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Hung CC, Wang YC, Shih HY, Liu CH, He JL, Chen JC, Chang WS, Su CH, Bau DAT, Tsai CW. Significant Association of Matrix Metalloproteinase-9 Polymorphisms With Triple Negative Breast Cancer Risk. Cancer Genomics Proteomics 2025; 22:258-270. [PMID: 39993804 PMCID: PMC11880922 DOI: 10.21873/cgp.20500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 10/07/2024] [Accepted: 10/09/2024] [Indexed: 02/26/2025] Open
Abstract
BACKGROUND/AIM Matrix metalloproteinase-9 (MMP-9) has been associated with the development and progression of breast cancer (BCa). However, the relationship between MMP-9 genetic variants and BCa susceptibility remains contentious and inconclusive. This study aimed to evaluate the association of MMP-9 rs3918242 promoter polymorphisms with BCa, with a particular focus on the risk of triple-negative breast cancer (TNBC). MATERIALS AND METHODS A case-control study was conducted involving 1,232 BCa patients and 1,232 healthy controls. The MMP-9 rs3918242 genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. RESULTS The genotype distribution of MMP-9 rs3918242 among the control group adhered to Hardy-Weinberg equilibrium (p=0.3265). No statistically significant differences were observed in the genotype frequencies between BCa cases and controls (p for trend=0.2555). Although the homozygous variant genotype (TT) showed a potential risk-increasing effect, this was not statistically significant [odds ratio (OR)=1.43, 95% confidence interval (CI)=0.88-2.36, p=0.1869]. Similarly, allele frequency analysis indicated no significant association between the variant T allele and overall BCa risk (OR=1.13, 95%CI=0.97-1.33, p=0.1265). Additionally, no interaction was detected between MMP-9 rs3918242 genotypes and the age of BCa onset (both p>0.05). Notably, the TT genotype of MMP-9 rs3918242 was significantly associated with an increased risk of TNBC (OR=2.49, 95%CI=1.32-4.72, p=0.0072). CONCLUSION The MMP-9 rs3918242 TT genotype may serve as a potential predictive biomarker for TNBC in the Taiwanese population.
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Affiliation(s)
- Chih-Chiang Hung
- Division of Breast Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan, R.O.C
| | - Yun-Chi Wang
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C
- Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - Hou-Yu Shih
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C
- Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - Chia-Hua Liu
- Division of Breast Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan, R.O.C
| | - Jie-Long He
- Department of Post-Baccalaureate Veterinary Medicine, Asia University, Taichung, Taiwan, R.O.C
| | - Jaw-Chyun Chen
- Department of Medicinal Botanicals and Foods on Health Applications, Da-Yeh University, Changhua, Taiwan, R.O.C
| | - Wen-Shin Chang
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C
- Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - Chen-Hsien Su
- Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - DA-Tian Bau
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C.;
- Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C
- Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan, R.O.C
| | - Chia-Wen Tsai
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C.;
- Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C
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Wu L, Liu C, Hu W. Comprehensive investigation of matrix metalloproteinases in skin cutaneous melanoma: diagnostic, prognostic, and therapeutic insights. Sci Rep 2025; 15:2152. [PMID: 39820824 PMCID: PMC11739484 DOI: 10.1038/s41598-025-85887-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 01/07/2025] [Indexed: 01/19/2025] Open
Abstract
The dysregulation of matrix metalloproteinases (MMPs) in skin cutaneous melanoma (SKCM) represents a critical aspect of tumorigenesis. In this study, we investigated the diagnostic, prognostic, and therapeutic aspects of the MMPs in SKCM. Thirteen SKCM cell lines and seven normal skin cell lines were cultured under standard conditions for experimental analyses. RNA and DNA were extracted, followed by RT-qPCR to assess MMP expression and promoter methylation analysis to determine methylation levels. Functional assays, including cell proliferation, colony formation, and wound healing, were conducted post-MMP7 knockdown using siRNA in A375 cells. Databases like GEPIA2, HPA, MEXPRESS, and miRNet were employed for expression, survival, methylation, and miRNA-mRNA network analyses. We investigated the expression and promoter methylation landscape of MMPs in SKCM cell lines, revealing significant (p-value < 0.05) up-regulation of MMP1, MMP7, MMP9, MMP10, MMP11, MMP12, MMP13, MMP14, and MMP25, alongside down-regulation of MMP2, MMP3, and MMP21. Furthermore, our analysis demonstrated a significant (p-value < 0.05) inverse correlation between MMP expression levels and promoter methylation status, suggesting a potential regulatory role of DNA methylation in MMP dysregulation. Notably, MMP7, MMP11, and MMP14 exhibited significant (p-value < 0.05) associations with the overall survival of SKCM patients, emphasizing their prognostic significance. Additionally, Receiver operating characteristic (ROC) curve analysis highlighted the significant (p-value < 0.05) diagnostic potential of MMP7, MMP11, and MMP14 in distinguishing SKCM from normal individuals. Subsequent validation across multiple cohorts confirmed significant (p-value < 0.05) elevated MMP expression levels in SKCM tissues, particularly in advanced disease stages, further emphasizing their role in tumor progression. Furthermore, we elucidated potential regulatory pathways involving miR-22-3p, which targets MMP7, MMP11, and MMP14 genes in SKCM. Our findings also revealed associations between MMP expression and immune modulation, drug sensitivity, and functional states of SKCM cells. Lastly, MMP7 knockdown in A375 cells significantly significant (p-value < 0.05) impacted several characteristics, including cell proliferation, colony formation, and wound healing. Our findings highlight the diagnostic, prognostic, and therapeutic potential of MMP7, MMP11, and MMP14 in SKCM. These MMPs could serve as biomarkers for early detection and targets for therapy. Future efforts should focus on preclinical and clinical validation to translate these insights into personalized diagnostic and therapeutic strategies.
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Affiliation(s)
- Lingxia Wu
- Dermatology, Changzhi Second People's Hospital, Changzhi, 046000, Shanxi, China
| | - Chenxiaoxiao Liu
- The First Clinical Institute, Zunyi Medical University, Zunyi, 520300, Guizhou, China
| | - Weicai Hu
- Dermatology, Changzhi Second People's Hospital, Changzhi, 046000, Shanxi, China.
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Foroughi F, Keshavarz Sadegh R, Khalaji M, Lashgari M, Javadi A, Sahmani M, Nonejad S, Keshavarz Shahbaz S. Association between matrix metalloproteinase-9-1562C/T gene polymorphism and MMP-9 serum level in rheumatoid arthritis. J Immunoassay Immunochem 2024; 45:362-381. [PMID: 38863179 DOI: 10.1080/15321819.2024.2365699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/13/2024]
Abstract
BACKGROUND Rheumatoid arthritis (RA) is an autoimmune disease indicated by joint inflammation and cartilage destruction. Matrix metalloproteinase (MMP) enzymes play an influential role in inflammation by affecting the invasion and degradation of anatomical barriers. In this way, the current study investigated the relationship between the MMP-9-1562C/T gene polymorphism and this enzyme's serum level in RA. METHODS The serum levels of MMP-9 in RA patients and healthy controls were measured using the enzyme-linked immunosorbent assay (ELISA). RA was confirmed using rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP), and C-reactive protein (CRP). Then the MMP-9-1562C/T gene polymorphism was analyzed utilizing polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). Also, multivariate analysis investigated the connection between this polymorphism and the risk of RA. RESULTS In this study, the increase of MMP-9 in patients due to the development of single nucleotide polymorphism in the promoter region of this gene (-1562 C→T) was confirmed by increasing the frequency of heterozygous genotype (CT). Logistic regression analysis also demonstrated that the chance of development of RA is higher in people with CT/CC genotype than in other alleles. CONCLUSIONS We demonstrated that MMP-9-1562C/T gene polymorphism can play a significant role in the occurrence of RA.
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Affiliation(s)
- Farshad Foroughi
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran
- Department of Immunology, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
- USERN Office, Qazvin University of Medical Science, Qazvin, Iran
| | - Roghaye Keshavarz Sadegh
- USERN Office, Qazvin University of Medical Science, Qazvin, Iran
- Student Research Committee, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Maryam Khalaji
- USERN Office, Qazvin University of Medical Science, Qazvin, Iran
- Department of Biochemistry & Genetics, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Mahin Lashgari
- USERN Office, Qazvin University of Medical Science, Qazvin, Iran
- Metabolic Disease Research Center, Research Institute for prevention of non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Amir Javadi
- USERN Office, Qazvin University of Medical Science, Qazvin, Iran
- Medical informatics, Department of Community Medicine, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Mehdi Sahmani
- USERN Office, Qazvin University of Medical Science, Qazvin, Iran
- Department of Biochemistry & Genetics, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Shamim Nonejad
- USERN Office, Qazvin University of Medical Science, Qazvin, Iran
- Department of Biochemistry & Genetics, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Sanaz Keshavarz Shahbaz
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran
- USERN Office, Qazvin University of Medical Science, Qazvin, Iran
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Ding Q, Cao C, Shi Y, Fan Z, Li F, Tu W, Jin X, Zhu H, Fan B. A functional MMP-9-1562C>T polymorphism, MMP-9 serum levels and nephrolithiasis risk in a southern Chinese population. Front Med (Lausanne) 2023; 10:1175798. [PMID: 37332754 PMCID: PMC10272514 DOI: 10.3389/fmed.2023.1175798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 05/15/2023] [Indexed: 06/20/2023] Open
Abstract
Background The role of matrix metalloproteinase 9 (MMP-9) in the pathophysiology of chronic kidney disease (CKD), which is associated with a nearly two-fold greater risk for urinary calculi compared to people without CKD, has been demonstrated. The aim of the research is to evaluate the association between MMP-9-1562C>T polymorphism, MMP-9 serum levels and nephrolithiasis risk. Methods A hospital-based case-control study involving 302 kidney stone patients and 408 controls without kidney stone from southern China was conducted. Sanger sequencing was used to genotype the MMP-9-1562C>T polymorphism. The serum MMP-9 was measured in 105 kidney stone patients and 77 controls by enzyme-linked immunosorbent assay. Results Compared to the control group, the CT genotype was more frequent in nephrolithiasis patients (adjusted OR = 1.60, 95% CI = 1.09-2.37: the risk of developing nephrolithiasis in individuals with CT genotype compared to CC genotype). Moreover, there was also a higher frequency of CT/TT genotypes among patients with nephrolithiasis (adjusted OR = 1.49, 95% CI = 1.02-2.19: the risk of developing nephrolithiasis in individuals with CT/TT genotypes compared to CC genotype). The risk remained for the subgroups of patients aged >53, smokers with pack-years of smoking >20, non-drinkers, non-diabetic patients, patients with hypertension, recurrent episodes and calcium oxalate stones (OR = 2.26, 95% CI = 1.31-3.91; OR = 5.47, 95% CI = 1.10-27.30; OR = 1.76, 95% CI = 1.14-2.72; OR = 1.54, 95% CI = 1.03-2.30; OR = 1.97, 95% CI = 1.01-3.82; OR = 1.67, 95% CI = 1.06-2.62; OR = 1.54, 95% CI = 1.02-2.32, respectively). Biochemical parameters did not differ between genotypes. Compared to controls (18.57 ± 5.80 ng/mL), nephrolithiasis patients had significantly higher serum MMP-9 levels (30.17 ± 6.78 ng/mL, p < 0.001). The serum MMP-9 levels of patients with CT/TT genotypes of MMP-9-1562C>T were significantly higher than those with CC genotype (32.00 ± 6.33 vs. 29.13 ± 6.85 ng/mL, p = 0.037). Conclusion The MMP-9-1562C>T polymorphism in association with its soluble protein increased the risk of kidney stone, thus suggesting it could be used as a susceptibility biomarker for nephrolithiasis. Further functional studies and larger studies that include environmental exposure data are needed to confirm the findings.
