Japanese Journal of Clinical Oncology Advance Access originally published online on November 28, 2005
Japanese Journal of Clinical Oncology 2005 35(12):739-744; doi:10.1093/jjco/hyi195
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© 2005 Foundation for Promotion of Cancer Research
Clinicopathologic and Prognostic Significance of MMP-7 (Matrilysin) Expression in Human Rectal Cancer
1 Department of Gastrointestinal Surgery, 2 Institute of Digestive Surgery and Organ Microcirculation and 3 National Key Laboratory of Biotherapy of West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
For reprints and all correspondence: Zong-guang Zhou, Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, 37 Guo Xue Xiang, Chengdu 610041, Sichuan Province, China. E-mail: Zhou767{at}21cn.com
Received June 28, 2005; accepted October 9, 2005
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Abstract |
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 TOP Abstract INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONSReferences |
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Objective: There is increasing evidence to indicate that MMP-7 plays a more important role in tumor progression than other MMPs. The aim of this study was to detect MMP-7 expression in human rectal cancer and normal rectal tissue and to determine whether it is correlated with invasion and metastasis of human rectal cancer.
Methods: Eighty-six paired samples of rectal cancer and distant normal rectal tissue obtained from 100 inpatients were allocated into two groups (cancer group and control group). MMP-7 mRNA was detected by relative quantitative real-time RT–PCR and MMP-7 protein was examined by immunohistochemical staining and computerized image analysis.
Results: MMP-7 mRNA expression in cancer group was higher than that in control group (P = 0.006), the expression ratios of 31 samples (37.35%) were <1 and 52 (62.65%) were >1. The mRNA expression level was correlated with Dukes Staging, histological differentiation grade and CEA level. The MMP-7 protein expression was in accordance with mRNA expression level. The positive degree of immunohistochemical staining in cancer group (1.82 ± 0.03) was different from that in control group (1.17 ± 0.13, P = 0.002). Moreover, in cancer group the positive staining degree in high-level mRNA cancers (2.04 ± 0.18, n = 52) was higher than that in low-level mRNA ones (1.58 ± 0.23, n = 31, P = 0.008).
Conclusions: Our results suggest that MMP-7 plays an important role in the progression of human rectal cancer. MMP-7 may be selected as a clinical diagnosis and prognosis index in rectal cancer.
Key Words: MMP-7 • expression • rectal cancer
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INTRODUCTION |
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TOPAbstractINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONSReferences |
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Matrix metalloproteases (MMPs) is an enzyme family capable of degrading extracellular matrix (ECM), which has a broad proteolytic activity after being activated. It is now becoming recognized that the matrix metalloproteinases play a key role in a variety of biological processes that are distinct from their well-defined role in matrix degradation. Many studies have suggested that MMPs take part in physiological processes (1) such as wound healing, tissue development and delivery. Moreover, MMPs also take part in many pathological processes such as rheumatic arthritis and atherosclerosis. MMP-7 (matrix metalloproteinase-7, matrilysin), a member of MMPs, is thought to be related to progression of many kinds of carcinomas (2–6). Previous study suggested that MMP-7 play a more important role in the invasion and progression of tumor than other MMPs because of its minimum molecular (28 kDa) and unique structure (7). MMP-7 expression was shown to be a powerful independent prognostic indicator and potentially of considerable clinical value among pancreatic cancer (8). Though the expression of MMP-7 was believed to increase in the early stage of colorectal carcinoma (9), till now, the MMP-7 expression has not been quantitatively detected in considerable number in rectal cancer. In this study, mRNA and protein expression of MMP-7 in matched rectal samples were measured by real-time RT–PCR and immunohistochemical staining, respectively, and the correlationship between MMP-7 expression level and clinicopathologic features was further investigated. Through this work we hoped to elucidate the role of MMP-7 in the invasion and metastasis of rectal cancer and to provide basis for its clinic diagnosis and outcome prediction. For this purpose we employed real-time RT–PCR and immunohistochemical staining as major methods. Case control of fixed pair match was designed.
