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      Expression of apoptosis repressor with caspase recruitment domain (ARC) in familial adenomatous polyposis (FAP) adenomas and its correlation with DNA mismatch repair proteins, p53, Bcl-2, COX-2 and beta-catenin

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          Abstract

          Background

          Colorectal familial adenomatous polyposis (FAP) adenomas exhibit a uniform pathogenetic basis caused by a germline mutation in the adenomatous polyposis gene ( APC), but the molecular changes leading to their development are incompletely understood. However, dysregulated apoptosis is known to substantially affect the development of colonic adenomas. One of the key regulatory proteins involved in apoptosis is apoptosis repressor with caspase recruitment domain (ARC).

          Methods

          The expression of nuclear and cytoplasmic ARC in 212 adenomas from 80 patients was analyzed by immunohistochemistry. We also compared expression levels of ARC with the expression levels of p53, Bcl-2, COX-2, and MMR proteins. Statistical analyses were performed by Spearman’s rank correlation and linear regression test.

          Results

          ARC was overexpressed in the nuclei and cytoplasm of most FAP adenomas investigated. Cytoplasmic ARC staining was moderately stronger (score 2) in 49.1% (n = 104/212) and substantially stronger (score 3) in 32.5% (n = 69/212) of adenomas compared to non-tumorous colorectal mucosa. In 18.4% (n = 39/212) of adenomas, cytoplasmic ARC staining was equivalent to that in non-tumorous mucosa.

          Nuclear expression of ARC in over 75% of cells was present in 30.7% (n = 65/212) of investigated adenomas, and nuclear expression in 10–75% of cells was detected in 62.7% (n = 133/212). ARC expression in under 10% of nuclei was found in 6.6% (n = 14/212) of adenomas.

          The correlation between nuclear ARC expression and cytoplasmic ARC expression was highly significant ( p = 0.001). Moreover, nuclear ARC expression correlated positively with overexpression of Bcl-2, COX-2 p53 and β-catenin. Cytoplasmic ARC also correlated with overexpression of Bcl-2. Sporadic MMR deficiency was detected in very few FAP adenomas and showed no correlation with nuclear or cytoplasmic ARC.

          Conclusions

          Our results demonstrated that both cytoplasmic and nuclear ARC are overexpressed in FAP adenomas, thus in a homogenous collective. The highly significant correlation between nuclear ARC and nuclear β-catenin suggested that ARC might be regulated by β-catenin in FAP adenomas. Because of its further correlations with p53, Bcl-2, and COX-2, nuclear ARC might play a substantial role not only in carcinomas but also in precursor lesions.

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          Most cited references 53

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          Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2).

          Two cyclooxygenase isozymes catalyze conversion of arachidonic acid to prostaglandin H2: constitutive COX-1 and inducible COX-2. To assess the role of COX-2 in colorectal tumorigenisis, we determined the effects of COX-2 gene (Ptgs2) knockouts and a novel COX-2 inhibitor on Apc delta716 knockout mice, a model of human familial adenomatous polyposis. A Ptgs2 null mutation reduced the number and size of the intestinal polyps dramatically. Furthermore, treating Apc delta716 mice with a novel COX-2 inhibitor reduced the polyp number more significantly than with sulindac, which inhibits both isoenzymes. These results provide direct genetic evidence that COX-2 plays a key role in tumorigenesis and indicate that COX-2-selective inhibitors can be a novel class of therapeutic agents for colorectal polyposis and cancer.
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            Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis.

            Familial adenomatous polyposis is an autosomal dominant disorder characterized by the formation of hundreds of colorectal adenomas and eventual colorectal cancer. Administration of the nonsteroidal antiinflammatory drug sulindac has been followed by regression of polyps in patients with this disorder, but no controlled trial of this drug in patients who have not had surgery has been reported. We conducted a randomized, double-blind, placebo-controlled study of 22 patients with familial adenomatous polyposis, including 18 who had not undergone colectomy. The patients received sulindac at a dose of 150 mg orally twice a day for nine months or identical-appearing placebo tablets. The number and size of the polyps were evaluated every three months for one year. A statistically significant decrease in the mean number of polyps and their mean diameter occurred in patients treated with sulindac, as compared with those given placebo. When treatment was stopped at nine months, the number of polyps had decreased to 44 percent of base-line values and the diameter of the polyps to 35 percent of base-line values (P = 0.014 and P < 0.001, respectively, for the comparison with the changes in the group given placebo). No patient had complete resolution of polyps. Three months after treatment with sulindac was stopped, both the number and the size of the polyps increased in sulindac-treated patients but remained significantly lower than the values at base line. No side effects from sulindac were noted. Sulindac reduces the number and size of colorectal adenomas in patients with familial adenomatous polyposis, but its effect is incomplete, and it is unlikely to replace colectomy as primary therapy.
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              The Arc of synaptic memory

              The immediate early gene Arc is emerging as a versatile, finely tuned system capable of coupling changes in neuronal activity patterns to synaptic plasticity, thereby optimizing information storage in the nervous system. Here, we attempt to overview the Arc system spanning from transcriptional regulation of the Arc gene, to dendritic transport, metabolism, and translation of Arc mRNA, to post-translational modification, localization, and degradation of Arc protein. Within this framework we discuss the function of Arc in regulation of actin cytoskeletal dynamics underlying consolidation of long-term potentiation (LTP) and regulation of AMPA-type glutamate receptor endocytosis underlying long-term depression (LTD) and homeostatic plasticity. Behaviorally, Arc has a key role in consolidation of explicit and implicit forms of memory, with recent work implicating Arc in adaptation to stress as well as maladaptive plasticity connected to drug addiction. Arc holds considerable promise as a “master regulator” of protein synthesis-dependent forms of synaptic plasticity, but the mechanisms that modulate and switch Arc function are only beginning to be elucidated.
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                Author and article information

                Contributors
                christoph.roser@med.uni-heidelberg.de
                herrcsabatoth@yahoo.de
                marcus.renner@med.uni-heidelberg.de
                esther.herpel@googlemail.com
                peter.schirmacher@med.uni-heidelberg.de
                Journal
                Cell Commun Signal
                Cell Commun Signal
                Cell Communication and Signaling : CCS
                BioMed Central (London )
                1478-811X
                12 February 2021
                12 February 2021
                2021
                : 19
                Affiliations
                [1 ]GRID grid.5253.1, ISNI 0000 0001 0328 4908, Institute of Pathology, , Heidelberg University Hospital, ; Im Neuenheimer Feld 224, 69120 Heidelberg, Germany
                [2 ]GRID grid.5253.1, ISNI 0000 0001 0328 4908, Department of Orthodontics and Dentofacial Orthopaedics, , Heidelberg University Hospital, ; Im Neuenheimer Feld 400, 69120 Heidelberg, Germany
                [3 ]GRID grid.5253.1, ISNI 0000 0001 0328 4908, Tissue Bank of the National Center for Tumor Diseases (NCT), ; Im Neuenheimer Feld 224, 69120 Heidelberg, Germany
                [4 ]Trier MVZ for Histology, Cytology and Molecular Diagnostics, Max-Planck-Straße 5, 54296 Trier, Germany
                Article
                702
                10.1186/s12964-020-00702-x
                7879509
                33579312
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                Funding
                Funded by: Projekt DEAL
                Categories
                Research
                Custom metadata
                © The Author(s) 2021

                Cell biology

                arc, apoptosis, fap, bcl-2, cox-2, p53, β-catenin, mismatch repair protein

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