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      Association between MCP-1 -2518A/G Polymorphism and Cancer Risk: Evidence from 19 Case-Control Studies

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          Abstract

          Background

          Single nucleotide polymorphisms (SNPs) may affect the development of diseases. The -2518A/G polymorphism in the regulatory region of the monocyte chemo-attractant protein-1 (MCP-1) gene has been reported to be associated with cancer risk. However, the results of previous studies were inconsistent. Therefore, we performed a meta-analysis to obtain a more precise estimation of the relationship between the -2518A/G polymorphism and cancer risk.

          Methodology/Principal Findings

          We performed a meta-analysis, including 4,162 cases and 5,173 controls, to evaluate the strength of the association between the −2518A/G polymorphism and cancer risk. Odds ratio (OR) and 95% confidence intervals (95% CIs) were used to assess the strength of association. Overall, the results indicated that the −2518A/G polymorphism was not statistically associated with cancer risk. However, sub-group analysis revealed that individuals with GG genotypes showed an increased risk of cancer in digestive system compared with carriers of the A allele (GG vs. AA: OR = 1.43, 95%CI = 1.05–1.96, P heterogeneity = 0.08; GG vs. AG/AA: OR = 1.29, 95%CI = 1.02–1.64, P heterogeneity = 0.14). In addition, the increased risk of GG genotype was also observed in Caucasians (GG vs. AG/AA: OR = 1.81, 95%CI = 1.10–2.96, P heterogeneity = 0.02).

          Conclusion

          This meta-analysis suggests that the MCP-1 −2518A/G polymorphism may have some relation to digestive system cancer susceptibility or cancer development in Caucasian. Large-scale and well-designed case-control studies are needed to validate the findings.

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          Most cited references33

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          Significance of macrophage chemoattractant protein-1 in macrophage recruitment, angiogenesis, and survival in human breast cancer.

          T. Ueno, M. Toi, H Saji … (2000)
          Tumor cells stimulate the formation of stroma that secretes various mediators pivotal for tumor growth, including growth factors, cytokines, and proteases. However, little is known about the local regulation of these soluble mediators in the human tumor microenvironment. In this study, the local expression of cytokines, chemokines, and angiogenic factors was investigated in primary breast cancer tissue. The concentrations of interleukin (IL)-1, IL-4, IL-6, IL-10, IL-12, tumor necrosis factor (TNF)-alpha, IFN-gamma, IL-8, macrophage chemoattractant protein (MCP)-1, epithelial-neutrophil activating peptide-78, vascular endothelial growth factor, and thymidine phosphorylase (TP) were measured in 151 primary breast cancer extracts by ELISA. Tumor-associated macrophages (TAMs) were also examined by immunohistochemistry with anti-CD68 antibodies. The correlation between soluble mediators and the relationship between TAM count and soluble mediators were evaluated. MCP-1 concentration was correlated significantly with the level of vascular endothelial growth factor, TP, TNF-alpha, and IL-8, which are potent angiogenic factors. IL-4 concentration was correlated significantly with IL-8 and IL-10. On the other hand, an inverse association was observed between TP and IL-12. The level of MCP-1 was associated significantly with TAM accumulation. In the immunohistochemical analysis, MCP-1 expression was observed in both infiltrating macrophages and tumor cells. Prognostic analysis revealed that high expression of MCP-1, as well as of VEGF, was a significant indicator of early relapse. These findings indicate that interaction between the immune network system and angiogenesis is important for progression of human breast cancer, and that MCP-1 may play an important role in the regulation of angiogenesis and the immune system.
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            The rising burden of cancer in the developing world.

            P Kanavos (2006)
            Cancer remains one of the leading causes of morbidity and mortality worldwide. It is predicted that by 2020, the number of new cases of cancer in the world will increase to more than 15 million, with deaths increasing to 12 million. Much of the burden of cancer incidence, morbidity, and mortality will occur in the developing world. This forms part of a larger epidemiological transition in which the burden of chronic, non-communicable disease-once limited to industrialized nations-is now increasing in less developed countries. In addition to the accumulating risks associated with diet, tobacco, alcohol, lack of exercise, and industrial exposures, the developing world is already burdened by cancers some of which are attributable to infectious diseases. These disparities in cancer risk combined with poor access to epidemiological data, research, treatment, and cancer control and prevention combine to result in significantly poorer survival rates in developing countries for a range of specific malignancies. This paper summarizes the recent trends in the epidemiology and survival of cancers in the developing and developed world, and explores potential causes and policy responses to the disproportionate and growing cancer burden in less developed countries. Such responses may include raising awareness as well as education and training to foster better informed decision-making, together with improved cancer surveillance, early detection and emphasis on prevention. Improved health care financing and international initiatives and/or partnerships could also provide additional impetus in targeting resources where needed urgently.
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              A novel polymorphism in the MCP-1 gene regulatory region that influences MCP-1 expression.

              Lingeng Lu, Brad H Rovin, Richa Saxena (1999)
              Two novel polymorphisms in the distal regulatory region of the MCP-1 gene were identified by directly sequencing PCR amplified genomic DNA. These polymorphisms are located at positions -2518 (G or A) and -2076 (A or T) relative to the major transcriptional start site of the gene. To examine the effect of these polymorphisms on MCP-1 transcription, polymorphic variants of the MCP-1 distal regulatory region were placed upstream of a luciferase reporter gene and transfected into A172 cells. IL-1beta-induced luciferase activity was significantly greater from cells transfected with constructs containing G at position -2518. The polymorphism at -2076 did not affect MCP-1 transcription. IL-1beta-treated peripheral blood mononuclear cells from individuals heterozygous or homozygous for G at -2518 produced more MCP-1 than cells from individuals homozygous for A at -2518. These data identify a polymorphism in the MCP-1 distal regulatory region that affects the level of MCP-1 expression in response to an inflammatory stimulus. Copyright 1999 Academic Press.
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                Author and article information

                Contributors
                Xiaoping Miao: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2013
                Publication date (Electronic): 18 December 2013
                Volume: 8
                Issue: 12
                Electronic Location Identifier: e82855
                Affiliations
                [1 ]The First Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
                [2 ]Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, China
                [3 ]Wannan Medical College, Wuhu, Anhui, China
                [4 ]Department of Ultrasonic Medicine, Wannan Medical College Affiliated Yijishan Hospital, Wuhu, Anhui, China
                MOE Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, China
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: LSD FJ LX. Performed the experiments: LSD YZ. Analyzed the data: LSD YZ SZ. Contributed reagents/materials/analysis tools: LSD YZ YCQ QZ. Wrote the paper: LSD YZ.

                Article
                Publisher ID: PONE-D-13-39551
                DOI: 10.1371/journal.pone.0082855
                PMC ID: 3867394
                PubMed ID: 24367564
                SO-VID: 67354ec8-a11c-45f6-952b-368120a1592a
                Copyright statement: Copyright @ 2013
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 26 September 2013
                Date accepted : 29 October 2013
                Page count
                Pages: 7
                Funding
                The authors have no support or funding to report.
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Uncategorized
                Data availability:
                ScienceOpen disciplines: Uncategorized

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