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de Oliveira VA, Chagas DC, Amorim JR, Pereira RDO, Nogueira TA, Borges VML, Campos-Verde LM, Martins LM, Rodrigues GP, Nery EDJ, Sampaio FA, Lopes-Costa PV, Sousa JMDCE, Silva VC, da Silva FCC, da Silva BB. Association between matrix metalloproteinase-9 gene polymorphism and breast cancer in Brazilian women. Clinics (Sao Paulo) 2020; 75:e1762. [PMID: 33146350 PMCID: PMC7561070 DOI: 10.6061/clinics/2020/e1762] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 05/15/2020] [Indexed: 12/04/2022] Open
Abstract
OBJECTIVE This study aimed to determine the relationship between rs17576 (MMP-9) polymorphism and increased cancer risk in a Brazilian breast cancer cohort. METHODS This study included 141 women (71 breast cancer patients and 70 controls without breast cancer) who donated 3 mL of their peripheral blood for genomic DNA extraction. This DNA was then genotyped using a real-time polymerase chain reaction. RESULTS The AG (rs17576) genotype was identified in 26 (18.43%) participants in the case group and in 22 (15.60%) participants in the control group (p=0.274), while the GG genotype was identified in ten (7.09%) participants in the case group and in one (0.70%) participant in the control group (p<0.003 - OR (95% CI) 13.13 (1.73, 593.08). No significant difference in the incidence rates was observed for AG or GG rs17576 genotypes in premenopausal women, p=0.813 and p=0.556, respectively. However, in postmenopausal women, the AG genotype was shown to occur in 14 (22.5%) participants in the case group and in 4 (6.45%) participants in the control (p<0.043), while GG genotype occurred in eight (12.90%) of the individuals in the case group and in none of the individuals in the control group (p<0.006). CONCLUSION In this study, the MMP-9 rs17576 GG polymorphic variant was shown to be significantly associated with breast cancer risk in premenopausal women, while the AG and GG genotypes were associated with increased cancer risk in postmenopausal women.
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Affiliation(s)
- Victor Alves de Oliveira
- Programa de Pos-Graduacao em Ciencias e Saude, Universidade Federal do Piaui, PI, BR
- *Corresponding author. E-mail:
| | - Diego Cipriano Chagas
- Programa de Pos-Graduacao em Ciencias e Saude, Universidade Federal do Piaui, PI, BR
| | | | | | - Thais Alves Nogueira
- Programa de Pos-Graduacao em Ciencias e Saude, Universidade Federal do Piaui, PI, BR
| | | | - Larysse Maira Campos-Verde
- Programa de Doutorado em Biotecnologia Rede Nordeste de Biotecnologia (RENORBIO), Universidade Federal do Piaui, PI, BR
| | - Luana Mota Martins
- Programa de Pos-Graduacao em Ciencias e Saude, Universidade Federal do Piaui, PI, BR
| | - Gilmara Peres Rodrigues
- Programa de Doutorado em Biotecnologia Rede Nordeste de Biotecnologia (RENORBIO), Universidade Federal do Piaui, PI, BR
| | - Elmo de Jesus Nery
- Programa de Doutorado em Biotecnologia Rede Nordeste de Biotecnologia (RENORBIO), Universidade Federal do Piaui, PI, BR
| | - Fabiane Araújo Sampaio
- Programa de Doutorado em Biotecnologia Rede Nordeste de Biotecnologia (RENORBIO), Universidade Federal do Piaui, PI, BR
| | | | - João Marcelo de Castro e Sousa
- Programa de Pos-Graduacao em Ciencias e Saude, Universidade Federal do Piaui, PI, BR
- Programa de Doutorado em Biotecnologia Rede Nordeste de Biotecnologia (RENORBIO), Universidade Federal do Piaui, PI, BR
| | - Vladmir Costa Silva
- Programa de Doutorado em Biotecnologia Rede Nordeste de Biotecnologia (RENORBIO), Universidade Federal do Piaui, PI, BR
| | | | - Benedito Borges da Silva
- Programa de Pos-Graduacao em Ciencias e Saude, Universidade Federal do Piaui, PI, BR
- Programa de Doutorado em Biotecnologia Rede Nordeste de Biotecnologia (RENORBIO), Universidade Federal do Piaui, PI, BR
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Tavera G, Morgan DR, Williams SM. Tipping the Scale Toward Gastric Disease: A Host-Pathogen Genomic Mismatch? CURRENT GENETIC MEDICINE REPORTS 2018; 6:199-207. [PMID: 30775159 PMCID: PMC6373874 DOI: 10.1007/s40142-018-0153-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW Chronic infection with Helicobacter pylori infection is necessary but not sufficient to initiate development of intestinal-type gastric adenocarcinoma. It is not clear what additional factors tip the scale from commensal bacteria towards a pathogen that facilitates development of gastric cancer. Genetic variants in both the pathogen and host have been implicated, but neither alone explains a substantial portion of disease risk. RECENT FINDINGS In this review, we consider studies that address the important role of human and bacterial genetics, ancestry and their interactions in determining gastric disease risk. We observe gaps in the current literature that should guide future work to confirm the hypothesis of the interacting roles of host and bacterial genetics that will be necessary to translate these findings into clinically relevant information. SUMMARY We summarize genetic risk factors for gastric disease in both H. pylori and human hosts. However, genetic variation of one or the other organism in isolation insufficiently explains gastric disease risk. The most promising models of gastric disease risk simultaneously consider the genetic variation of both the H. pylori and human host, under a co-evolution model.