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Affiliation(s)
- Qi Ding
- Department of Urology, The First People’s Hospital of Changshu, The Changshu Hospital Affiliated to Soochow University, Changshu, China
| | - Cheng Cao
- Department of Urology, The First People’s Hospital of Changshu, The Changshu Hospital Affiliated to Soochow University, Changshu, China
| | - Ying Shi
- Department of Gastroenterology, The First People’s Hospital of Changshu, The Changshu Hospital Affiliated to Soochow University, Changshu, China
| | - Zhijiang Fan
- Department of Urology, The First People’s Hospital of Changshu, The Changshu Hospital Affiliated to Soochow University, Changshu, China
| | - Feng Li
- Department of Urology, The First People’s Hospital of Changshu, The Changshu Hospital Affiliated to Soochow University, Changshu, China
| | - Wenjian Tu
- Department of Urology, The First People’s Hospital of Changshu, The Changshu Hospital Affiliated to Soochow University, Changshu, China
| | - Xiaohua Jin
- Department of Urology, The First People’s Hospital of Changshu, The Changshu Hospital Affiliated to Soochow University, Changshu, China
| | - Hailiang Zhu
- Department of Urology, The First People’s Hospital of Changshu, The Changshu Hospital Affiliated to Soochow University, Changshu, China
| | - Bo Fan
- Department of Urology, The First People’s Hospital of Changshu, The Changshu Hospital Affiliated to Soochow University, Changshu, China
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Huang C, Xu S, Luo Z, Li D, Wang R, Wang T. Epidemiological Evidence Between Variants in Matrix Metalloproteinases-2, -7, and -9 and Cancer Risk. Front Oncol 2022; 12:856831. [PMID: 35574300 PMCID: PMC9095957 DOI: 10.3389/fonc.2022.856831] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 03/31/2022] [Indexed: 12/31/2022] Open
Abstract
Background Matrix metalloproteinases (MMPs), a kind of proteases, have a critical function in cancer occurrence, invasion, and migration. MMP gene variants (e.g., MMP-2, MMP-7, and MMP-9) can affect the biological functions of these enzymes and lead to the occurrence and progression of cancer, which has become a hot topic in recent years, but the corresponding results are still controversial. In this context, here, the meta-analysis was conducted for assessing the relations of variants in MMP-2, MMP-7, and MMP-9 with the risk of various cancers. Methods PubMed, Web of Science, and Medline were systemically searched, and data were extracted from all eligible studies so as to investigate the susceptibility of MMP-2, MMP-7, and MMP-9 to different types of cancers. The association between a variant in MMP and cancer susceptibility was analyzed through odds ratios (ORs) as well as 95% CIs. The Venice criteria and false-positive report probability (FPRP) were adopted to evaluate epidemiological evidence of significant associations discovered. Results The associations between the variants of MMPs and cancer risk in 36,530 cases and 41,258 controls were found, with 12 associations (MMP-2 rs243865 with esophageal cancer and lung cancer, MMP-7 rs11568818 with bladder and cervical cancer, and MMP-9 rs3918242 with breast cancer) rated as strong associations for cancer risk and 7 and 15 as moderate and weak associations, respectively. These significant associations were mostly found in Asians. Conclusions These findings support the relations between variants of MMP-2, MMP-7, and MMP-9 and various cancers risk, demonstrating the credibility of these relations.
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Affiliation(s)
- Chenglu Huang
- Department of Thoracic Surgery, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Suqin Xu
- Department of Radiology, Chongqing University Cancer Hospital, Chongqing, China
| | - Zhilin Luo
- Department of Thoracic Surgery, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Dong Li
- Department of Thoracic Surgery, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Rui Wang
- Department of Thoracic Surgery, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Tianhu Wang
- Department of Thoracic Surgery, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Pezeshkian Z, Nobili S, Peyravian N, Shojaee B, Nazari H, Soleimani H, Asadzadeh-Aghdaei H, Ashrafian Bonab M, Nazemalhosseini-Mojarad E, Mini E. Insights into the Role of Matrix Metalloproteinases in Precancerous Conditions and in Colorectal Cancer. Cancers (Basel) 2021; 13:cancers13246226. [PMID: 34944846 PMCID: PMC8699154 DOI: 10.3390/cancers13246226] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/06/2021] [Accepted: 12/07/2021] [Indexed: 01/06/2023] Open
Abstract
Simple Summary Colorectal cancer (CRC) is one of the most common cancer worldwide. CRC is derived from polyps and many factors, such as Matrix Metalloproteinases (MMPs) can gain the progression of colorectal carcinogenesis. Many investigations have indicated the role of MMPs in CRC development while there is not enough knowledge about the function of MMPs in precancerous conditions. This review summarizes the current information about the role of MMPs in polyps and CRC progression. Abstract Colorectal cancer (CRC) is the third and second cancer for incidence and mortality worldwide, respectively, and is becoming prevalent in developing countries. Most CRCs derive from polyps, especially adenomatous polyps, which can gradually transform into CRC. The family of Matrix Metalloproteinases (MMPs) plays a critical role in the initiation and progression of CRC. Prominent MMPs, including MMP-1, MMP-2, MMP-7, MMP-8, MMP-9, MMP-12, MMP-13, MMP-14, and MMP-21, have been detected in CRC patients, and the expression of most of them correlates with a poor prognosis. Moreover, many studies have explored the inhibition of MMPs and targeted therapy for CRC, but there is not enough information about the role of MMPs in polyp malignancy. In this review, we discuss the role of MMPs in colorectal cancer and its pathogenesis
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Affiliation(s)
- Zahra Pezeshkian
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19835-178, Iran; (Z.P.); (N.P.); (B.S.); (H.A.-A.)
| | - Stefania Nobili
- Department of Neurosciences, Imaging and Clinical Sciences, “G. D’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy;
- Center for Advanced Studies and Technology (CAST), University “G. D’Annunzio” Chieti-Pescara, 66100 Chieti, Italy
| | - Noshad Peyravian
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19835-178, Iran; (Z.P.); (N.P.); (B.S.); (H.A.-A.)
| | - Bahador Shojaee
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19835-178, Iran; (Z.P.); (N.P.); (B.S.); (H.A.-A.)
| | - Haniye Nazari
- Department of Microbiology, Faculty of Advanced Science and Technology, Tehran Medical Science, Islamic Azad University, Tehran 19395-1495, Iran;
| | - Hiva Soleimani
- Department of General Biology, Faculty of Fundamental Science, Islamic Azad University of Shahr-E-Qods, Tehran 37515-374, Iran;
| | - Hamid Asadzadeh-Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19835-178, Iran; (Z.P.); (N.P.); (B.S.); (H.A.-A.)
| | - Maziar Ashrafian Bonab
- School of Medicine, University of Sunderland, City Campus, Chester Road, Sunderland SR1 3SD, UK;
| | - Ehsan Nazemalhosseini-Mojarad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19835-178, Iran
- Correspondence: (E.N.-M.); (E.M.)
| | - Enrico Mini
- Department of Health Sciences, University of Florence, 50139 Florence, Italy
- DENOTHE Excellence Center, University of Florence, 50139 Florence, Italy
- Correspondence: (E.N.-M.); (E.M.)
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Association of MMP9-1562C/T and MMP13-77A/G Polymorphisms with Non-Small Cell Lung Cancer in Southern Chinese Population. Biomolecules 2019; 9:biom9030107. [PMID: 30889876 PMCID: PMC6468416 DOI: 10.3390/biom9030107] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Revised: 03/04/2019] [Accepted: 03/12/2019] [Indexed: 12/22/2022] Open
Abstract
Background: Matrix metalloproteinases (MMPs) are capable of degrading and modifying most components of the extracellular matrix (ECM) and the basal membrane (BM), and play crucial roles in cancer invasion and metastasis. MMP gene expressions were regulated primarily at the transcriptional level, which was associated with tumor spread and patient prognosis. Polymorphisms in MMPs have been reported to be associated with non-small cell lung cancer (NSCLC). The objective of this study aim to evaluate the serum levels and polymorphisms of MMP-9 and MMP-13 in non-small cell lung cancer patients compared to normal subjects and their correlation to non-small cell lung cancer histopathology findings in Southern Chinese people. Methods: This case–control study included 245 patients with NSCLC and 258 healthy controls. Genomic DNA was extracted by using DNA extraction kit, genotyping was confirmed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct DNA sequencing, and serum levels of MMP-9 and MMP-13 were measured by using a specific ELISA, Human Matrix Metalloproteinase Enzyme Immunoassay Kits. Statistical analysis was carried out using the SPSS 23.0 software package. Results: The subjects carrying the TT genotype had a decreased risk of lung cancer in MMP9-1562C/T comparing with the CC genotype (p = 0.00, OR = 0.45, 95% CI = 0.29–0.68), and the MMP13-77 AA genotype was associated with a decreased risk of NSCLC by comparing with the GG genotype (p = 0.03, OR = 0.56, 95% CI = 0.33–0.94). Moreover, the C allele of MMP9-1562C/T could increase serum level of NSCLC in compared with the A allele (OR = 1.19, 95% CI = 0.75–1.89). Similarly, the AA genotype of MMP13 might be a marker of decreased serum level of lung cancer (OR = 0.76, 95% CI = 0.51–1.14). Conclusions: The results of these analyses underline the support of the notion that the CC genotype of MMP9-1562C/T and GG genotypes of MMP13-77G/A were associated with the increased risk NSCLC, and the serum levels of MMP9 and MMP13 were consistent with the results of the SNP analysis. MMP13 and MMP9 might be function as a key oncogene in NSCLC with a Southern Chinese population. Combined detection of SNP and enzyme activity between MMP9 and MMP13 are expected to be a potential diagnostic method of non-small cell lung cancer.