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MATERIALS AND METHODS |
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PATIENTS AND TISSUE SAMPLES
One hundred paired samples of rectal cancer and distant normal rectal tissue were obtained from 100 inpatients undergone surgical operation (from 2003 to 2004 in West China Hospital of Sichuan University). These inpatients did not receive any chemotherapy or radiotherapy before operation. This study was carried out with Medical Ethical Committee approval and all patients provided written informed consent to participate in the study. The rectal cancer and paired normal rectal tissues were allocated into cancer group and control group. Some parts of each sample were fixed by formalin and embedded in paraffin wax. Tumor histotype and grade of differentiation were defined according to the WHO criteria (10). The clinical and pathological stages were defined according to Dukes Staging. The histopathological examination was conducted by Pathological Research Institution of West China Hospital. Fourteen samples were excluded because of their invasion and metastasis in ‘normal rectal tissue’.
TOTAL RNA EXTRACTION
Total RNA was extracted from each sample by using Trizol (Beyozol Co., Ltd) method. The concentration of RNA was detected spectrophotometrically. Toal RNA of each sample was dissolved in RNase-free water and stored in the refrigerator at –80°C before use.
PRIMERS AND PROBES
As shown in Table 1, specific primers and probes for MMP-7 gene and glyceraldehyde phosphate dehydrogenase (GAPDH) gene (reference gene) were designed. We conducted BLAST searches to confirm the gene specificity of the nucleotide sequences. Primers and probes were placed at the junction between two exons. The primers and probes were purchased from Takara Biotechnology Co. (Dalian, China).
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REAL-TIME RT–PCR
Two step methods were adopted. Reverse transcription was performed according to the manufacturer's protocol (Takara Biotechnology Co.). Conditions for all PCRs were optimized on iCycler iQ (Bio-Rad, USA) and the optimum annealing temperature was 53.1°C. The following iCycler iQ run protocol was used: denaturation program (95°C, 5 min), amplification and quantification programs repeated 50 times (95°C for 20 s, 53.1°C for 30 s and 72°C for 30 s). In addition, a no-template control (ddH2O control) was analysed for each template. All samples were amplified simultaneously in triplicate in a one assay-run. The relative expression ratio (R) of a MMP-7 gene was calculated based on PCR efficiency (E) and the Ct deviation of an unknown sample versus a control, Ratio = (Emmp–7)
Ctmmp–7 (control–cancer)/(EGAPDH)CtGAPDH (control–cancer) [Equation 1 in Ref. (11)], Ct was the Ct deviation of MMP-7 and GAPDH, PCR efficiency (E) was calculated according to E = 10–1/slope (12). The ratio >1 represented mRNA expression of MMP-7 in rectal cancer was up-regulated.
IMMUNOHISTOCHEMISTRY
Sections were dewaxed in xylene and rehydrated in alcohol. The endogenous peroxidase activity was suppressed by 3% hydrogen peroxide for 10 min. After rinsed twice in phosphate-buffered saline (PBS), the sections were treated for 16 h with mouse antihuman monoclonal antibodies of MMP-7 according to the manufacturer's recommended concentration (ZYMED, USA). PBS was used as a negative control. After washing three times in PBS, the sections were treated with biotinylated goat antimouse immunoglobulin (ZYMED) for 40 min and then by horseradish peroxidase–streptavidin complex (S-A/HRP; ZYMED) for 40 min, diluted as recommended by the manufacturer. The slides were then washed three times in PBS and developed in DAB. The sections were counterstained in hematoxylin and mounted. Images were collected by Olympus DD70 BX51 (Olympus, Japan) and analysed by IMAGE-PRO plus 4.1 software (Media Cybernetics, USA). Eight visual fields in every section were randomly selected and mean value of relative optical density (OD) was measured and calculated by taking the OD of background as 1. The extent of immunohistochemical staining was categorized as positive (1–1.5) and strongly positive (>1.5).
STATISTICAL ANALYSIS
Group-wise comparison and statistical analysis in mRNA relative expression was analysed by the Relative Expression Software Tool (REST) (13). Chi-square test was verified between MMP-7 mRNA or protein expression and clinical and pathological features. P-value of <0.05 was considered statistically significant.
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RESULTS |
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PATIENTS AND CLINICOPATHOLOGIC FEATURES
Carcinoma cell could be observed in all rectal cancers under light microscope. Samples at Dukes Staging A, B, C and D were 10, 26, 33 and 14, respectively. There were 30 papillary adenocarcinomas, 37 tubular adenocarcinomas, 8 mucoid adenocarcinomas, 7 signet-ring cell carcinomas and one squamous carcinoma by histological classification. The samples in histological differentiation grades I, II and III were 17, 61 and 5.