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Affiliation(s)
- Gloria Tavera
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA
| | - Douglas R Morgan
- Vanderbilt Ingram Cancer Center, Nashville, Tennessee
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Scott M Williams
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA
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3
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Li W, Ng JMK, Wong CC, Ng EKW, Yu J. Molecular alterations of cancer cell and tumour microenvironment in metastatic gastric cancer. Oncogene 2018; 37:4903-4920. [PMID: 29795331 PMCID: PMC6127089 DOI: 10.1038/s41388-018-0341-x] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Revised: 05/07/2018] [Accepted: 05/08/2018] [Indexed: 02/07/2023]
Abstract
The term metastasis is widely used to describe the endpoint of the process by which tumour cells spread from the primary location to an anatomically distant site. Achieving successful dissemination is dependent not only on the molecular alterations of the cancer cells themselves, but also on the microenvironment through which they encounter. Here, we reviewed the molecular alterations of metastatic gastric cancer (GC) as it reflects a large proportion of GC patients currently seen in clinic. We hope that further exploration and understanding of the multistep metastatic cascade will yield novel therapeutic targets that will lead to better patient outcomes.
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Affiliation(s)
- Weilin Li
- Department of Surgery, The Chinese University of Hong Kong, Hong Kong, Hong Kong.,Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Jennifer Mun-Kar Ng
- Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Chi Chun Wong
- Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Enders Kwok Wai Ng
- Department of Surgery, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
| | - Jun Yu
- Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
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Burkitt MD, Duckworth CA, Williams JM, Pritchard DM. Helicobacter pylori-induced gastric pathology: insights from in vivo and ex vivo models. Dis Model Mech 2017; 10:89-104. [PMID: 28151409 PMCID: PMC5312008 DOI: 10.1242/dmm.027649] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Gastric colonization with Helicobacter pylori induces diverse human pathological conditions, including superficial gastritis, peptic ulcer disease, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric adenocarcinoma and its precursors. The treatment of these conditions often relies on the eradication of H. pylori, an intervention that is increasingly difficult to achieve and that does not prevent disease progression in some contexts. There is, therefore, a pressing need to develop new experimental models of H. pylori-associated gastric pathology to support novel drug development in this field. Here, we review the current status of in vivo and ex vivo models of gastric H. pylori colonization, and of Helicobacter-induced gastric pathology, focusing on models of gastric pathology induced by H. pylori, Helicobacter felis and Helicobacter suis in rodents and large animals. We also discuss the more recent development of gastric organoid cultures from murine and human gastric tissue, as well as from human pluripotent stem cells, and the outcomes of H. pylori infection in these systems.
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Affiliation(s)
- Michael D Burkitt
- Gastroenterology Research Unit, Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK
| | - Carrie A Duckworth
- Gastroenterology Research Unit, Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK
| | - Jonathan M Williams
- Pathology and Pathogen Biology, Royal Veterinary College, North Mymms AL9 7TA, UK
| | - D Mark Pritchard
- Gastroenterology Research Unit, Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK
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Okada R, Naito M, Hattori Y, Seiki T, Wakai K, Nanri H, Watanabe M, Suzuki S, Kairupan TS, Takashima N, Mikami H, Ohnaka K, Watanabe Y, Katsuura-Kamano S, Kubo M, Hamajima N, Tanaka H. Matrix metalloproteinase 9 gene polymorphisms are associated with a multiple family history of gastric cancer. Gastric Cancer 2017; 20:246-253. [PMID: 27053167 DOI: 10.1007/s10120-016-0608-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Accepted: 03/30/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND A family history of gastric cancer (GC) is a well-known risk factor of GC. Genetic variations in genes of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) have been related to the risk of GC, but their association with familial background is not clear. We investigated whether individuals with a multiple family history of GC have more risk genotypes of MMP/TIMP genes. METHODS We genotyped ten common functional polymorphisms of MMP/TIMP genes in 4427 individuals aged 35-69 years without a history of GC who were enrolled in the Japan Multi-institutional Collaborative Cohort Study. Individuals who have two or more first-degree relatives (parents and siblings) with GC were categorized as having a multiple family history. Odds ratios (ORs) for multiple family history compared with no family history were calculated. RESULTS MMP9 279QQ (rs17576) was more frequently observed in individuals whose both parents had a history of GC (n = 23) and in individuals for whom one parent and their sibling(s) had a history of GC (n = 36) compared with those with no family history (n = 3816) [30.4 % vs 11.6 %, OR 4.34, 95 % confidence interval (CI) 1.45-13.03 and 16.7 % vs 11.6 %, OR 2.26, 95 % CI 0.81-6.27 after adjustment for age, sex, and current smoking]. The population attributable fraction was 38.1 %. The haplotype MMP9-1562C/279Q/668Q was more frequently observed in individuals whose both parents had a history of GC and in individuals for whom one parent and their sibling(s) had a history of GC compared with those with no family history (OR 3.35, 95 % CI 0.75-14.96 and OR 3.51, 95 % CI 1.35-9.15 respectively). CONCLUSIONS MMP9 polymorphisms were associated with a multiple family history of GC. Screening for these genotypes together with familial background may help us to identify individuals at an increased risk of GC.