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Liu JW, Chen DQ. Correlations of MMP-2 and MMP-9 gene polymorphisms with the risk of hepatopulmonary syndrome in cirrhotic patients: A case-control study. Kaohsiung J Med Sci 2018; 34:634-642. [DOI: 10.1016/j.kjms.2018.06.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2018] [Revised: 03/21/2018] [Accepted: 06/14/2018] [Indexed: 12/17/2022] Open
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Synergistic effect of collagenase-1 (MMP1), stromelysin-1 (MMP3) and gelatinase-B (MMP9) gene polymorphisms in breast cancer. PLoS One 2017; 12:e0184448. [PMID: 28961241 PMCID: PMC5621673 DOI: 10.1371/journal.pone.0184448] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 08/24/2017] [Indexed: 12/11/2022] Open
Abstract
Background Extracellular matrix degradation by matrix metalloproteinases (MMPs) is an important mechanism involved in tumor invasion and metastasis. Genetic variations of MMPs have shown association with multiple cancers. The present study is focused to elucidate the association of MMP-1, 3 and 9 genetic variants with respect to epidemiological and clinicopathological variables by haplotype, LD, MDR, survival in silico analyses among South Indian women. Material and methods MMP3–1171 5A/6A and MMP9–1562 C/T SNPs were genotyped by Allele specific polymerase chain reaction and MMP1-1607 1G/2G polymorphism by restriction fragment length polymorphism assays respectively, in 300 BC patients and age-matched 300 healthy controls. Statistical analysis was performed using the SNPStats and SPSS software. Linkage disequilibrium and gene-gene interactions were performed using Haploview and MDR software respectively. Further, transcription factor binding sites in the promoter regions of SNPs under study were carried out using AliBaba2.1 software. Results We have observed an increased frequency of 2G-allele of MMP1, 6A-allele of MMP3 and T-allele of MMP9 (p<0.05) respectively in BC subjects. The 2G-6A haplotype (minor alleles of MMP-1 and MMP-3 respectively) has shown an increased susceptibility to BC. Further, MMP polymorphisms were associated with the clinical characteristics of BC patients such as steroid hormone receptor status, lymph node involvement and metastasis. SNP combinations were in perfect LD in controls. MDR analysis revealed a positive interaction between the SNPs. 5-years survival rate and cox-regression analysis showed a significant association with clinicopathological variables. Conclusion Our results suggest that MMP1–1607 1G/2G, MMP3–1171 5A/6A and MMP9–1562 C/T gene polymorphisms have synergistic effect on breast cancer. The interactions of MMPs clinical risk factors such as lymph node involvement has shown a strong correlation and might influence the 5-years survival rate, suggesting their potential role in the breast carcinogenesis.
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A loss of host-derived MMP-7 promotes myeloma growth and osteolytic bone disease in vivo. Mol Cancer 2017; 16:49. [PMID: 28241871 PMCID: PMC5330156 DOI: 10.1186/s12943-017-0616-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Accepted: 02/20/2017] [Indexed: 01/07/2023] Open
Abstract
Matrix metalloproteinases (MMPs) play a critical role in cancer pathogenesis, including tumor growth and osteolysis within the bone marrow microenvironment. However, the anti-tumor effects of MMPs are poorly understood, yet have significant implications for the therapeutic potential of targeting MMPs. Host derived MMP-7 has previously been shown to support the growth of bone metastatic breast and prostate cancer. In contrast and underscoring the complexity of MMP biology, here we identified a tumor-suppressive role for host MMP-7 in the progression of multiple myeloma in vivo. An increase in tumor burden and osteolytic bone disease was observed in myeloma-bearing MMP-7 deficient mice, as compared to wild-type controls. We observed that systemic MMP-7 activity was reduced in tumor-bearing mice and, in patients with multiple myeloma this reduced activity was concomitant with increased levels of the endogenous MMP inhibitor, tissue inhibitor of metalloproteinases-1 (TIMP-1). Our studies have identified an unexpected tumour-suppressive role for host-derived MMP-7 in myeloma bone disease in vivo, and highlight the importance of elucidating the effect of individual MMPs in a disease-specific context.
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Zhang C, Chen L, Gu Y. Polymorphisms of MMP-1 and MMP-3 and susceptibility to rheumatoid arthritis. A meta-analysis. Z Rheumatol 2016; 74:258-62. [PMID: 25854159 DOI: 10.1007/s00393-014-1537-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To determine the correlation between rheumatoid arthritis (RA) and polymorphisms of the matrix metalloproteinase (MMP) genes MMP-1 and MMP-3. BACKGROUND The 1607 1G/2G and 1171 5A/6A polymorphisms of MMP genes MMP-1 and MMP-3 have been discovered to be functional, and may be conducive to RA. In order to determine whether MMP-1 and MMP-3 gene polymorphisms correlate with RA development, we performed a meta-analysis to further validate the function of these polymorphisms in RA. METHODS We searched PubMed, ISI Web of Knowledge, MEDLINE, Embase, Google Scholar Chinese Biomedical Literature Database, and Wanfang Data to identify all published case-control studies on the MMP-1-1607 1G/2G and MMP-3-1171 5A/6A polymorphisms and RA risk. Odds ratios (OR) and 95 % confidence intervals (CI) were used to estimate the association between these polymorphisms and RA risk. RESULTS After being assessed, five articles fulfilled the inclusion criteria. To assess associations, the pooled OR with 95 % CIs was calculated. Neither the MMP-1-1607 1G/2G nor the MMP-3-1171 5A/6A polymorphism was statistically associated with RA in any of the five models, nor in the subgroup analysis models of MMP-3-1171 5A/6A in Caucasian and Asian patients. CONCLUSION Our study suggests that MMP-1 and MMP-3 polymorphisms have no significant association with the risk of RA.
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Affiliation(s)
- C Zhang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, No 188 ShiziStreet, 215006, Suzhou, China
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12
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Peng Q, Xu Y. Association between promoter polymorphisms of matrix metalloproteinase-1 and risk of gastric cancer. Onco Targets Ther 2015; 8:2519-26. [PMID: 26392779 PMCID: PMC4574801 DOI: 10.2147/ott.s83004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Growing evidences show that matrix metalloproteinase-1 (MMP1) plays important roles in tumorigenesis and cancer metastasis. The interactions between MMP1-1607 1G>2G polymorphism and risk of gastric cancer (GC) have been reported, but results remained ambiguous. To determine the association between MMP1-1607 1G>2G polymorphism and risk of GC, we conducted a meta-analysis and identified the outcome data from all the research papers estimating the association between MMP1-1607 1G>2G polymorphism and GC risk, which was based on comprehensive searches using databases such as PubMed, Elsevier Science Direct, Excerpta Medica Database (EMBASE), and Chinese National Knowledge Infrastructure (CNKI). The fixed-effects model was used in this meta-analysis. Data were extracted, and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. In this meta-analysis, six studies involving 1,377 cases and 1,543 controls were included. We identified the significant association between MMP1-1607 1G>2G polymorphism and GC risk for allele model (OR =1.05; 95% CI, 1.01-1.08), for dominant model (OR =1.11; 95% CI, 1.08-1.15), and for recessive model (OR =1.06; 95% CI, 0.98-1.14). In summary, our analysis demonstrated that MMP1-1607 1G>2G polymorphism was significantly associated with an increased risk of GC.
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Affiliation(s)
- Qisong Peng
- Department of Laboratory Medicine, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Yong Xu
- Department of Laboratory Medicine, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, People's Republic of China
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13
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Tao L, Li Z, Lin L, Lei Y, Hongyuan Y, Hongwei J, Yang L, Chuize K. MMP1, 2, 3, 7, and 9 gene polymorphisms and urinary cancer risk: a meta-analysis. Genet Test Mol Biomarkers 2015; 19:548-55. [PMID: 26301605 DOI: 10.1089/gtmb.2015.0123] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND The matrix metalloproteinases (MMPs) are a family of highly conserved, metal-dependent proteolytic enzymes that play an important role in tumor invasion and metastasis. Many studies have been carried out on the association between polymorphisms in the MMP1, MMP2, MMP3, MMP7, and MMP9 genes and urinary cancer risk. However, the data from these published studies are conflicting and have low statistical power. METHODS In this study, we performed a meta-analysis of 12 different publications from the PubMed and WanFang databases, published up to May 2015, to better assess the purported associations. Odds ratios (OR) and 95% confidence intervals (CI) were determined to reveal association strengths. RESULTS Some significant associations were found. For the MMP1 -1607 1G/2G polymorphism, a negative association was identified for the 2G allele in bladder cancer (2G2G+2G1G vs. 1G1G: OR = 0.57, 95% CI = 0.36-0.93, pheterogeneity = 0.001) and renal cell carcinoma (2G1G vs. 1G1G: OR = 0.57, 95% CI = 0.39-0.82, pheterogeneity = 0.567). For the MMP2 -1306 C/T polymorphism, there was a negative association with the T allele for bladder cancer in the Asian population (TT+TC vs. CC: OR = 0.41, 95% CI = 0.18-0.94, pheterogeneity = 0.195). For the MMP7 -181 A/G polymorphism, a decreased bladder cancer risk was found (G-allele vs. A-allele: OR = 0.81, 95% CI = 0.66-0.98, pheterogeneity =0.325). CONCLUSION In summary, our study showed evidence that genetic polymorphisms in MMP1 for all populations, but only in the Asian population for MMP2 and MMP7, may protect against bladder cancer risk. Future studies with larger sample sizes are warranted to further evaluate these associations in more detail.