MMP-7 mRNA EXPRESSION IN TWO GROUPS
RT–PCR products were the desired length (MMP-7, 122 bp; GAPDH, 141 bp). No primer–dimers were generated during the applied 50 real-time PCR amplification cycles. Real-Time RT–PCR amplification efficiencies were calculated from the given slopes in FTC-2000 software (FENGLING Co., Shanghai) and the REST, and the amplification efficiency in two groups was 2.
Among 86 paired samples, Ct values in two groups were normally distributed. The Ct values of three samples in control group were infinitely high and the mRNA expression of MMP-7 cannot be detected, so the mRNA expression levels of MMP-7 in the three matched cancer samples were up-regulated significantly. In the other 83 paired samples, the MMP-7 expression ratios of 31 (37.35%) were <1, 52 (62.65%) were >1. REST analysis showed mRNA expression of MMP-7 in cancer group was remarkably different from that in the control group with the P-value of 0.006, which was up-regulated in comparison with the control group. Randomization data are shown in Table 2.
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RELATIONSHIP BETWEEN mRNA EXPRESSION OF MMP-7 AND CLINICOPATHOLOGIC FEATURES
The expression ratio values were not normally distributed and chi-square test was verified between mRNA expression and clinical and pathological features. As shown in Table 3, the mRNA expression at Dukes Staging C + D was different from that at Dukes Staging A + B (P < 0.001). The expression ratio >1 at Dukes Staging C + D accounted for 72.3%, whereas at Dukes Staging A + B, it only accounted for 50%, which indicated that the mRNA expression of MMP-7 was up-regulated with the Dukes Staging increasing. The percentage of mRNA expression ratio >1 in node-positive group (72.72%) was higher than that in node-negative group (51.28%, P < 0.001). The expression ratio >1 in young group (73.9%, 17/23) was different from that in aged group (58.3%, 35/60). Moreover, analysis of CEA level and tumor invasion depth showed association with approximately statistical significance. Correlation with sex and histological differentiation grades were not statistically significant.
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To further investigate the linearity relationship between mRNA expression level and clinicopathologic features, we conducted series correlation analysis. As shown in Table 4, the mRNA expression level of MMP-7 was positively correlated with Dukes Staging and CEA level, negatively correlated with histological differentiation grade and was not significantly associated with lymph node status and tumor invasion depth.
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IMMUNOHISTOLOGICAL EXPRESSION OF MMP-7 IN RECTAL CANCER
The representative results are shown in Fig. 1. The cytoplasm and membranes of rectal cancer cells were positively stained, but the stromal components were not. Protein expression of MMP-7 in normal rectal cancer was very weak. There was no detectable immunoreactivity in the PBS control slide. The positive degree of immunohistochemical staining in cancer group (1.82 ± 0.03) was higher than that in the control group (1.17 ± 0.13, P = 0.002). Moreover, in cancer group the degree of positive staining in high-level mRNA cancers (2.04 ± 0.18, n = 52) was higher than that in low-level mRNA ones (1.58 ± 0.23, n = 31, P = 0.008). As shown in Table 5, MMP-7 expression was correlated with Dukes Staging, age and nodal metastasis, the percentage of positive staining of cancer cells over 1.5 at Dukes Staging C + D, node-positive group and young rectal cancer patients were 63.83, 86.36 and 86.96%.
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DISCUSSION |
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TOPAbstractINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONSReferences |
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The matrix metalloproteinases are a group of enzymes that have been best characterized for their ability to degrade extracellular matrix proteins and have been extensively studied in various cancers. MMP-7, a member of the matrix metalloproteinase family, is believed to play a significant role in invasion and metastasis of colorectal carcinoma (14). In this study, quantitative real-time RT–PCR was used to detect MMP-7 mRNA expression in pure rectal cancer and normal rectal tissue. Why did we choose quantitative real-time RT–PCR as one of our major experimental methods? Although traditional PCR and RT–PCR may also yield relatively precise results, to perform that, they not only need rather large amount of template for the analysis of a sample (15) but also require post-PCR analytical steps which risk cross-contamination of samples with PCR products. However, real-time RT–PCR can overcome such disadvantages and yield rapid (20–30 min/experiment) and very precise results for both RNA and DNA quantification (16).