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Affiliation(s)
- Rieko Okada
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 4668550, Japan.
| | - Mariko Naito
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 4668550, Japan
| | - Yuta Hattori
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 4668550, Japan
| | - Toshio Seiki
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 4668550, Japan
| | - Kenji Wakai
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 4668550, Japan
| | - Hinako Nanri
- Department of Public Health, Showa University School of Medicine, Tokyo, Japan
| | - Miki Watanabe
- Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.,Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Sadao Suzuki
- Department of Public Health, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Tara Sefanya Kairupan
- Department of International Island and Community Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Naoyuki Takashima
- Department of Health Science, Shiga University of Medical Science, Otsu, Japan
| | - Haruo Mikami
- Division of Cancer Prevention and Epidemiology, Cancer Prevention Center, Chiba Cancer Center Research Institute, Chiba, Japan
| | - Keizo Ohnaka
- Department of Geriatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshiyuki Watanabe
- Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan
| | - Sakurako Katsuura-Kamano
- Department of Preventive Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Michiaki Kubo
- RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Nobuyuki Hamajima
- Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hideo Tanaka
- Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.,Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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AbdRaboh NR, Bayoumi FA. Gene polymorphism of matrix metalloproteinases 3 and 9 in breast cancer. GENE REPORTS 2016. [DOI: 10.1016/j.genrep.2016.10.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Li PY, Lv J, Qi WW, Zhao SF, Sun LB, Liu N, Sheng J, Qiu WS. Tspan9 inhibits the proliferation, migration and invasion of human gastric cancer SGC7901 cells via the ERK1/2 pathway. Oncol Rep 2016; 36:448-54. [PMID: 27177197 DOI: 10.3892/or.2016.4805] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2016] [Accepted: 02/17/2016] [Indexed: 11/05/2022] Open
Abstract
Tetraspanins are a heterogeneous group of 4-transmembrane proteins that recruit other cell surface receptors and signaling proteins into tetraspanin-enriched microdomains (TEMs). TEMs of various types are involved in the regulation of cell growth, migration and invasion of several tumor cell types, both as suppressors or promotors. Tetraspanin 9 (Tspan9, NET-5, PP1057), a member of the transmembrane 4 superfamily (TM4SF) of tetraspanins, reportedly regulates platelet function in concert with other platelet tetraspanins and their associated proteins. Our previous study demonstrated that Tspan9 is also expressed in gastric cancer (GC), but the role of Tspan9 in GC has not been well characterized. In this study, we investigated the influence of Tspan9 on proliferation, migration and invasion of human gastric cancer SGC7901 cells using CCK-8 assay, cell cycle analysis, wound-healing assay and Transwell assay. Western blot analysis and ELISA assay were also performed to identify the potential mechanisms involved. The proliferation, migration and invasion of human gastric cancer SGC7901 cells were significantly inhibited by overexpression of Tspan9. In addition, Tspan9 downregulated the phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and the secretion levels of proteins related to tumor metastasis, such as matrix metalloproteinase-9 (MMP-9) and urokinase plasminogen activator (uPA). Our study indicated that Tspan9 inhibited SGC7901 cell proliferation, migration and invasion through the ERK1/2 pathway.
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Affiliation(s)
- Pai-Yun Li
- Department of Oncology, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Jing Lv
- Department of Oncology, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Wei-Wei Qi
- Department of Oncology, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Shu-Fen Zhao
- Department of Oncology, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Li-Bin Sun
- Department of Oncology, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Ning Liu
- Department of Oncology, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Jie Sheng
- Department of Oncology, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Wen-Sheng Qiu
- Department of Oncology, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
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8
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Verma S, Kesh K, Gupta A, Swarnakar S. An Overview of Matrix Metalloproteinase 9 Polymorphism and Gastric Cancer Risk. Asian Pac J Cancer Prev 2015; 16:7393-400. [DOI: 10.7314/apjcp.2015.16.17.7393] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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9
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Clinicopathological correlation of keratinocyte growth factor and matrix metalloproteinase-9 expression in human gastric cancer. TUMORI JOURNAL 2015; 101:566-71. [PMID: 26350198 DOI: 10.5301/tj.5000367] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/22/2015] [Indexed: 02/01/2023]
Abstract
AIMS AND BACKGROUND Keratinocyte growth factor (KGF) is reported to be implicated in the growth of some cancer cells. Matrix metalloproteinase 9 (MMP-9) is thought to enhance the tumor invasion and metastasis ability. This study was aimed at analyzing the relationship between KGF and MMP-9 expression and patients' clinicopathological characteristics to clarify the clinical significance of the expression of KGF and MMP-9 in gastric cancer. METHODS Tissue samples from 161 patients with primary gastric cancer were investigated using immunohistochemistry. The relationship between KGF and/or MMP-9 expression and clinicopathological characteristics was analyzed. RESULTS KGF expression and MMP-9 expression in gastric cancer tissue were observed in 62 cases (38.5%) and 97 cases (60.2%), respectively. MMP-9 was significantly associated with depth of invasion, lymph node metastasis and TNM stage. The prognosis of MMP-9-positive patients was significantly poorer than that of MMP-9-negative patients (p = 0.009). KGF expression was positively correlated with MMP-9 expression in gastric cancer, and the prognosis of patients with both KGF- and MMP-9-positive tumors was significantly worse than that of patients with negative tumors for either factor (p = 0.045). Expression of MMP-9 was revealed to be an independent prognostic factor (p = 0.026). CONCLUSIONS Coexpression of KGF and MMP-9 in gastric cancer could be a useful prognostic factor, and MMP-9 might also serve as a novel target for both prognostic prediction and therapeutics.
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Ojetti V, Persiani R, Cananzi FCM, Sensi C, Piscaglia AC, Saulnier N, Biondi A, Gasbarrini A, D'Ugo D. cDNA-microarray analysis as a new tool to predict lymph node metastasis in gastric cancer. World J Surg 2015; 38:2058-64. [PMID: 24696059 DOI: 10.1007/s00268-014-2529-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND The aim of the present study was to investigate whether microarray gene expression analysis can be used to predict lymph node status in gastric cancer. METHODS Twenty-nine patients undergoing gastrectomy for cancer were enrolled and subdivided according to the pathologic nodal involvement of their disease (N+ vs. N0). Molecular profiling was performed by cDNA microarray on tumor tissue and healthy mucosa. Data were processed to identify differently expressed genes. Selected genes were categorized with gene ontology. RESULTS Compared to healthy gastric mucosa, 52 genes were differently expressed in N+ patients, and 50 genes in N0 patients. Forty-five genes were similarly regulated in N+ and N0 patients, whereas 12 genes were differently expressed between N+ and N0 patients. Seven genes were exclusively expressed in N+ patients: Egr-1 was upregulated; Claudin-18, AKR1C2, Cathepsin E, CA II, TFF 1, and progastricsin were downregulated. Five genes were exclusively expressed in N0 patients: Complement C5 receptor 1, PLA2/VII, and MMP- 9 were upregulated; MAO-A and ID-4 were downregulated. CONCLUSIONS Microarray analysis could be a valuable tool to identify genes associated with lymph node metastasis in gastric cancer. This technique could improve the selection of patients with locally advanced disease who are candidates for extended lymph node dissection, multimodal treatment options, or alternative therapeutic strategies.