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Affiliation(s)
- Liu Tao
- 1 Department of Urology, The First Hospital of China Medical University , Shenyang, People's Republic of China
| | - Zuo Li
- 2 Department of Urology, The Second People's Hospital of Nanjing Medical University , Changzhou, People's Republic of China
| | - Li Lin
- 3 Department of Rehabilitation, Shengjing Hospital of China Medical University , Shenyang, People's Republic of China
| | - Yin Lei
- 1 Department of Urology, The First Hospital of China Medical University , Shenyang, People's Republic of China
| | - Yu Hongyuan
- 1 Department of Urology, The First Hospital of China Medical University , Shenyang, People's Republic of China
| | - Jing Hongwei
- 1 Department of Urology, The First Hospital of China Medical University , Shenyang, People's Republic of China
| | - Liu Yang
- 1 Department of Urology, The First Hospital of China Medical University , Shenyang, People's Republic of China
| | - Kong Chuize
- 1 Department of Urology, The First Hospital of China Medical University , Shenyang, People's Republic of China
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Sharma KL, Rai R, Srivastava A, Sharma A, Misra S, Kumar A, Mittal B. A multigenic approach to evaluate genetic variants of PLCE1, LXRs, MMPs, TIMP, and CYP genes in gallbladder cancer predisposition. Tumour Biol 2014; 35:8597-8606. [PMID: 24863943 DOI: 10.1007/s13277-014-2094-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2014] [Accepted: 05/13/2014] [Indexed: 12/29/2022] Open
Abstract
Gallbladder cancer (GBC) is a violent neoplasm associated with late diagnosis, unsatisfactory treatment, and poor prognosis. The disease shows complex interplay between multiple genetic variants. We analyzed 15 polymorphisms in nine genes involved in various pathways to find out combinations of genetic variants contributing to GBC risk. The genes included in the study were matrix metalloproteinases (MMP-2, MMP-7, and MMP-9), tissue inhibitor of metalloproteinases (TIMP-2), cytochrome P450 (CYP)1A1, CYP1B1, phospholipase C epsilon 1 (PLCE1), liver X receptor (LXR)-alpha, and LXR-beta. Genotypes were determined by PCR-RFLP and TaqMan probes. Statistical analysis was done by SPSS version 16. Multilocus analysis was performed by Classification and Regression Tree (CART) analysis and multifactor dimensionality reduction (MDR) to gene-gene interactions in modifying GBC risk. In silico analysis was done using various bioinformatics tools (F-SNP, FAST-SNP). Single locus analysis showed association of MMP-2 (-735 C > T, -1306 C > T), MMP-7 - 181 A > G, MMP-9 (P574R, R668Q), TIMP-2 - 418 G > C, CYP1A1-MspI, CYP1A1-Ile462Val, PLCE1 (rs2274223 A > G, rs7922612 T > C) and LXR-beta T > C (rs3546355 G > A, rs2695121 T > C) polymorphisms with GBC risk (p < 0.05) whereas CYP1B1 and LXR-α variants were not associated with GBC risk. Multidimensional reduction analysis revealed LXR-β (rs3546355 G > A, rs2695121 T > C), MMP-2 (-1306 C > T), MMP-9 (R668Q), and PLCE1 rs2274223 A > G to be key players in GBC causation (p < 0.001, CVC = 7/10). The results were further supported by independent CART analysis (p < 0.001). In silico analysis of associated variants suggested change in splicing or transcriptional regulation. Interactome and STRING analysis showed network of associated genes. The study found PLCE1 and LXR-β network interactions as important contributory factors for genetic predisposition in gallbladder cancer.
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Affiliation(s)
- Kiran Lata Sharma
- Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), Lucknow, Uttar Pradesh, 226014, India,
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Pereira FV, Ferreira-Guimarães CA, Paschoalin T, Scutti JAB, Melo FM, Silva LS, Melo ACL, Silva P, Tiago M, Matsuo AL, Juliano L, Juliano MA, Carmona AK, Travassos LR, Rodrigues EG. A natural bacterial-derived product, the metalloprotease arazyme, inhibits metastatic murine melanoma by inducing MMP-8 cross-reactive antibodies. PLoS One 2014; 9:e96141. [PMID: 24788523 PMCID: PMC4005744 DOI: 10.1371/journal.pone.0096141] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2013] [Accepted: 04/04/2014] [Indexed: 11/23/2022] Open
Abstract
The increased incidence, high rates of mortality and few effective means of treatment of malignant melanoma, stimulate the search for new anti-tumor agents and therapeutic targets to control this deadly metastatic disease. In the present work the antitumor effect of arazyme, a natural bacterial-derived metalloprotease secreted by Serratia proteomaculans, was investigated. Arazyme significantly reduced the number of pulmonary metastatic nodules after intravenous inoculation of B16F10 melanoma cells in syngeneic mice. In vitro, the enzyme showed a dose-dependent cytostatic effect in human and murine tumor cells, and this effect was associated to the proteolytic activity of arazyme, reducing the CD44 expression at the cell surface, and also reducing in vitro adhesion and in vitro/in vivo invasion of these cells. Arazyme treatment or immunization induced the production of protease-specific IgG that cross-reacted with melanoma MMP-8. In vitro, this antibody was cytotoxic to tumor cells, an effect increased by complement. In vivo, arazyme-specific IgG inhibited melanoma lung metastasis. We suggest that the antitumor activity of arazyme in a preclinical model may be due to a direct cytostatic activity of the protease in combination with the elicited anti-protease antibody, which cross-reacts with MMP-8 produced by tumor cells. Our results show that the bacterial metalloprotease arazyme is a promising novel antitumor chemotherapeutic agent.
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Affiliation(s)
- Felipe V. Pereira
- Department of Microbiology, Immunology, and Parasitology, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
| | - Carla A. Ferreira-Guimarães
- Department of Microbiology, Immunology, and Parasitology, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
| | | | - Jorge A. B. Scutti
- Department of Microbiology, Immunology, and Parasitology, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
| | - Filipe M. Melo
- Department of Microbiology, Immunology, and Parasitology, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
| | - Luis S. Silva
- Department of Microbiology, Immunology, and Parasitology, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
| | - Amanda C. L. Melo
- Department of Microbiology, Immunology, and Parasitology, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
| | - Priscila Silva
- Department of Microbiology, Immunology, and Parasitology, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
| | - Manoela Tiago
- School of Pharmaceutical Sciences, University of São Paulo (USP), São Paulo, Brazil
| | - Alisson L. Matsuo
- Department of Microbiology, Immunology, and Parasitology, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
| | - Luiz Juliano
- Department of Biophysics, EPM-UNIFESP, São Paulo, Brazil
| | | | | | - Luiz R. Travassos
- Department of Microbiology, Immunology, and Parasitology, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
| | - Elaine G. Rodrigues
- Department of Microbiology, Immunology, and Parasitology, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
- * E-mail:
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Wieczorek E, Wasowicz W, Gromadzinska J, Reszka E. Functional polymorphisms in the matrix metalloproteinase genes and their association with bladder cancer risk and recurrence: a mini-review. Int J Urol 2014; 21:744-52. [PMID: 24635493 DOI: 10.1111/iju.12431] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2013] [Accepted: 02/04/2014] [Indexed: 12/31/2022]
Abstract
Molecular pathogenesis of muscle invasive bladder cancer and non-muscle invasive bladder cancer is incompletely elucidated. It is believed that matrix metalloproteinases, which are involved in the processes of uncontrolled extracellular matrix substrates degradation and participate in modulating the activity of a variety of non-matrix proteins, can contribute to carcinogenesis. Polymorphisms in the MMP genes associated with unique genomic changes in bladder cancer patients are still being investigated to discover direct links with pathophysiological mechanisms. Because of the functional polymorphisms in the MMP genes, which have a proven or likely effect on their protein expression, they could possibly affect the tumor process. The current mini-review synthesizes findings regarding the association of genetic polymorphisms in the MMP genes with bladder cancer risk and recurrence in patients. We discuss the current views on the feasibility of genetic polymorphisms in the MMP1, 2, 3, 7, 8, 9 and 12 genes as a risk, and prognostic markers for patients with bladder cancer. The majority of the research described in the present mini-review proves that the genetic polymorphism in the MMP1 (rs1799750) is the most widely studied, and suggests that the rare genotype, 2G2G, of that gene might show increased susceptibility for bladder cancer, especially among smokers. However, existing statistically significant associations between the genetic polymorphisms in the MMP genes and bladder cancer risk have not been clearly shown, and further studies are necessary in order to positively confirm them or dispel potential false hopes.
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Affiliation(s)
- Edyta Wieczorek
- Department of Toxicology and Carcinogenesis, Nofer Institute of Occupational Medicine, Lodz, Poland
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Said AH, Raufman JP, Xie G. The role of matrix metalloproteinases in colorectal cancer. Cancers (Basel) 2014; 6:366-75. [PMID: 24518611 PMCID: PMC3980606 DOI: 10.3390/cancers6010366] [Citation(s) in RCA: 165] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Revised: 01/24/2014] [Accepted: 01/26/2014] [Indexed: 12/15/2022] Open
Abstract
In the United States, colorectal cancer (CRC) is the third leading cause of cancer mortality, with limited treatment options for those with advanced disease. Matrix metalloproteinases (MMPs) are important for maintaining extracellular homeostasis but also play a prominent role in cancer cell invasion and dissemination. Expression levels of MMP-1, -2, -7, -9 and -13 correlate with worse outcomes; MMP-12 expression appears to be protective. Hence, MMPs are attractive therapeutic targets. Previous clinical trials using broad-spectrum MMP inhibitors were disappointing because of off-target toxicity and lack of efficacy. Now, the availability of safer, more selective inhibitors has renewed interest in therapeutic targeting of MMPs.