The result suggested that the mRNA expression level of MMP-7 was up-regulated in cancer group. MMP-7 mRNA expression was also found to be significantly associated with Dukes Staging and lymph node status, which confirmed the role of MMP-7 in the progression of rectal cancer. The same results were found in a previous report on mRNA expression of MMP-7 in colorectal cancers (17). As shown in this study, the percentage of expression ratio >1 in node-positive group (72.72%) was higher than that in node-negative group (51.28%), which tempted us to speculate that MMP-7 facilitates the lymph metastasis of rectal cancer. These results indicate that overexpression of MMP-7 might play an essential role in invasion and metastasis of rectal cancer, which is in agreement with the report of Roeb et al. (18). Thus, MMP-7 mRNA expression assay could be an important method in the clinical diagnosis and prediction of prognosis in rectal cancer.
The result of the correlation analysis between MMP-7 expression ratio and clinicopathologic factors is important, because the prognostic significance of MMP-7 expression in colorectal cancer had already been reported (19). This study indicated that MMP-7 mRNA expression level is positively associated with the CEA level, Dukes Staging and is negatively correlated with histological differentiation grade, which is in contrasted to the result reported by Sumi et al. (20). However, the negative correlation may represent the relationship between the degree of malignancy of rectal cancer and the mRNA expression level of MMP-7. Meanwhile, correlation analysis in the study showed that MMP-7 expression level was not significantly correlated with the lymph node status, which is not in agreement with the similar study in colon cancer (21). The result also contradicted the relationship analysis of expression ratio with the clinical and pathological feature, which may be related to sampling errors or insufficient experiment samples.
Our study is first to find out that MMP-7 mRNA is expressed in normal rectal tissue, whereas other studies (17,22) suggested that MMP-7 mRNA only expressed in colorectal cancer. We suggest that this can be explained as MMP-7 mRNA expression in normal rectal tissue was too low to be detected by traditional RT–PCR or sample size was small.
Our study demonstrated that MMP-7 protein expression in rectal cancer was also associated with Dukes Staging and lymph node status. Similar results were reported for colon cancer (23). Ours and previous study (23) found that MMP-7 expression in colorectal cancer cells showed diffuse cytoplasmic or membranous staining, which was usually most pronounced at the invasive front of the colorectal cancer (24). Thus, MMP-7 plays an important role in the invasion and metastasis of colorectal cancer. Immunohistological staining suggested weak protein expression of MMP-7 in normal rectal cancer, a result which was not found in previous reports on colon cancer. We also found that MMP-7 expression level in young patients with rectal cancer was significantly higher than that in older suffers. Thus may indicate that the proteolytic activity of MMP-7 in younger patients is higher, a possibility deserving further analysis. Therefore, it is tempting for us to speculate that MMP-7 plays an important role in rectal carcinogenesis. With respect to the mechanisms underlying the difference of MMP-7 expression between rectal cancer and colon cancer, gene mutation in different cancer cells and histological specificity after transcription of MMP-7 mRNA may play a key role (25). Moreover, the expression of MMP-7 in human colon cancer can be up-regulated by epidermal growth factor (EGF) (26).
Though MMP-7 plays an important role in the progression of rectal cancer, till now, the exact mechanisms about the regulation of MMP-7 expression in rectal cancer have been unknown. MMP-7 expression can be regulated by signal transduction pathway resulting in a loss of APC function (27). Previous study also suggested Nobiletin down-regulated MMP-7 expression in HT-29 human colorectal cancer cells by reduction of activator protein-1 (AP-1) DNA binding activity (28).
In order to further understand the regulation mechanisms of MMP-7 expression, our future studies will be directed to the effects of signaling pathway on MMP-7 expression in rectal cancer.
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CONCLUSIONS |
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TOPAbstractINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONSReferences |
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This study suggests that MMP-7 plays a key role in the invasion and metastasis of human rectal cancer and thus its assessment may become useful for clinical diagnosis and predicting prognosis of rectal cancer.
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Acknowledgments |
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We thank Professor Zhou and Xia for guiding this study, the members of Pathological Research Institution of West China Hospital and Department of Surgical Laboratory for useful assistance and colleagues of the Department of Gastrointestinal Surgery for providing experimental specimens. This study was supported by the National Natural Science Foundation of China, No. 39925032.
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References |
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