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Affiliation(s)
- V Ojetti
- Department of Internal Medicine, Catholic University of Rome, Largo A. Gemelli 8, 00168, Rome, Italy
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Kim EK, Tang Y, Kim YS, Hwang JW, Choi EJ, Lee JH, Lee SH, Jeon YJ, Park PJ. First evidence that Ecklonia cava-derived dieckol attenuates MCF-7 human breast carcinoma cell migration. Mar Drugs 2015; 13:1785-97. [PMID: 25830682 PMCID: PMC4413187 DOI: 10.3390/md13041785] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2015] [Revised: 03/09/2015] [Accepted: 03/18/2015] [Indexed: 12/23/2022] Open
Abstract
We investigated the effect of Ecklonia cava (E. cava)-derived dieckol on movement behavior and the expression of migration-related genes in MCF-7 human breast cancer cell. Phlorotannins (e.g., dieckol, 6,6'-biecko, and 2,7″-phloroglucinol-6,6'-bieckol) were purified from E. cava by using centrifugal partition chromatography. Among the phlorotannins, we found that dieckol inhibited breast cancer cell the most and was selected for further study. Radius™-well was used to assess cell migration, and dieckol (1-100 µM) was found to suppress breast cancer cell movement. Metastasis-related gene expressions were evaluated by RT-PCR and Western blot analysis. In addition, dieckol inhibited the expression of migration-related genes such as matrix metalloproteinase (MMP)-9 and vascular endothelial growth factor (VEGF). On the other hand, it stimulated the expression of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. These results suggest that dieckol exerts anti-breast cancer activity via the regulation of the expressions of metastasis-related genes, and this is the first report on the anti-breast cancer effect of dieckol.
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Affiliation(s)
- Eun-Kyung Kim
- Division of Food Bio Science, College of Biomedical and Health Sciences, Konkuk University, Chungju 380-701, Korea.
- Korea Nokyong Research Center, Konkuk University, Chungju 380-701, Korea.
| | - Yujiao Tang
- Division of Food Bio Science, College of Biomedical and Health Sciences, Konkuk University, Chungju 380-701, Korea.
- Korea Nokyong Research Center, Konkuk University, Chungju 380-701, Korea.
| | - Yon-Suk Kim
- Korea Nokyong Research Center, Konkuk University, Chungju 380-701, Korea.
- Department of Biotechnology, Konkuk University, Chungju 380-701, Korea.
| | - Jin-Woo Hwang
- Korea Nokyong Research Center, Konkuk University, Chungju 380-701, Korea.
- Department of Biotechnology, Konkuk University, Chungju 380-701, Korea.
| | - Eun-Ju Choi
- Division of Sport Science, Konkuk University, Chungju, 380-701, Korea.
| | - Ji-Hyeok Lee
- Department of Marine Life Science, Jeju National University, Jeju 690-756, Korea.
| | - Seung-Hong Lee
- Division of Food Bio Science, College of Biomedical and Health Sciences, Konkuk University, Chungju 380-701, Korea.
- Korea Nokyong Research Center, Konkuk University, Chungju 380-701, Korea.
| | - You-Jin Jeon
- Department of Marine Life Science, Jeju National University, Jeju 690-756, Korea.
| | - Pyo-Jam Park
- Korea Nokyong Research Center, Konkuk University, Chungju 380-701, Korea.
- Department of Biotechnology, Konkuk University, Chungju 380-701, Korea.
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Matsumoto N, Morine Y, Utsunomiya T, Imura S, Ikemoto T, Arakawa Y, Iwahashi S, Saito Y, Yamada S, Ishikawa D, Takasu C, Miyake H, Shimada M. Role of CD151 expression in gallbladder carcinoma. Surgery 2014; 156:1212-7. [PMID: 24890568 DOI: 10.1016/j.surg.2014.04.053] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Accepted: 04/24/2014] [Indexed: 12/12/2022]
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13
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Farina AR, Mackay AR. Gelatinase B/MMP-9 in Tumour Pathogenesis and Progression. Cancers (Basel) 2014; 6:240-96. [PMID: 24473089 PMCID: PMC3980597 DOI: 10.3390/cancers6010240] [Citation(s) in RCA: 150] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Revised: 01/20/2014] [Accepted: 01/21/2014] [Indexed: 12/14/2022] Open
Abstract
Since its original identification as a leukocyte gelatinase/type V collagenase and tumour type IV collagenase, gelatinase B/matrix metalloproteinase (MMP)-9 is now recognised as playing a central role in many aspects of tumour progression. In this review, we relate current concepts concerning the many ways in which gelatinase B/MMP-9 influences tumour biology. Following a brief outline of the gelatinase B/MMP-9 gene and protein, we analyse the role(s) of gelatinase B/MMP-9 in different phases of the tumorigenic process, and compare the importance of gelatinase B/MMP-9 source in the carcinogenic process. What becomes apparent is the importance of inflammatory cell-derived gelatinase B/MMP-9 in tumour promotion, early progression and triggering of the "angiogenic switch", the integral relationship between inflammatory, stromal and tumour components with respect to gelatinase B/MMP-9 production and activation, and the fundamental role for gelatinase B/MMP-9 in the formation and maintenance of tumour stem cell and metastatic niches. It is also apparent that gelatinase B/MMP-9 plays important tumour suppressing functions, producing endogenous angiogenesis inhibitors, promoting inflammatory anti-tumour activity, and inducing apoptosis. The fundamental roles of gelatinase B/MMP-9 in cancer biology underpins the need for specific therapeutic inhibitors of gelatinase B/MMP-9 function, the use of which must take into account and substitute for tumour-suppressing gelatinase B/MMP-9 activity and also limit inhibition of physiological gelatinase B/MMP-9 function.