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Affiliation(s)
- Anan H Said
- Division of Gastroenterology and Hepatology, Veterans Affairs Maryland Health Care System, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
| | - Jean-Pierre Raufman
- Division of Gastroenterology and Hepatology, Veterans Affairs Maryland Health Care System, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
| | - Guofeng Xie
- Division of Gastroenterology and Hepatology, Veterans Affairs Maryland Health Care System, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
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Abstract
PURPOSE Matrix metalloproteinases (MMPs) are implicated in cancer cells invasion and metastasis processes and have been investigated as potential cancer biomarkers. In this study MMP-9 gene expression and MMP-9 -1562 C/T polymorphism in breast and non-small cell lung cancer patients' blood and tumor samples and its correlation with clinicopathological parameters were investigated. MATERIAL/METHODS MMP-9 gene expression was assessed by reverse transcription - polymerase chain reaction method in 108 cancer patients' blood and tumor samples. MMP-9 -1562 C/T polymorphism was determined by the polymerase chain reaction - based restriction fragment length polymorphism method. RESULTS Significant relationship of MMP-9 gene expression and tumor differentiation grade was found only between groups with G1 and G3 breast tumors. Low survival rates were identified among positive MMP-9 expression in blood and ductal carcinoma of the breast (p=0.01) and negative progesterone receptor reaction (p=0.04). Significant differences in the distribution among genotypes were found between groups with stage I and stages III/IV (p=0.005) as well as between groups with lymph node status N0 and N1 (p<0.001). Breast cancer patients with tumor differentiation grade G3 and identified CC variant had a longer survival time (p=0.014). Shorter survival time was found among positive MMP-9 expression in tumor and stage I non-small cell lung cancer patients with negative lymph node (p=0.012) and squamous cell carcinoma (p=0.019). CONCLUSIONS Expression of MMP-9 in blood and tumor together indicates worse prognosis for breast cancer patients.
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Matrix metalloproteinase7 -181A/G polymorphism is associated with increased cancer risk among high-quality studies: Evidence from a meta-analysis. Clin Biochem 2013; 46:1649-54. [DOI: 10.1016/j.clinbiochem.2013.07.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2012] [Revised: 06/15/2013] [Accepted: 07/15/2013] [Indexed: 01/15/2023]
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Wieczorek E, Reszka E, Jablonowski Z, Jablonska E, Krol MB, Grzegorczyk A, Gromadzinska J, Sosnowski M, Wasowicz W. Genetic polymorphisms in matrix metalloproteinases (MMPs) and tissue inhibitors of MPs (TIMPs), and bladder cancer susceptibility. BJU Int 2013; 112:1207-14. [PMID: 23819551 DOI: 10.1111/bju.12230] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
OBJECTIVES To elucidate genetic polymorphisms of the matrix metalloproteinases (MMPs) MMP1 (rs1799750), MMP2 (rs243865), MMP9 (rs3918242), MMP12 (rs2276109) and tissue inhibitors of MMPs (TIMPs) TIMP1 (rs2070584) and TIMP3 (rs9619311) genes that may be involved in susceptibility to bladder cancer (BC). PATIENTS AND METHODS We enrolled 241 patients with BC and 199 controls. Genomic DNA samples were extracted from peripheral blood and polymorphisms were analysed by high-resolution melting analysis and by real-time polymerase chain reaction using TaqMan fluorescent probes. RESULTS Of the six evaluated polymorphisms of MMPs and TIMPs, only one was found to be associated with BC risk. There was a significant difference for MMP1 (rs1799750) 2G/1G+1G/1G genotype (odds ratio [OR] 0.62, 95% confidence interval [CI] 0.39-0.98; P = 0.042). Additionally, there was a joint effect of this genotype on BC risk among 'ever smokers' (OR 0.51, 95% CI 0.28-0.89; P = 0.019), but not in 'never smokers'. The combined genotype MMP2 -1306C/T (rs243865) allele T with MMP9 -1562C/T (rs3918242) allele T was found to increase BC risk (OR 2.00, 95% CI 1.10-3.62; P = 0.022). CONCLUSIONS Our results suggest that genetic variations in five polymorphisms of MMPs and TIMPs are not associated with a high risk of BC. Only MMP1 polymorphism may be related to the risk of BC, notably in 'ever smokers'. Our study suggests that the effects of polymorphisms of MMPs and TIMPs on BC risk deserve further investigation.
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Affiliation(s)
- Edyta Wieczorek
- Department of Toxicology and Carcinogenesis, Nofer Institute of Occupational Medicine, Lodz, Poland
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Yang X, Liu Y, Yang Y, Li B. Update meta-analysis on MMP-7 −181A>G polymorphism and cancer risk: Evidence from 25 studies. Gene 2013; 521:252-8. [DOI: 10.1016/j.gene.2013.03.079] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2012] [Revised: 02/25/2013] [Accepted: 03/15/2013] [Indexed: 11/30/2022]
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Herszényi L, Hritz I, Lakatos G, Varga MZ, Tulassay Z. The behavior of matrix metalloproteinases and their inhibitors in colorectal cancer. Int J Mol Sci 2012; 13:13240-13263. [PMID: 23202950 PMCID: PMC3497324 DOI: 10.3390/ijms131013240] [Citation(s) in RCA: 117] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2012] [Revised: 10/08/2012] [Accepted: 10/10/2012] [Indexed: 02/06/2023] Open
Abstract
Matrix metalloproteinases (MMPs) play an important role in the degradation of extracellular matrix components crucial for tumor growth, invasion and metastasis. MMPs are controlled by natural inhibitors called tissue inhibitors of metalloproteinases (TIMPs). We and others have demonstrated that MMPs and TIMPs are especially important in the process of tumor invasion, progression and the metastasis of colorectal cancer (CRC). It has been proposed that MMPs and TIMPs might play a part not only in tumor invasion and initiation of metastasis but also in carcinogenesis from colorectal adenomas. Several recent studies demonstrated that high preoperative serum or plasma MMP-2, MMP-9 and TIMP-1 antigen levels are strong predictive factors for poor prognosis in patients with CRC and their determination might be useful for identification of patients with higher risk for cancer recurrence. MMP-9 and TIMP-1 have significant potential tumor marker impact in CRC. Their diagnostic sensitivity is consistently higher than those of conventional biomarkers. The pharmacological targeting of CRC by the development of a new generation of selective inhibitors of MMPs, that is highly specific for certain MMPs, is a promising and challenging area for the future.
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Affiliation(s)
- László Herszényi
- Second Department of Medicine, Semmelweis University, H-1088 Budapest, Szentkirályi str. 46, H-1088, Hungary; E-Mails: (I.H.); (G.L.); (M.Z.V.); (Z.T.)
| | - István Hritz
- Second Department of Medicine, Semmelweis University, H-1088 Budapest, Szentkirályi str. 46, H-1088, Hungary; E-Mails: (I.H.); (G.L.); (M.Z.V.); (Z.T.)
- First Department of Medicine, Fejér County Szent György Hospital, Székesfehérvár, H-8000, Hungary
| | - Gábor Lakatos
- Second Department of Medicine, Semmelweis University, H-1088 Budapest, Szentkirályi str. 46, H-1088, Hungary; E-Mails: (I.H.); (G.L.); (M.Z.V.); (Z.T.)
- Department of Oncology, Szent László Hospital, Budapest, H-1097, Hungary
| | - Mária Zsófia Varga
- Second Department of Medicine, Semmelweis University, H-1088 Budapest, Szentkirályi str. 46, H-1088, Hungary; E-Mails: (I.H.); (G.L.); (M.Z.V.); (Z.T.)
| | - Zsolt Tulassay
- Second Department of Medicine, Semmelweis University, H-1088 Budapest, Szentkirályi str. 46, H-1088, Hungary; E-Mails: (I.H.); (G.L.); (M.Z.V.); (Z.T.)
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Trovó de Marqui AB. Polimorfismos genéticos e endometriose: A contribuição dos genes que regulam a função vascular e o remodelamento de tecidos. Rev Assoc Med Bras (1992) 2012; 58:620-32. [DOI: 10.1590/s0104-42302012000500022] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2011] [Accepted: 05/11/2012] [Indexed: 01/11/2023] Open
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Trovó de Marqui AB. Polimorfismos genéticos e endometriose: A contribuição dos genes que regulam a função vascular e o remodelamento de tecidos. Rev Assoc Med Bras (1992) 2012. [DOI: 10.1016/s0104-4230(12)70259-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
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Sharma KL, Misra S, Kumar A, Mittal B. Higher risk of matrix metalloproteinase (MMP-2, 7, 9) and tissue inhibitor of metalloproteinase (TIMP-2) genetic variants to gallbladder cancer. Liver Int 2012; 32:1278-1286. [PMID: 22621753 DOI: 10.1111/j.1478-3231.2012.02822.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2012] [Revised: 03/24/2012] [Accepted: 04/20/2012] [Indexed: 12/23/2022]
Abstract
BACKGROUND Matrix metalloproteinase belong to family of pericellular collagenases which degrade extracellular matrix (ECM), and is involved in the modulation and susceptibility of various cancers. METHODOLOGY The present study included 410 gallbladder (GBC) cases and 230 healthy controls from North India. Study examined the associations of polymorphisms of MMP-2c.735C>T (rs2285053), MMP-2c.1306 C>T (rs243865), MMP7c.181A>G (rs11568818), MMP-9p.R279Q (rs17556) MMP-9p.P574R (rs2250889), MMP-9 p.R668Q (rs17577) and TIMP2c.418 G>C (rs8179090) to GBC susceptibility. Genotyping was carried out by PCR-RFLP. Statistical analysis was performed by using SPSS ver16. RESULTS The MMP-2 c.735 [CT+TT], MMP-2c.1306 [CT+TT], MMP7 c.181 [AG+GG] and MMP-9 p.668 [RQ+QQ],TIMP2c.418 [GG+GC] genotypes were significantly associated with increased risk of GBC (P = 0.01; [OR]1.87, P = 0.02; [OR] 1.68, P = 0.02; [OR]=1.61, P = 0.002; [OR]=1.91,P = 0.01; [OR]=1.78 and (P = 0.03; [OR]=1.68; P = 0.01; [OR]=1.78 respectively). Haplotypes [C(-735) -T(-1306) ] and [T(-1306) -C(-735) ] of MMP-2 (P = <0.005; [OR] =1.78 P = <0.0001; [OR] =2.09) and haplotype [Q(279) -P(574) -Q(668) ]of the MMP-9 (P = 0.04; [OR] =2.75) were significantly associated with GBC risk. On stratification of GBC patients with/without gallstones, MMP-2 haplotypes were associated with higher GBC risk in patients accompanying gallstones whereas MMP-9 haplotypes showed risk in patients without stones. Combined effect of > 3 MMP/TIMP variant containing genotypes imparted increased risk of GBC (P < 0.0001; [OR] =3.36). Multivariate logistic regression results also supported association of MMP-2 (c.735C>T, c.1306 C>T), MMP-9 p.R668Q and TIMP2c.418G>C variants with GBC susceptibility. CONCLUSION This study suggests that genetic variants in MMP-2,7,9 and TIMP-2genes are associated with higher susceptibility of gallbladder cancer.
