bladder tumors and urinary BC. The summary standard mean difference (SMD) or odds ratios (ORs) with 95% confidence interval (CI) were calculated to provide quantitative evidence for the association of MMP-9 and BC in a random-effects model or a fixed-effects model.[24] The significance of overall results was further examined by Z-test and the forest plot was drawn to display SMD or OR with 95%CI.


 > Results Top


Baseline characteristics

The difference of the baseline characteristics between experimental and control groups such as age and gender, did not reach statistical significance (P > 0.05). Similarly, there was no statistically significant difference in the patients' clinical data according to UICC-TNM criteria (P > 0.05).

Positive expression of matrix metalloproteinase-9 protein

Semiquantitive positive expressions statuses of MMP-9 in experimental and control groups are shown in [Figure 1]a and [Figure 1]b, respectively. A total of 53 of the 92 BC tissues in the experimental group showed positive expression of MMP-9 (57.6%) while in the 63 normal bladder mucosa tissues of the control group, only four tissues (6.3%) showed positive expression, indicating that the positive expression status of MMP-9 in experimental group was significantly higher than the control group, with statistical significance as P < 0.05 [Figure 2].
Figure 1: Positive expression status of matrix metalloproteinase-9 protein in bladder cancer (BC) tissue of experimental group and normal bladder mucosa tissue of control group, respectively (a) In BC; (b) In normal bladder mucosa tissue

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Figure 2: Histogram presenting the comparison of the positive expression of matrix metalloproteinase-9 protein between experimental group and control group

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Expression levels of matrix metalloproteinase-9 protein

The results form ELISA also clearly showed that the expression levels of MMP-9 protein in experimental group were significantly higher than the control group, and the difference between the two groups was statistically significant ([7.91 ± 3.35] μg/L vs. [1.12 ± 0.18] μg/L, P < 0.001) [Figure 3].
Figure 3: Histogram presenting the comparison of the expression levels of matrix metalloproteinase-9 protein between experimental group and control group

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Positive expression of matrix metalloproteinase-9 protein in histology

Positive expressions of MMP-9 in different histological grades were compared on the basis of the WHO criteria for histological grade of BC (G1: 8 [34.87%]; G2: 27 [55.1%]; G3: 18 [90.0%]; G1/G2: 35 [48.6%]). The differences in the positive expressions of MMP-9 protein in tissue samples between G1 and G3 (P < 0.001), G2 and G3 (P < 0.05), and G1/G2 and G3 (P = 0.001) were statistically significant. However, there was no statistically significant difference between G1 and G2 (P > 0.05) [Table 1].
Table 1: Comparison of positive expression of MMP-9 protein in different histological grade

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Meta-analysis results

A total of 23 studies were eligible for our meta-analysis based on predefined inclusion criteria. These 23 studies contained a total of 1040 BC patients and 244 healthy controls.[15],[16],[17],[18],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43] The meta-analysis results from 17 studies indicated that the positive expressions of MMP-9 protein in the tumor tissues of experimental group were significantly higher than control group (OR = 18.59, 95%CI = 11.63–29.71, P < 0.001) [Figure 4]. Data collected from seven published studies suggested that the expression levels of MMP-9 protein in experimental group were significantly higher than control group (SMD = 1.51, 95%CI = 0.63–2.39, P= 0.001) [Figure 5]. Further, 15 studies showed positive expressions of MMP-9 protein in G1/G2 notably lower than G3 (OR = 0.24, 95%CI = 0.15–0.36, P < 0.001) [Figure 6].
Figure 4: Forest plots about the positive expression of matrix metalloproteinase-9 protein between bladder cancer tissue of experimental group and normal bladder mucosa tissue of control group

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Figure 5: Forest plots about the expression levels of matrix metalloproteinase-9 protein between bladder cancer tissue of experimental group and normal bladder mucosa tissue of control group

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Figure 6: Forest plots about the expression levels of matrix metalloproteinase-9 protein between histology G1/G2 grade and histology G3 grade

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 > Discussion Top


In this study, we examined the association of MMP-9 expression with the development and progression of BC. The main results of our study indicated that both the positive expression status in tumor tissues and expression levels of MMP-9 protein in BC patients were significantly higher than found in normal bladder mucosal tissues and the tissue of healthy controls. Degradation of ECM and basement membrane is a crucial step in tumor invasion and confers tumors the necessary capacity for progression of the disease into a metastatic phenotype.[44] MMP activity is displayed against extracellular components, where they primarily affect the cell behavior by proteolytic processing of different ECM molecules, release of ECM-bound cytokines and peptide growth factors, disrupt cell adhesion molecules, generate chemokines, and other types of glycoproteins and receptors.[45] MMP activity is controlled at posttranslational level by their specific tissue inhibitors of metalloproteinases (TIMPs) and the balance between MMPs secretion and TIMPs activity is important in maintaining connective tissue homeostasis under normal healthy conditions.[34] MMP-9 is a gelatinase that exhibits activities influencing distinct targets including growth factors, ECM, chemokines and cytokine, which in turn activate major signaling pathways involved in cell growth, invasion, inflammation, migration and angiogenesis.[46] MMP-9 secreted by tumor cells is associated with high metastatic capability because MMP-9 can degrade type IV, V, VII, IX, and X collagen. Type IV collagen is the main constituent of basement membranes and is particularly abundant in vascular endothelial basement membranes, acting as a physical barrier for tumor invasion and metastasis.[47] Our findings in this study showed that the positive expression levels of MMP-9 protein in BC patients were significantly higher than healthy controls, and MMP-9 expression was not associated with age, gender, or tumor location. Consistent with our cohort-control results, both Offersen et al. and our meta-analysis demonstrated that positive expression of MMP-9 protein in BC patients was significantly higher compared with healthy controls.[48]

Another important finding of our study was that the positive expressions of MMP-9 protein in low-grade BC (G1/G2) were notably lower than the high-grade BC (G3). MMP-9 mediates the recruitment of pericytes and activates endothelial cell migration. Previous studies also reported that MMPs possessed antiangiogenic activities by generating antiangiogenic factors that are derived from peptide fragments of larger ECM molecules present in the basement membrane of vessels or the ECM.[49],[50] G3 grade of tumor is characterized by higher invasive potential compared to well-differentiated tumors (G1 and G2), which are associated with better prognosis.[51] MMP-9 expression was highly correlative to the depth of tumor invasion, since statistically significant differences were detected between G1/G2 and G3 in our study, suggesting MMP-9 plays a major role in ECM breakdown, allowing rapid invasion of solid tumors. Consistent with our findings of our cohort-control study, our meta-analysis and Gunes et al. showed that the expression levels of MMP-9 protein correlate with tumor grade, tumor stage, tumor size, and tumor progression.[15]


 > Conclusion Top


Our study demonstrated that both positive expressions in tumor tissue and expression levels of MMP-9 protein were significantly elevated in BC patients. Thus, MMP-9 can be a valuable biomarker for determining the degree of BC malignancy. Further studies with larger sample size will be necessary to confirm the influence of MMP-9 levels on BC progression and verify its potential as a reliable diagnostic marker in BCs.


 > Acknowledgments Top


We would like to show our sincere gratitude to our instructors for their valuable advices. We also appreciate the reviewers who give us precious comments on this article.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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