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Affiliation(s)
- Antonietta Rosella Farina
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, Via Vetoio, Coppito 2, L'Aquila 67100, Italy.
| | - Andrew Reay Mackay
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, Via Vetoio, Coppito 2, L'Aquila 67100, Italy.
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Shi M, Zheng D, Sun L, Wang L, Lin L, Wu Y, Zhou M, Liao W, Liao Y, Zuo Q, Liao W. XB130 promotes proliferation and invasion of gastric cancer cells. J Transl Med 2014; 12:1. [PMID: 24387290 PMCID: PMC3882781 DOI: 10.1186/1479-5876-12-1] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2013] [Accepted: 12/27/2013] [Indexed: 01/24/2023] Open
Abstract
Background XB130 has been reported to be expressed by various types of cells such as thyroid cancer and esophageal cancer cells, and it promotes the proliferation and invasion of thyroid cancer cells. Our previous study demonstrated that XB130 is also expressed in gastric cancer (GC), and that its expression is associated with the prognosis, but the role of XB130 in GC has not been well characterized. Methods In this study, we investigated the influence of XB130 on gastric tumorigenesis and metastasis in vivo and in vitro using the MTT assay, clonogenic assay, BrdU incorporation assay, 3D culture, immunohistochemistry and immunofluorescence. Western blot analysis was also performed to identify the potential mechanisms involved. Results The proliferation, migration, and invasion of SGC7901 and MNK45 gastric adenocarcinoma cell lines were all significantly inhibited by knockdown of XB130 using small hairpin RNA. In a xenograft model, tumor growth was markedly inhibited after shXB130-transfected GC cells were implanted into nude mice. After XB130 knockdown, GC cells showed a more epithelial-like phenotype, suggesting an inhibition of the epithelial-mesenchymal transition (EMT) process. In addition, silencing of XB130 reduced the expression of p-Akt/Akt, upregulated expression of epithelial markers including E-cadherin, α-catenin and β-catenin, and downregulated mesenchymal markers including fibronectin and vimentin. Expression of oncoproteins related to tumor metastasis, such as MMP2, MMP9, and CD44, was also significantly reduced. Conclusions These findings indicate that XB130 enhances cell motility and invasiveness by modulating the EMT-like process, while silencing XB130 in GC suppresses tumorigenesis and metastasis, suggesting that it may be a potential therapeutic target.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Qiang Zuo
- Department of Oncology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, 510515 Guangzhou, China.
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Functional polymorphisms of matrix metalloproteinase-9 and survival in patients with locoregionally advanced nasopharyngeal carcinoma treated with chemoradiotherapy. Med Oncol 2013; 30:685. [PMID: 23955812 DOI: 10.1007/s12032-013-0685-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Accepted: 07/31/2013] [Indexed: 10/26/2022]
Abstract
To investigate the prognostic role of major matrix metalloproteinase (MMP) gene polymorphisms in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) treated with chemoradiotherapy. Four hundred twenty-one consecutive NPC patients were prospectively recruited. Two hundred patients were randomly selected as the training cohort, and the remaining 221 patients were the validation cohort. Twelve polymorphisms in the MMP-1, 2, 3, 7, 8, and 9 genes were genotyped by ligase detection reaction-PCR. MMP-9 rs2250889 PR/RR (HR = 2.287, 95% CI 1.400-3.735) and rs17576 RQ/QQ (HR = 2.347, 95% CI 1.431-3.849) genotypes were significantly related with increased death risk in the training cohort. Analysis of the validation cohort confirmed these results (rs2250889: HR = 2.231, 95% CI 1.281-3.886; rs17576: HR = 2.987, 95% CI 1.674-5.330). Multivariate analysis showed that rs17576 (HR = 2.284, 95% CI 1.123-4.643, P = 0.023) was still an independent prognostic factor. The MMP-9 rs17576 is a novel independent prognostic marker in patients with locoregionally advanced NPC treated with chemoradiotherapy.
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Fu F, Wang C, Chen LM, Huang M, Huang HG. The influence of functional polymorphisms in matrix metalloproteinase 9 on survival of breast cancer patients in a Chinese population. DNA Cell Biol 2013; 32:274-82. [PMID: 23570558 DOI: 10.1089/dna.2012.1928] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Matrix metalloproteinase 9 (MMP9) plays a critical role in cancer aggression, and its overexpression is associated with a poor prognosis in breast cancer. Because common genetic variants can alter the expression or function of MMPs, we hypothesized that potentially functional single-nucleotide polymorphisms (SNPs) in the MMP9 gene may be associated with the survival of patients with invasive breast cancer. In this case-cohort follow-up study, a total of 245 breast cancer patients in southeast China were investigated, and five haplotype tagging SNPs (htSNPs) in the MMP9 gene were genotyped by using matrix-assisted laser desorption/ionization mass spectrometry and polymerase chain reaction-restriction fragment length polymorphism methods. Disease-free survival (DFS) and distance disease-free survival (DDFS) analyses were used to identify the SNPs associated with prognosis and determine their interdependence with the recognized prognostic factors. We found that the MMP9 rs3787268 GA+AA genotypes were significantly associated with poor DFS and DDFS of patients with breast cancer (log-rank p-values 0.045 and 0.028, respectively), especially in some subgroups of patients. Multivariate Cox regression and stepwise COX regression analyses suggested that rs3787268 may be a candidate independent biomarker to predict breast cancer survival in this population. Further, among estrogen receptor (ER)+/epidermal growth receptor 2 (HER-2)- patients, the rs3787268 GA+AA genotypes and rs17577 GG genotype showed a locus-dosage effect between combined the genotypes and decreased survival (adjusted HR 2.59, 95% confidence interval [CI] 1.29-5.19 and adjusted HR 3.25, 95% CI 1.39-7.58, respectively, for DFS and DDFS). Our results suggest that the polymorphisms in the MMP9 gene may be genetic modifiers for breast cancer prognosis in this Chinese population.