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Affiliation(s)
- Kiran L Sharma
- Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
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Fakhoury HM, Noureddine S, Tamim H, Chmaisse H, Makki R. Association ofMMP3-1171(5A>6A) Polymorphism with Lung Cancer in Lebanon. Genet Test Mol Biomarkers 2012; 16:988-90. [DOI: 10.1089/gtmb.2012.0042] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Hana M.A. Fakhoury
- Department of Basic Sciences, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Kingdom of Saudi Arabia
| | - Sara Noureddine
- Department of Biological and Environmental Sciences, Faculty of Science, Beirut Arab University, Beirut, Lebanon
| | - Hani Tamim
- Department of Medical Education, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Kingdom of Saudi Arabia
| | - Hania Chmaisse
- Department of Pharmacology, Faculty of Pharmacy, Beirut Arab University, Beirut, Lebanon
| | - Rajaa Makki
- Department of Biological and Environmental Sciences, Faculty of Science, Beirut Arab University, Beirut, Lebanon
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Fan W, Zhou K, Hu D, Song X, Zhao Y, Chen H, Wei Q, Chen G, Shi J, Du G, Mao Y, Lu D, Zhou L. Single nucleotide polymorphisms of matrix metallopeptidase 3 and risk of gliomas in a Chinese Han population. Mol Carcinog 2011; 51 Suppl 1:E1-10. [PMID: 21853476 DOI: 10.1002/mc.20842] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2011] [Revised: 06/16/2011] [Accepted: 07/13/2011] [Indexed: 12/30/2022]
Abstract
Matrix metallopeptidases (MMPs) play an important role in central nervous system tumor growth, invasion and spreading. The currently available data provide clear evidence for the involvement of MMP3 in the pathophysiology of glioma. The study aims to explore the association of single nucleotide polymorphisms (SNPs) across the MMP3 gene with glioma risk. Three haplotype tagging and additional two promoter SNPs were genotyped among 766 glioma patients and 824 cancer-free controls from East China. None of these polymorphisms alone had a significant effect on risk of gliomas. However, when three promoter polymorphisms were evaluated together by the number of putative risk of genotypes (i.e., rs645419AA, 632478CA+AA, rs522616AA), a statistically significantly increased risk of gliomas was associated with the combined genotypes with two to three risk genotypes, compared with those with zero to one risk genotypes (adjusted odds ratio (OR) = 1.32; 95% confidence interval (CI) = 1.03-1.68). This increased risk was also more pronounced among adults (adjusted OR = 1.14, 95%CI = 1.02-1.27), males (adjusted OR = 1.19, 95%CI = 1.05-1.36), smokers (adjusted OR = 1.28, 95%CI = 1.07-1.52), subjects with no family history of cancer (adjusted OR = 1.21, 95%CI = 1.07-1.37), and patients with nonastrocytic gliomas (adjusted OR = 1.23, 95%CI = 1.06-1.43). In summary, our results suggest that any one of MMP3 variants may not have a substantial effect on glioma risk, but a joint effect of MMP3 promoter polymorphisms may contribute to risk of gliomas, particularly for adult gliomas.
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Affiliation(s)
- Weiwei Fan
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes for Biomedical Sciences, Fudan University, Shanghai, China
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Zhang LF, Mi YY, Cao Q, Wang W, Qin C, Wei JF, Zhou YJ, Li YF, Tang M, Liu WM, Zhang W, Zou JG. Update analysis of studies on the MMP-9 -1562 C>T polymorphism and cancer risk. Mol Biol Rep 2011; 39:3435-41. [PMID: 21717058 DOI: 10.1007/s11033-011-1115-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2011] [Accepted: 06/17/2011] [Indexed: 10/18/2022]
Abstract
Polymorphisms in the matrix metalloproteinase (MMP) gene have been hypothesized to be functional and may contribute to genetic susceptibility to cancers. The common sequence variation in MMP-9 -1562 C>T (rs3918242), has been involved in cancer risk. However, results of the related published studies were somewhat controversial and underpowered in general. To clarify the role of MMP-9 -1562 C>T genotype in global cancer, we performed a meta-analysis of all the available published studies involving 4,124 cancer patients and 4,728 control subjects. The overall results indicated that there was no major association of the variant on cancer risk. However, stratified analysis by cancer type showed that the MMP-9 -1562 C>T polymorphism has a lower risk in colorectal cancer (OR = 0.80, 95%CI = 0.66-0.96, P (heterogeneity) = 0.391) and lung cancer (OR = 0.70, 95%CI = 0.51-0.96, P (heterogeneity) = 0.959) by allelic contrast. Furthermore, association of the MMP-9 -1562 C>T polymorphism and cancer risk was also observed in hospital-based studies under the dominant genetic model (OR = 0.87, 95%CI = 0.78-0.97, P (heterogeneity) = 0.355), allelic contrast (OR = 0.85, 95%CI = 0.75-0.96, P (heterogeneity) = 0.271) and heterozygote comparison (OR = 0.89, 95%CI = 0.79-0.99, P (heterogeneity) = 0.402). This pooled analysis showed evidence that the MMP-9 -1562 C>T polymorphism may decrease both the colorectal and lung cancer risk. Further prospective studies with larger numbers of participants worldwide are required to evaluate the association in more detail.
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Affiliation(s)
- Li-Feng Zhang
- Department of Urology, Changzhou No. 2 People's Hospital Affiliated to Nanjing Medical University, Changzhou, 213003, Jiangsu Province, China
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Langers AM, Verspaget HW, Hommes DW, Sier CF. Single-nucleotide polymorphisms of matrix metalloproteinases and their inhibitors in gastrointestinal cancer. World J Gastrointest Oncol 2011; 3:79-98. [PMID: 21731908 PMCID: PMC3124635 DOI: 10.4251/wjgo.v3.i6.79] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2011] [Revised: 05/27/2011] [Accepted: 06/03/2011] [Indexed: 02/05/2023] Open
Abstract
Matrix metalloproteinases (MMPs) are implicated in cancer development and progression and are associated with prognosis. Single-nucleotide polymorphisms (SNPs) of MMPs, most frequently located in the promoter region of the genes, have been shown to influence cancer susceptibility and/or progression. SNPs of MMP-1, -2, -3, -7, -8, -9, -12, -13 and -21 and of the tissue inhibitor of metalloproteinases (TIMPs) TIMP-1 and TIMP-2 have been studied in digestive tract tumors. The contribution of these polymorphisms to the cancer risk and prognosis of gastrointestinal tumors are reviewed in this paper.
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Affiliation(s)
- Alexandra Mj Langers
- Alexandra MJ Langers, Hein W Verspaget, Daniel W Hommes, Cornelis FM Sier, Department of Gastroenterology and Hepatology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
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Zhou P, Du LF, Lv GQ, Yu XM, Gu YL, Li JP, Zhang C. Current evidence on the relationship between four polymorphisms in the matrix metalloproteinases (MMP) gene and breast cancer risk: a meta-analysis. Breast Cancer Res Treat 2011; 127:813-8. [PMID: 21161369 DOI: 10.1007/s10549-010-1294-0] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2010] [Accepted: 12/03/2010] [Indexed: 01/13/2023]
Abstract
The matrix metalloproteinases (MMP) can degrade various components of the extracellular matrix and its functional genetic polymorphisms may be associated with breast cancer risk. However, this relationship remains controversial. A meta-analysis was conducted in order to investigate the potential association between four polymorphisms in the MMP gene and breast cancer risk. A database search yielded a total of 9 studies involving 2,597 cases and 2,618 controls. Four polymorphisms were included in the meta-analysis: MMP-1 -1607 2G/1G (rs1799750), MMP-2 -1306 C/T (rs243865), MMP-3 -1171 6A/5A (rs3025058) and MMP-9 -1562 C/T (rs3918242). Crude odds ratios (OR) with 95% confidence intervals (CI) were used to assess the strength of association. When all the studies were pooled into the meta-analysis, we found that breast cancer cases had a significantly higher frequency of CC genotype (OR = 1.27, 95% CI = 1.10, 1.47; P = 0.001) and lower frequency of CT genotype (OR = 0.78, 95% CI = 0.67, 0.91; P = 0.001) of MMP-2. No significant difference was found in any genotype of MMP-1, MMP-3 or MMP-9. In conclusion, this meta-analysis suggested that MMP-2 -1306 C/T polymorphism may contribute to breast cancer susceptibility. More studies were needed especially in Asians in the future.
