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      Association between nucleotide excision repair gene polymorphism and colorectal cancer risk

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          Abstract

          Background

          The nucleotide excision repair system removes a wide variety of DNA lesions from the human genome, and plays an important role in maintaining genomic stability. Single nucleotide polymorphisms (SNPs) in nucleotide excision repair are associated with the various forms of tumor susceptibility. However, the relationship between NER polymorphism and colorectal cancer is not clear.

          Methods

          In this study, three candidate SNPs including ERCC4 (rs6498486), ERCC1 (rs3212986), and ERCC5 (rs17655) were analyzed in 1101colorectal cancer patients and 1175 healthy control patients from Jiangsu province (China). Then, we performed Immunohistochemistry, qPCR, and luciferase assay to determine the potential mechanisms.

          Results

          The ERCC4 rs6498486 AC/CC genotypes show lower susceptibility to CRC than those carrying rs6498486 AA (Adjusted OR = 0.82, 95% CI = 0.69‐0.97). However, we did not observe any association between the colorectal cancer risk and the rs3212986(ERCC1) and rs17655(ERCC5) polymorphisms. Immunohistochemistry, qPCR, and luciferase assay revealed that rs6498486 A > C polymorphism in the ERCC4 promoter region could lessen the expression level of ERCC4 by impacting the binding ability of the transcription factor NF‐kB, thereby affecting the transcription activity of the ERCC4 gene and decreased ERCC4 gene expression.

          Conclusion

          In brief, our finding demonstrated that ERCC4 rs6498486 serves as a potential biomarker of CRC susceptibility for the development of colorectal cancer.

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          Most cited references29

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          NF-kappaB signaling in cerebral ischemia.

          The transcription factor NF-kappaB is a key regulator of hundreds of genes involved in cell survival and inflammation. There is ample evidence that NF-kappaB is activated in cerebral ischemia, mainly in neurons. Despite its well known role as an antiapoptotic factor, in cerebral ischemia NF-kappaB contributes to neuronal cell death, at least if the ischemia is severe enough to lead to irreversible brain damage. In contrast, NF-kappaB also seems to be responsible for the preconditioning effect of a transient and sublethal ischemia, perhaps by dampening its own subsequent full activation. Among the five NF-kappaB subunits, RelA and p50 are responsible for the detrimental effect in cerebral ischemia. Activation of NF-kappaB signaling is mediated by the upstream kinase inhibitor of kappaB kinase and is triggered by hypoxia, reactive oxygen species, and several inflammatory mediators. Interestingly, the complex NF-kappaB signaling pathway provides drug targets at several levels. Modulation of NF-kappaB signaling has the potential to interrupt multiple inflammatory and apoptotic mechanisms through one specific molecular target.
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            Genetics, Cytogenetics, and Epigenetics of Colorectal Cancer

            Most of the colorectal cancer (CRC) cases are sporadic, only 25% of the patients have a family history of the disease, and major genes causing syndromes predisposing to CRC only account for 5-6% of the total cases. The following subtypes can be recognized: MIN (microsatellite instability), CIN (chromosomal instability), and CIMP (CpG island methylator phenotype). CIN occurs in 80–85% of CRC. Chromosomal instability proceeds through two major mechanisms, missegregation that results in aneuploidy through the gain or loss of whole chromosomes, and unbalanced structural rearrangements that lead to the loss and/or gain of chromosomal regions. The loss of heterozygosity that occur in the first phases of the CRC cancerogenesis (in particular for the genes on 18q) as well as the alteration of methylation pattern of multiple key genes can drive the development of colorectal cancer by facilitating the acquisition of multiple tumor-associated mutations and the instability phenotype.
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              Nuclear factor-kappaB contributes to infarction after permanent focal ischemia.