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Affiliation(s)
- Fangmeng Fu
- Department of General Surgery, Affiliated Union Hospital of Fujian Medical University, Fuzhou, China
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Zhang QW, Liu L, Chen R, Wei YQ, Li P, Shi HS, Zhao YW. Matrix metalloproteinase-9 as a prognostic factor in gastric cancer: a meta-analysis. Asian Pac J Cancer Prev 2013; 13:2903-8. [PMID: 22938481 DOI: 10.7314/apjcp.2012.13.6.2903] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Matrix metalloproteinase-9 (MMP-9) is associated with disruption of basement membranes of blood vessels and promotion of metastasis through the lymphatics. However, its prognostic value for survival in patients with gastric cancer remains controversial. METHOD We therefore conducted a meta-analysis of the published literature in order to clarify the impact of MMP-9. Clinical studies were selected for further analysis if they provided an independent assessment of MMP-9 in gastric cancer and reported analysis of survival data according to MMP-9 expression. RESULTS A total of 11 studies, covering 1700 patients, were included for meta- analysis. A summary hazard ratio (HR) of all studies and sub-group hazard ratios were calculated. The combined HR suggested that a positive MMP-9 expression had an impact on overall survival: 1.25 (95% confidence interval 1.11-1.40) in all eligible studies; 1.13 (1.06-1.20) in 8 studies detecting MMP-9 by immunohistochemistry; 1.36 (1.12-1.65) in 7 studies from Asia. Only one study for DFS showed a significant impact on disease free survival (HR 1.73, 95%CI 1.27-2.34). CONCLUSIONS Our findings suggested that MMP-9 protein expression might be a factor for a poor prognosis in patients with gastric cancer. However, the association was rather weak, so that more prospective studies should further explore the prognostic impact of MMP-9 mRNA and correlations between MMP-9 and clinicopathological characteristics.
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Affiliation(s)
- Qiong-Wen Zhang
- Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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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; 32:1278-86. [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] [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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Yang ZH, Li SN, Liu JX, Guo QX, Sun XW. MMP-9 polymorphisms are related to serum lipids levels but not associated with colorectal cancer susceptibility in Chinese population. Mol Biol Rep 2012; 39:9399-404. [PMID: 22729913 DOI: 10.1007/s11033-012-1804-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2012] [Accepted: 06/09/2012] [Indexed: 02/05/2023]
Abstract
Matrix metalloproteinases (MMPs) play an important role in cancer development and aggression. MMP-9 polymorphisms may affect MMPs expression and contribute to interindividual differences in susceptibility to a wide spectrum of cancers. The purpose of this study was to investigate the association of MMP-9 P574R and R668Q polymorphisms with colorectal cancer (CRC); and to explore the relationship among the polymorphisms and clinicopathologic parameters, serum tumor markers and lipids. The genotypes were determined by polymerase chain reaction-restriction fragment lengthy polymorphism (PCR-RFLP). Tumor markers were measured with the Electro ChemiL uminescence method. Lipids levels were analyzed using an automatic biochemistry analyzer. The both polymorphisms were not associated with the risk of CRC risk. The clinicopathologic parameters, tumor markers were not associated with MMP-9 polymorphisms. Total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were significantly higher in patients with P574R PP genotype compared with patients with P574R PR combined RR genotypes (P = 0.043 and P = 0.038 respectively). Our data suggested that MMP-9 P574R and R668Q were not associated with CRC risk, but P574R affected serum LDL-C and TC levels in CRC patients.
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Affiliation(s)
- Zhi-Hui Yang
- Department of Pathology, LuZhou Medical College, Luzhou, 646000 Sichuan, People's Republic of China.
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McLean MH, El-Omar EM. Genetics of inflammation in the gastrointestinal tract and how it can cause cancer. Recent Results Cancer Res 2011; 185:173-83. [PMID: 21822827 DOI: 10.1007/978-3-642-03503-6_11] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Genetic epidemiology is an important discipline that is helping to unravel the aetiology and pathogenesis of complex human diseases. In the context of gastrointestinal malignancy, the paradigm model of host genetic influence on disease outcome is H. pylori-associated gastric adenocarcinoma. This cancer represents a classic example of an inflammation-induced malignancy and highlights the importance of host genetics in disease development. This chapter gives an insight into how genetic epidemiology can play an important role in the development of gastric cancer. Increasing our understanding of host genetics in cancer development may allow particularly susceptible individuals to be targeted for screening or treatment to reduce risk of future malignant transformation.