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Affiliation(s)
- Ping Zhou
- Department of Intensive Care Unite, The Third Affiliated Hospital to Nantong University, Wuxi 214041, Jiangsu, China
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RATH TIMO, STÖCKLE JULIA, RODERFELD MARTIN, TSCHUSCHNER ANNETTE, GRAF JÜRGEN, ROEB ELKE. Matrix metalloproteinase-13 is regulated by toll-like receptor-9 in colorectal cancer cells and mediates cellular migration. Oncol Lett 2011; 2:483-488. [PMID: 22866107 PMCID: PMC3410494 DOI: 10.3892/ol.2011.276] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2010] [Accepted: 03/14/2011] [Indexed: 11/06/2022] Open
Abstract
Matrix metalloproteinases (MMPs) are associated with cancer cell invasion and metastasis, and are currently the most prominent proteases associated with tumorigenesis. In particular, abundant expression of MMP-13 in colorectal cancer (CRC) is correlated with poor survival and the existence of distant metastasis. As suggested by recent in vitro studies, MMP-13 expression is regulated in a toll-like receptor (TLR)-9-dependent manner. In this study, we quantified the expression of MMP-13, TLR-9 and second messengers of the TLR signal transduction in CRC cells compared to colonic fibroblasts by RT-PCR. Furthermore, the effects of a selective TLR-9 stimulation on the expression of MMP-13 in CRC cells and colonic fibroblasts were analyzed. MMP-13 and TLR-9 as well as associated second messengers were simultaneously up-regulated in LS174 and SW620 cells compared to fibroblasts. Selective TLR-9 agonism with CpG oligonucleotides led to a significant increase in MMP-13 gene expression after 12 h of incubation in LS174 cells and after 12 and 24 h in SW620 cells, but not when using GpC oligonucleotides as a control substance. By contrast, MMP-13 gene expression remained unchanged in colonic fibroblasts following treatment with CpG or GpC oligonucleotides. The effects of selective MMP-13 inhibition on cellular migration were analyzed in Boyden chamber experiments. In the presence of 10 and 20 μM of the specific MMP-13 inhibitor, CL-82198, migration of the LS174 cells was significantly reduced by 55 and 52%, respectively, compared to untreated cells. In conclusion, the results of this study provide evidence of the TLR-9-dependent regulation of MMP-13 in CRC cells, but not in colonic fibroblasts. Since the specific inhibition of MMP-13 significantly reduces the migration of LS174 cells, selective MMP-13 inhibition may be a promising therapeutic strategy in CRC.
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Affiliation(s)
- TIMO RATH
- Department of Gastroenterology, Medical Clinic II, Justus-Liebig-University, Giessen
| | - JULIA STÖCKLE
- Department of Gastroenterology, Medical Clinic II, Justus-Liebig-University, Giessen
| | - MARTIN RODERFELD
- Department of Gastroenterology, Medical Clinic II, Justus-Liebig-University, Giessen
| | - ANNETTE TSCHUSCHNER
- Department of Gastroenterology, Medical Clinic II, Justus-Liebig-University, Giessen
| | - JÜRGEN GRAF
- Deutsche Lufthansa AG, Aero Medical Center, Frankfurt
- Faculty of Medicine, Philipps-University Marburg, Marburg, Germany
| | - ELKE ROEB
- Department of Gastroenterology, Medical Clinic II, Justus-Liebig-University, Giessen
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Salehi F, Agur A, Scheithauer BW, Kovacs K, Lloyd RV, Cusimano M. Biomarkers of pituitary neoplasms: a review (Part II). Neurosurgery 2011; 67:1790-8; discussion 1798. [PMID: 21107210 DOI: 10.1227/neu.0b013e3181faa680] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Several new markers have shown a capacity to predict the clinicopathological behavior of pituitary neoplasms; these markers have shown potential to correlate with tumor subtype and size and patient age and sex. These various markers are involved in a host of cellular functions, including cell-cycle progression, cell proliferation, apoptosis, cell adhesion, and tumor vascularity. In this companion article to our first review of Ki-67 as a marker of pituitary adenomas, we present and analyze the literature regarding matrix metalloproteinases and their inhibitors (tissue inhibitor metalloproteinases), vascular endothelial growth factor, fibroblast growth factor and its receptor, apoptotic markers and p53, as well as cyclooxygenase-2, galectin-3, and pituitary tumor transforming gene. Some of these markers, such as fibroblast growth factor and fibroblast growth factor receptor and matrix metalloproteinases, show particular promise in their ability to identify pituitary tumors that behave in an aggressive manner. We suggest the need for uniform design and application of methods and standardized criteria for the interpretation of results. A uniform approach will establish clinicopathological utility of emerging markers.
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Affiliation(s)
- Fateme Salehi
- Department of Neurosurgery, St. Michael's Hospital, and Division of Anatomy, Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
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Park KS, Kim SJ, Kim KH, Kim JC. Clinical characteristics of TIMP2, MMP2, and MMP9 gene polymorphisms in colorectal cancer. J Gastroenterol Hepatol 2011; 26:391-7. [PMID: 21261731 DOI: 10.1111/j.1440-1746.2010.06504.x] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND AND AIM Genetic variations and the expression profile of matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) are involved in the invasion and metastasis of colorectal cancer. METHODS The gene profiles of TIMP2 and MMP were assayed from 333 colorectal cancer using polymerase chain reaction-restriction fragment length polymorphism. RESULTS TIMP2-418*G/*G, TIMP2 303*G/*G and MMP9-1562*C/*C were more frequent in patients than in controls (P = 0.020, P < 0.0001 and P < 0.044, respectively). Frequency of TIMP2-418*G/*G was higher in patients with metastasis than in those without metastasis, and that of TIMP2 303*G/*G was higher in patients with rectal cancer than in those with colon cancer (P = 0.008 and P =0.022, respectively). TIMP2-303*A/*A and MMP2-1575*G/*G were less frequent in patients than in controls (P = 0.001 and P = 0.005, respectively). The TIMP2-418*G303*G haplotype was more frequent (P < 0.0001) and MMP2-1575*G-735*C haplotype was less frequent in patients than in controls (P= 0.005). CONCLUSION Specific single-nucleotide polymorphism in TIMP2 and MMP appeared to be associated with tumorigenesis and biological behavior in colorectal cancer, which is expected be further verified in a larger cohort in the future.
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Affiliation(s)
- Kyung Sook Park
- Department of Biology, Sungshin Women's University, Seoul, Korea.
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Rath T, Roderfeld M, Halwe JM, Tschuschner A, Roeb E, Graf J. Cellular sources of MMP-7, MMP-13 and MMP-28 in ulcerative colitis. Scand J Gastroenterol 2010; 45:1186-1196. [PMID: 20568971 DOI: 10.3109/00365521.2010.499961] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Matrix metalloproteinases (MMPs) are considered the predominant proteases in the pathogenesis of mucosal ulcerations associated with inflammatory bowel disease (IBD). Whether the malignancy associated MMP-7 and MMP-13 or the recently cloned MMP-28 convey a certain meaning for intestinal homeostasis and pathogenesis of IBD is currently unknown. We therefore set off to analyze regulation patterns and cellular origins of these MMPs in mucosal tissues of patients with ulcerative colitis (UC). MATERIAL AND METHODS Biopsy samples of affected and healthy tissues were obtained from 35 Norwegian patients with UC. RNA was quantified by quantitative real-time polymerase chain reaction to study MMP gene expression in both pathological and healthy mucosal specimens. Cellular origins were determined by immunohistology using surrogate markers for inflammation, neovascularization, and epithelial structures. Protein expression of MMP-7 and MMP-13 was quantified using enzyme-linked immunosorbent assay. RESULTS MMP-7 and MMP-13 gene expression was significantly increased in UC affected colonic mucosa whereas MMP-28 showed a decreased expression in inflamed mucosa. Endothelial cells and infiltrating leukocytes were identified as the major cellular sources of MMP-7 and MMP-13 in UC. Enterocytes represented the major cellular source of MMP-28 in healthy and inflamed mucosa. CONCLUSIONS MMP-7 and MMP-13 expression in inflammatory and endothelial cells indicate a role of these MMPs for both colitis associated neoangiogenesis and inflammatory changes. Decreased MMP-28 expression in UC is most likely the result of colitis associated epithelial destruction and loss of cryptal architecture.
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Affiliation(s)
- Timo Rath
- Department of Internal Medicine, Division of Gastroenterology, Justus-Liebig-University Giessen, Giessen, Germany
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Fang WL, Liang WB, He H, Zhu Y, Li SL, Gao LB, Zhang L. Association of matrix metalloproteinases 1, 7, and 9 gene polymorphisms with genetic susceptibility to colorectal carcinoma in a Han Chinese population. DNA Cell Biol 2010; 29:657-61. [PMID: 20662554 DOI: 10.1089/dna.2010.1017] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Matrix metalloproteinases (MMPs) play an important role in colorectal cancer (CRC). Accumulated evidence suggests an association between MMP-1, MMP-7, and MMP-9 functional gene polymorphisms with several tumors. The aim of this study was to investigate the association of single-nucleotide polymorphism (SNP) at MMP-1 16071G/2G, MMP-7 181A/G, and MMP-9 279R/Q genes with CRC in the southwest Chinese Han population. The study used 237 CRC patients and 252 normal control matched by age and sex from Sichuan province in China. Samples were genotyped using both polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing. We found significant differences in the genotype and allele frequency of MMP-9 279 R/Q between the case and control group. Individuals who carried MMP-9 279 R allele were more susceptible to CRC (odds ratio = 1.737, 95% confidence interval = 1.323-2.281, p < 0.001). Moreover, the RR genotype of MMP-9 279 R/Q was associated with an increased risk of CRC compared with the QQ genotype (odds ratio = 2.213, 95% confidence interval = 1.248-3.926, p = 0.006). However, there were no significant differences in the genotype and allele frequency of the MMP-1 16071G/2G and MMP-7 181 A/G between the case and control group, and the latter may be due to lower minor allele frequency. The MMP-9 279R/Q alleles and genotypes may be associated with the risk of CRC in Han Chinese.