              Activation of transcription factor nuclear factor-kappaB (NF-kappaB) may induce expression of either proinflammatory/apoptotic genes or antiapoptotic genes. Because a considerable number of middle cerebral artery occlusions (MCAOs) in humans are not associated with reperfusion during the first 24 hours, the role of NF-kappaB after permanent MCAO (pMCAO) was investigated. Mice transgenic for a NF-kappaB-driven beta-globin reporter were exposed to pMCAO, and the expression of the reporter gene was quantified with real-time polymerase chain reaction. Mice lacking the p50 subunit of NF-kappaB and wild-type controls were exposed to pMCAO with or without treatment with pyrrolidinedithiocarbamate (PDTC), an NF-kappaB inhibitor. Brain sections of human stroke patients were immunostained for the activated NF-kappaB. pMCAO increased NF-kappaB transcriptional activity to 260% (36.9+/-4.5 compared with 14.4+/-2.6; n=10; P<0.01) in the brain; this NF-kappaB activation was completely blocked by PDTC (17.2+/-2.6; n=9; P<0.05). In p50-/- mice, pMCAO resulted in 41% (18+/-3.2 mm3; n=12) smaller infarcts compared with wild-type controls (32.9+/-3.8 mm3; n=9; P<0.05), which was comparable to the protection achieved with PDTC in wild-type mice (19.6+/-4.2 mm3; n=8). Pro-DTC, a PDTC analogue that does not cross the blood-brain barrier, had no effect, even though Pro-DTC and PDTC were equally protective in vitro. During the first 2 days of human stroke, NF-kappaB was activated in neurons in the penumbral areas. NF-kappaB is induced in neurons during human stroke, and activation of NF-kappaB in the brain may contribute to infarction in pMCAO.
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                Author and article information

                Contributors
                wangyigang43@163.com
                jwu1867@hotmail.com
                Journal
                J Clin Lab Anal
                J. Clin. Lab. Anal
                10.1002/(ISSN)1098-2825
                JCLA
                Journal of Clinical Laboratory Analysis
                John Wiley and Sons Inc. (Hoboken )
                0887-8013
                1098-2825
                30 September 2019
                October 2019
                : 33
                : 8 ( doiID: 10.1002/jcla.v33.8 )
                : e22956
                Affiliations
                [ 1 ] College of Life and Medicine Sciences Zhejiang Sci‐Tech University Hangzhou China
                [ 2 ] Key Laboratory of Environmental Medicine Engineering School of Public Health Southeast University Nanjing China
                [ 3 ] Department of Pathology, Zhejiang Provincial People’s Hospital People’s Hospital of Hangzhou Medical College Hangzhou China
                [ 4 ] Jiangsu Provincial Key Lab of Pharmaceutical Botany Jiangsu Normal university Xuzhou China
                Author notes
                [*] [* ] Correspondence

                Yigang Wang and Jiong Wu, College of Life and Medicine Sciences, Zhejiang Sci‐Tech University, Hangzhou 310018, China.

                Emails: wangyigang43@ 123456163.com (YW) and jwu1867@ 123456hotmail.com (JW)

                Author information
                https://orcid.org/0000-0002-1882-8127
                Article
                JCLA22956
                10.1002/jcla.22956
                6805325
                31568607
                f7afbead-c7c5-4fb3-9b7a-393462534289
                © 2019 The Authors. Journal of Clinical Laboratory Analysis Published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 09 April 2019
                : 28 May 2019
                : 29 May 2019
                Page count
                Figures: 2, Tables: 3, Pages: 9, Words: 5298
                Funding
                Funded by: Zhejiang Provincial Natural Science Foundation of China
                Award ID: LY16H160056
                Award ID: LY18C070002
                Funded by: National Nature Science Foundation of China
                Award ID: 81803069
                Funded by: Postgraduate Research & Practice Innovation Program of Jiangsu Province
                Award ID: KYCX17_0187
                Categories
                Research Article
                Research Articles
                Custom metadata
                2.0
                jcla22956
                October 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.7.0 mode:remove_FC converted:24.10.2019

                Clinical chemistry
                colorectal cancer,ercc4,polymorphism,rs6498486
                Clinical chemistry
                colorectal cancer, ercc4, polymorphism, rs6498486

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