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Affiliation(s)
- Mairi H McLean
- Gastrointestinal Research Group, Division of Applied Medicine, School of Medicine and Dentistry, Institute of Medical Sciences, Aberdeen University, Foresterhill, Aberdeen, Scotland, AB25 2ZD, UK
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Soon MS, Hsu LS, Chen CJ, Chu PY, Liou JH, Lin SH, Hsu JD, Yeh KT. Expression of Krűppel-like factor 5 in gastric cancer and its clinical correlation in Taiwan. Virchows Arch 2011; 459:161-6. [PMID: 21732124 DOI: 10.1007/s00428-011-1111-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2010] [Revised: 05/25/2011] [Accepted: 06/17/2011] [Indexed: 12/01/2022]
Abstract
Krűppel-like factors (KLFs), highly conserved zinc-finger proteins, play either anti- or pro-proliferation roles in different human cancers through regulating a wide range of genes' expression. Here, we investigated the expression of KLF5 in gastric cancers and its correlation with clinicopathological parameters and overall survival rates. In this study, KLF5 expression was measured by an immunohistochemical microarray assay of tissue taken from 76 surgical specimens. Higher KLF5 expression was significantly associated with lower tumor grade (P < 0.001). Nuclear staining of the KLF5 expression was significantly associated with a higher tumor grade (P = 0.000), higher clinical stage (P = 0.019), lymph node status (P = 0.016), and 2-year survival (P = 0.017). Patients with nuclear staining of KLF5 had a significantly lower disease-free survival rate compared to patients with negative nuclear staining, as defined by a log-rank test (P = 0.041). Our results revealed that KLF5 may play an oncogenetic role in gastric carcinogenesis.
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Affiliation(s)
- Maw-Soan Soon
- Department of Gastroenterology, Changhua Christian Hospital, Changhua, Taiwan
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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: 19] [Impact Index Per Article: 1.4] [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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Bioinformatic analyses identifies novel protein-coding pharmacogenomic markers associated with paclitaxel sensitivity in NCI60 cancer cell lines. BMC Med Genomics 2011; 4:18. [PMID: 21314952 PMCID: PMC3050680 DOI: 10.1186/1755-8794-4-18] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2010] [Accepted: 02/11/2011] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Paclitaxel is a microtubule-stabilizing drug that has been commonly used in treating cancer. Due to genetic heterogeneity within patient populations, therapeutic response rates often vary. Here we used the NCI60 panel to identify SNPs associated with paclitaxel sensitivity. Using the panel's GI50 response data available from Developmental Therapeutics Program, cell lines were categorized as either sensitive or resistant. PLINK software was used to perform a genome-wide association analysis of the cellular response to paclitaxel with the panel's SNP-genotype data on the Affymetrix 125 k SNP array. FastSNP software helped predict each SNP's potential impact on their gene product. mRNA expression differences between sensitive and resistant cell lines was examined using data from BioGPS. Using Haploview software, we investigated for haplotypes that were more strongly associated with the cellular response to paclitaxel. Ingenuity Pathway Analysis software helped us understand how our identified genes may alter the cellular response to paclitaxel. RESULTS 43 SNPs were found significantly associated (FDR<0.005) with paclitaxel response, with 10 belonging to protein-coding genes (CFTR, ROBO1, PTPRD, BTBD12, DCT, SNTG1, SGCD, LPHN2, GRIK1, ZNF607). SNPs in GRIK1, DCT, SGCD and CFTR were predicted to be intronic enhancers, altering gene expression, while SNPs in ZNF607 and BTBD12 cause conservative missense mutations. mRNA expression analysis supported these findings as GRIK1, DCT, SNTG1, SGCD and CFTR showed significantly (p<0.05) increased expression among sensitive cell lines. Haplotypes found in GRIK1, SGCD, ROBO1, LPHN2, and PTPRD were more strongly associated with response than their individual SNPs. CONCLUSIONS Our study has taken advantage of available genotypic data and its integration with drug response data obtained from the NCI60 panel. We identified 10 SNPs located within protein-coding genes that were not previously shown to be associated with paclitaxel response. As only five genes showed differential mRNA expression, the remainder would not have been detected solely based on expression data. The identified haplotypes highlight the role of utilizing SNP combinations within genomic loci of interest to improve the risk determination associated with drug response. These genetic variants represent promising biomarkers for predicting paclitaxel response and may play a significant role in the cellular response to paclitaxel.
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Kim JH, Pyun JA, Lee KJ, Cho SW, Kwack KB. Study on Association between Single Nucleotide Polymorphisms ofMMP7,MMP8,MMP9Genes and Development of Gastric Cancer and Lymph Node Metastasis. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2011; 58:245-51. [DOI: 10.4166/kjg.2011.58.5.245] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Affiliation(s)
- Ji Hye Kim
- Department of Biomedical Science, College of Life Science, CHA University, Seongnam, Korea
| | - Jung-A Pyun
- Department of Biomedical Science, College of Life Science, CHA University, Seongnam, Korea
| | - Kwang Jae Lee
- Department of Gastroenterology, Genomic Research Center for Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Sung Won Cho
- Department of Gastroenterology, Genomic Research Center for Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Kyu Bum Kwack
- Department of Biomedical Science, College of Life Science, CHA University, Seongnam, Korea
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Chu D, Zhang Z, Li Y, Zheng J, Dong G, Wang W, Ji G. Matrix metalloproteinase-9 is associated with disease-free survival and overall survival in patients with gastric cancer. Int J Cancer 2010; 129:887-95. [PMID: 20957628 DOI: 10.1002/ijc.25734] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2010] [Accepted: 09/30/2010] [Indexed: 02/06/2023]
Abstract
Matrix metalloproteinase-9 is a member of the Matrix metalloproteinases (MMP) family, which is overexpressed in some solid tumor and thought to enhance the tumor invasion and metastasis ability. Our study is to investigate the association of MMP-9 expression with disease-free survival and overall survival of patients with gastric cancer. Clinical gastric cancer specimens and adjacent normal tissues from 286 patients who had not received neoadjuvant chemotherapy were investigated by immunohistochemistry assay. Staining evaluation results were analyzed statistically in relation to various clinicopathological characters, disease-free survival and overall survival. High level of MMP-9 expression was detected in gastric cancer, significantly more than in adjacent normal epithelial cells. In gastric cancer, MMP-9 was significantly positively correlated with depth of invasion, lymph node metastasis and distant metastasis. However, no correlations between MMP-9 expression and patients' age, sex, tumor location or differentiation status were detected. The disease-free survival and overall survival were significantly shorter for patients with MMP-9 positive than those with MMP-9 negative tumors. Multivariate analysis identified MMP-9 was an independent prognostic factor for both disease-free survival and overall survival. Our findings provided convincing evidence for MMP-9 as an important role in human gastric cancer recurrence and prognosis. It might also serve as a novel target for both prognostic prediction and therapeutics.