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Affiliation(s)
- Wen-Liang Fang
- Department of Immunology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, PR China
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Kermani TA, Schäfer VS, Crowson CS, Hunder GG, Ytterberg SR, Matteson EL, Gabriel SE, Warrington KJ. Cancer preceding giant cell arteritis: a case-control study. ARTHRITIS AND RHEUMATISM 2010; 62:1763-9. [PMID: 20191583 PMCID: PMC2908278 DOI: 10.1002/art.27429] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE To study the association between previous cancer and giant cell arteritis (GCA). METHODS Using the resources of the Rochester Epidemiology Project, we identified incident cases of GCA diagnosed between January 1, 1950 and December 31, 2004. Each GCA patient was matched for age, sex, and length of medical history to 2 subjects without GCA from the same population. Medical records were reviewed. Diagnosis of cancer was confirmed by histopathologic analysis. RESULTS We identified 204 GCA cases and 407 controls. The GCA group included 163 women (80%) and 41 men (20%). Their mean +/- SD age was 76.0 +/- 8.2 years. The non-GCA group consisted of 325 women (80%) and 82 men (20%). Their mean +/- SD age was 75.6 +/- 8.4 years. At the index date, 45 GCA patients (22%) and 125 non-GCA patients (31%) had had a previous cancer. The odds ratio (OR) for previous cancer in cases compared with controls, adjusted for age, sex, and calendar year, was 0.63, and the 95% confidence interval (95% CI) was 0.42-0.94 (P = 0.022). The mean age at diagnosis of the first cancer before the index date was similar in the cases (67.5 +/- 11.9 years) and the controls (64.9 +/- 13.2 years) (P = 0.32). The mean +/- SD duration from the first cancer to the index date was 9.8 +/- 9.9 years in the cases and 11.7 +/- 10.8 years in the controls (P = 0.31). Cancer types were similar in both groups, but fewer gynecologic malignancies were noted in GCA patients (OR 0.39 [95% CI 0.13-1.15], P = 0.09). Colon cancer also appeared less commonly in the cases compared with the controls (OR 0.22 [95% CI 0.03-1.74], P = 0.15). CONCLUSION The findings of this population-based case-control study indicate that GCA patients had significantly fewer malignancies prior to the index date as compared with controls.
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Peng B, Cao L, Ma X, Wang W, Wang D, Yu L. Meta-analysis of association between matrix metalloproteinases 2, 7 and 9 promoter polymorphisms and cancer risk. Mutagenesis 2010; 25:371-9. [PMID: 20360147 DOI: 10.1093/mutage/geq015] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Matrix metalloproteinase (MMP) 2, MMP7 and MMP9 are important members of the MMP family. Four polymorphisms in the promoter region of these MMPs, which are MMP2 -1306 C>T, MMP2 -735 C>T, MMP7 -181 A>G and MMP9 -1562 C>T, have been reported to be functional and may contribute to genetic susceptibility to cancers. However, the associations between these polymorphisms and cancer risk remain inconclusive due to conflicting results from different case-control studies. To better evaluate the role of these polymorphisms in cancer development, we conducted a meta-analysis that included 51 studies, with more than 40,000 subjects. The results showed that under dominant genetic model, MMP2 -1306 T was associated with lower susceptibility to lung cancer [odds ratio (OR) = 0.50, 95% confidence interval (CI) 0.43-0.59, P(heterogeneity) = 0.147, I(2) = 44.1%], head and neck cancer (OR = 0.53, 95% CI 0.41-0.69, P(heterogeneity) = 0.974, I(2) = 0.0%) and oesophageal cancer (OR = 0.67, 95% CI 0.55-0.80, P(heterogeneity) = 0.593, I(2) = 0.0%); MMP2-735T was associated with lower risk in lung cancer (OR = 0.65, 95%CI 0.53-0.79, P(heterogeneity) = 0.42, I(2) = 0.0%) and oesophageal cancer (OR = 0.84, 95% CI 0.70-0.99, P(heterogeneity) = 0.206, I(2) = 37.4%); MMP7 -181 AG and GG genotype carriers had an increased gastric cancer risk (OR = 1.90, 95% CI 1.43-2.51, P(heterogeneity) = 0.992, I(2) = 0.0%) and MMP9 -1562 C>T was not associated with cancer risk in the whole group analysis (OR = 0.99, 95% CI 0.91-1.08, P(heterogeneity) = 0.419, I(2) = 3.0%) and subgroup analyses. In all, our meta-analysis suggests that MMP2 -1306 C>T, MMP2 -735 C>T and MMP7 -181 A>G may play allele-specific roles in cancer development, while MMP9 -1562 C>T may not be a major risk factor for most cancer types. Large case-control studies should be performed to clarify the possible roles of these four polymorphisms in different kinds of cancer in more detail.
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Affiliation(s)
- Bo Peng
- State Key Laboratory of Genetic Engineering, Department of Genetics, Institute of Genetics, School of Life Science, Fudan University, Shanghai, People's Republic of China
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Peng B, Cao L, Wang W, Xian L, Jiang D, Zhao J, Zhang Z, Wang X, Yu L. Polymorphisms in the promoter regions of matrix metalloproteinases 1 and 3 and cancer risk: a meta-analysis of 50 case-control studies. Mutagenesis 2010; 25:41-48. [PMID: 19843588 DOI: 10.1093/mutage/gep041] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Matrix metalloproteinase (MMP) 1 and MMP3 are enzymes that degrade the extracellular matrix and have been implicated to play an important role in cancer development. Many studies have been carried out on the association between polymorphisms of MMP1 -1607 1G>2G and MMP3 -1171 5A>6A and cancer risk. However, results from these studies remain inconclusive. Here, we performed a meta-analysis of >38 000 subjects to better assess the purported associations. For MMP1, -1607 2G/2G genotype carriers were found to have an increased risk of colorectal cancer [2G/2G versus 2G/1G + 1G/1G, odds ratio (OR) = 1.48, 95% confidence interval (CI) (1.26-1.74), P(heterogeneity) = 0.066, I(2) = 49.3%], head and neck cancer [2G/2G versus 2G/1G + 1G/1G, OR = 1.61, 95% CI (1.26-2.07), P(heterogeneity) = 0.002, I(2) = 64.7%] and renal cancer [2G/2G versus 2G/1G + 1G/1G, OR = 1.82, 95% CI (1.38-2.39), P(heterogeneity) = 0.589, I(2) = 0.0%] risk. For MMP3, no association was found between -1171 5A>6A polymorphism and cancer risk in the overall group [6A versus 5A, OR = 1.00, 95% CI (0.95-1.05), P(heterogeneity) = 0.124, I(2) = 24.9%] and individual cancer subgroups, but stratified analysis by smoking status showed that this polymorphism had different effects on smokers and non-smokers under recessive genetic model. In summary, our study suggests that MMP1 -1607 2G may be associated with an increased cancer risk for certain types of cancers, MMP3 -1171 5A>6A may not be a major risk factor for cancer, but it may be modified by certain environmental factors. Future studies with larger sample sizes are warranted to further evaluate these associations in more detail.
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Affiliation(s)
- Bo Peng
- State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University, Shanghai, People's Republic of China
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McColgan P, Sharma P. Polymorphisms of matrix metalloproteinases 1, 2, 3 and 9 and susceptibility to lung, breast and colorectal cancer in over 30,000 subjects. Int J Cancer 2009; 125:1473-8. [PMID: 19507256 DOI: 10.1002/ijc.24441] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
A variety of susceptibility genes have been associated with cancer but definitive conclusions have been difficult to draw partly hampered by the small number of subjects in each study. We undertook a comprehensive genetic meta-analysis of all matrix metalloproteinase (MMP) genes investigated using an allelic-association case-control model in the 3 major cancers of lung, breast and colorectal cancer. Electronic databases were searched until and including July 2008 for any MMP genetic association study in lung, breast and colorectal cancer. Odds ratio (OR) and 95% confidence intervals (CI) were determined for each gene disease association using fixed and random effect models. Twenty-five studies addressing 5 polymorphisms in 4 genes were analyzed among 30,651 individuals (15,328 cases and 15,253 controls). The MMP-1 nt-1607 polymorphism was significantly associated with colorectal cancer in both the dominant (OR, 1.66; 95% CI, 1.14-2.42; p = 0.008) and recessive (OR, 1.59; 95% CI, 1.15-2.20; p = 0.005) models. MMP-2(1306C-->T) (OR, 0.53; 95% CI, 0.40-0.72; p < 0.0001) and 735(C-->T) (OR, 0.65; 95% CI, 0.53-0.79; p < 0.0001) were significantly associated with protection against lung cancer. No association was found with the MMP 1, 2, 3 or 9 polymorphisms with breast cancer, MMP-1, 3 or 9 with lung cancer or MMP-2, 3 or 9 with colorectal cancer. There may be a genetic influence in the development of colorectal and lung cancer. Subjects with the MMP-1 nt-1607 polymorphism have an increased association with colorectal cancer. Those homozygous for either the MMP-2/1306T or 735T allele may be at reduced risk of lung cancer, although the evidence base is small.
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Affiliation(s)
- Peter McColgan
- Imperial College Cerebrovascular Research Unit, Imperial College London, Hammersmith Hospitals, London, United Kingdom
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Minisini R, Fabris C, Toniutto P, Pirisi M. Combinatorial use of single nucleotide polymorphisms to help predict liver fibrosis in patients with hepatitis C infections. ACTA ACUST UNITED AC 2009; 3:355-70. [DOI: 10.1517/17530050902893311] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Nan H, Niu T, Hunter DJ, Han J. Missense polymorphisms in matrix metalloproteinase genes and skin cancer risk. Cancer Epidemiol Biomarkers Prev 2008; 17:3551-7. [PMID: 19064570 PMCID: PMC2664625 DOI: 10.1158/1055-9965.epi-08-0606] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Matrix metalloproteinases (MMP) degrade various components of the extracellular matrix, and their overexpression has been implicated in tumor progression. Nonsynonymous single nucleotide polymorphisms (SNPs) lead to amino acid substitutions that can alter the function of the encoded protein. We evaluated the associations of six nonsynonymous SNPs in the MMP3, MMP8, and MMP9 genes with skin cancer risk in a nested case-control study of Caucasians within the Nurses' Health Study among 218 melanoma cases, 285 squamous cell carcinoma (SCC) cases, 300 basal cell carcinoma (BCC) cases, and 870 normal controls. We observed that the MMP9 Arg668Gln polymorphism was significantly associated with a decreased risk of SCC. Compared with the Arg/Arg group, the multivariate odds ratio was 0.67 (95% confidence interval, 0.47-0.97) for the Arg/Gln group and 0.21 (95% confidence interval, 0.05-0.97) for the Gln/Gln group (P(trend) = 0.004). We did not observe any association of this SNP with the risks of melanoma and basal cell carcinoma. No associations were found for other SNPs with skin cancer risk. This study provides evidence for the contribution of the MMP9 Arg668Gln to SCC development.
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Affiliation(s)
- Hongmei Nan
- Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA.
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