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Affiliation(s)
- Dake Chu
- Department of Gastrointestinal Surgery, State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi Province, China
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Srivastava P, Mandhani A, Kapoor R, Mittal RD. Role of MMP-3 and MMP-9 and Their Haplotypes in Risk of Bladder Cancer in North Indian Cohort. Ann Surg Oncol 2010; 17:3068-75. [DOI: 10.1245/s10434-010-1153-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2010] [Indexed: 11/18/2022]
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Brooks R, Kizer N, Nguyen L, Jaishuen A, Wanat K, Nugent E, Grigsby P, Allsworth JE, Rader JS. Polymorphisms in MMP9 and SIPA1 are associated with increased risk of nodal metastases in early-stage cervical cancer. Gynecol Oncol 2009; 116:539-43. [PMID: 19906411 DOI: 10.1016/j.ygyno.2009.09.037] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2009] [Revised: 09/21/2009] [Accepted: 09/26/2009] [Indexed: 10/20/2022]
Abstract
OBJECTIVE Heritable polymorphisms modulate metastatic efficiency in Cancer Single nucleotide polymorphisms (SNPs) in MMP9 (rs17576) and SIPA1 (rs746429, rs931127) have been associated with nodal metastases in multiple cancers. We investigated the association of these SNPs with nodal metastases in early-stage cervical cancer. METHODS Consecutive patients with stage IB cervical cancer who underwent a pelvic lymph node (LN) dissection were included. Cases (>1 positive LN, n=101) were compared with controls (negative LN pathology, n=273). Genotyping was performed on genomic DNA in the 3 SNPs using a TaqMan assay and correlated with clinical variables. RESULTS The G allele at SIPA1 rs931127 was associated with an increased risk of nodal disease (OR 1.9, P=0.03) and approached significance at SIPA 1 rs746429 (OR 2.2, P=0.09) and MMP9 rs17576 (OR 1.5, 0.08). In patients with stage Ib1 lesions (n=304), the G allele at both SIPA1 SNPs was associated with LN metastases (rs746429 OR 10.1, P=0.01; rs931127 OR 2.4, P=0.01). In patients with no lymph vascular space invasion, SIPA1 SNPs were again associated with LN metastases, and all patients with nodal disease had at least one G allele at SIPA1 rs746429. CONCLUSIONS In this case-control study, SNPs in SIPA1 varied statistically in cervical cancer patients with and without nodal metastases and in MMP9 after controlling for stage and lymphvascular space invasion. Further work is needed to characterize inherited polymorphisms that provide a permissive background for the metastatic cascade.
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Affiliation(s)
- Rebecca Brooks
- Washington University School of Medicine/Barnes-Jewish Hospital, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, 4911 Barnes Jewish Hospital Plaza Box 8064, Saint Louis, MO 63110, USA.
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Matrix Metalloproteinase-9 (MMP9)-A Mediating Enzyme in Cardiovascular Disease, Cancer, and Neuropsychiatric Disorders. Cardiovasc Psychiatry Neurol 2009; 2009:904836. [PMID: 20037727 PMCID: PMC2796208 DOI: 10.1155/2009/904836] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2009] [Accepted: 06/30/2009] [Indexed: 01/29/2023] Open
Abstract
Matrix metalloproteinase-9 (MMP9) has been implicated in numerous somatic illnesses, including cardiovascular disorders and cancer. Recently, MMP9 has been shown to be increasingly important in several aspects of central nervous system activity. Furthermore, a pathogenic role for this enzyme has been suggested in such neuropsychiatric disorders as schizophrenia, bipolar illness, and multiple sclerosis. In this paper, the results of biochemical and molecular-genetic studies on MMP9 that have been performed in these pathological conditions will be summarized. Furthermore, I hypothesize that the MMP9 gene, as shown by functional −1562 C/T polymorphism studies, may be mediating the relationship of neuropsychiatric illnesses (schizophrenia, bipolar mood disorder, multiple sclerosis) that are comorbid with cardiovascular disease and cancer.
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Abstract
Chronic inflammation underlies many human diseases including cancer. The magnitude and direction of the inflammatory response is often directed by host genetic factors interacting with environmental exposures. Quite often, the environmental trigger is a microbial agent and the host's genetically determined response is crucial in setting the right tone for handling this threat. An inadequate response runs the risk of allowing the infection to become permanently established causing chronic damage, while too vigorous a response might cause collateral damage to the host's essential physiological pathways. Helicobacter pylori-induced gastric cancer is a paradigm for microbially induced and chronic inflammation-driven malignancy. In this review, we summarise current knowledge about the role of host genetic factors in the pathogenesis of this malignancy. The review illustrates the basic principles of genetic epidemiology and host-bacterial interactions and offers an example of how basic knowledge of the pathophysiology of a disease directed the search for the relevant host genetic factors. This contrasts with current approaches, driven by advanced technology, where genetic risk factors are being identified first with the hope that these will shed light on the pathogenesis of disease. Both approaches are necessary to make advances in reducing disease burden in society.
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