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      Activation and overexpression of the aryl hydrocarbon receptor contribute to cutaneous squamous cell carcinomas: an immunohistochemical study

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          Abstract

          Background

          In vitro studies showed that the aryl hydrocarbon receptor (AHR) contributed to the development of cutaneous squamous cell carcinomas, but supporting clinical data are lacking.

          Methods

          Immunohistochemical analysis was used to detect the expression of AHR, CYP1A1, EGFR, and Ki-67 in 10 actinic keratosis (AK) cases, 10 Bowen disease (BD) cases, 20 cutaneous squamous cell carcinoma (cSCC) cases and 20 normal skin samples. H-scores were used to assess the immunoreactivity.

          Results

          Weak positive AHR immunoreactivity was found in all normal skin samples, while strong positive AHR immunoreactivity was found in atypical squamous proliferation (AK, BD and cSCC) cases. H-scores and the rate of strong immunostaining of the atypical squamous proliferation cases were higher than those of normal controls ( p < 0.01). Nuclear expression of AHR was higher in atypical squamous proliferation cases than in normal controls ( p < 0.01). H-scores and the nuclear expression rate of AHR were significantly higher in AK and BD cases than cSCC cases ( p < 0.01). CYP1A1 expression was low and showed no differences among the four studied groups ( p > 0.05). The H-score of AHR was positively correlated with EGFR expression ( r = 0.54, p < 0.01) in atypical squamous proliferation cases but was not correlated with CYP1A1 ( r = − 0.17, p = 0.295) and Ki-67 ( r = − 0.48, p = 0.222) expression.

          Conclusion

          AHR plays a vital role in cSCC pathogenesis. The overexpression and activation of AHR are involved in the early development of skin cancers. AHR expression correlates with EGFR expression and may influence cell proliferation. AHR is a valuable therapeutic target for skin cancers.

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          Most cited references18

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          Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer.

          The mammalian CYP1A1, CYP1A2, and CYP1B1 genes (encoding cytochromes P450 1A1, 1A2, and 1B1, respectively) are regulated by the aromatic hydrocarbon receptor (AHR). The CYP1 enzymes are responsible for both metabolically activating and detoxifying numerous polycyclic aromatic hydrocarbons (PAHs) and aromatic amines present in combustion products. Many substrates for CYP1 enzymes are AHR ligands. Differences in AHR affinity between inbred mouse strains reflect variations in CYP1 inducibility and clearly have been shown to be associated with differences in risk of toxicity or cancer caused by PAHs and arylamines. Variability in the human AHR affinity exists, but differences in human risk of toxicity or cancer related to AHR activation remain unproven. Mouse lines having one or another of the Cyp1 genes disrupted have shown paradoxical effects; in the test tube or in cell culture these enzymes show metabolic activation of PAHs or arylamines, whereas in the intact animal these enzymes are sometimes more important in the role of detoxification than metabolic potentiation. Intact animal data contradict pharmaceutical company policies that routinely test drugs under development; if a candidate drug shows CYP1 inducibility, further testing is generally discontinued for fear of possible toxic or carcinogenic effects. In the future, use of "humanized" mouse lines, containing a human AHR or CYP1 allele in place of the orthologous mouse gene, is one likely approach to show that the AHR and the CYP1 enzymes in human behave similarly to that in mouse.
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            Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation.

            UVB radiation-induced signaling in mammalian cells involves two major pathways: one that is initiated through the generation of DNA photoproducts in the nucleus and a second one that occurs independently of DNA damage and is characterized by cell surface receptor activation. The chromophore for the latter one has been unknown. Here, we report that the UVB response involves tryptophan as a chromophore. We show that through the intracellular generation of photoproducts, such as the arylhydrocarbon receptor (AhR) ligand 6-formylindolo[3,2-b]carbazole, signaling events are initiated, which are transferred to the nucleus and the cell membrane via activation of the cytoplasmatic AhR. Specifically, AhR activation by UVB leads to (i) transcriptional induction of cytochrome P450 1A1 and (ii) EGF receptor internalization with activation of the EGF receptor downstream target ERK1/2 and subsequent induction of cyclooxygenase-2. The role of the AhR in the UVB stress response was confirmed in vivo by studies employing AhR KO mice.
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              Benzo[a]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor.

              The contribution of the aryl hydrocarbon receptor (AhR) in induction of a battery of xenobiotic-metabolizing enzymes has been studied extensively. However, no direct proof has been obtained that it plays a role in modulating carcinogenesis. To address the question of whether AhR is required for tumor induction, we have investigated the response of AhR-deficient mice to benzo[a]pyrene (B[a]P), a widely distributed environmental carcinogen. B[a]P treatment induced expression of the cytochrome P450 gene Cyp1a1 in the skin and liver of AhR-positive mice bearing +/+ and +/- genotypes and did not induce expression of the cytochrome P450 gene Cyp1a1 in AhR-null mice in either skin or liver. In contrast, Cyp1a2 gene expression was positive in liver irrespective of the presence or absence of the AhR gene, or B[a]P treatment, although its inducibility was lost in the AhR(-/-) mouse. All AhR-positive male mice of both +/+ and +/- genotypes that received subcutaneous injection of B[a]P (2 mg) on the first and the eighth days had developed subcutaneous tumors at the site of injection at the end of the 18-week experiment. In contrast, no tumors were apparent in any of the AhR-deficient mice. Likewise, topical application of B[a]P (200 microg) at weekly intervals to the skin of female mice for 25 weeks produced skin tumors only in the AhR-positive mice. Thus the carcinogenic action of B[a]P may be determined primarily by AhR, a transcriptional regulator of the gene for CYP1A1. The results of the present study provide direct evidence that AhR is involved in carcinogenesis.
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                Author and article information

                Contributors
                Paneth@msn.com
                chenjia_doc@163.com
                haomibb@163.com
                tingtinghu1988@163.com
                490260721@qq.com
                qiangju401@sina.com , Qiangju401@sina.com
                Journal
                Diagn Pathol
                Diagn Pathol
                Diagnostic Pathology
                BioMed Central (London )
                1746-1596
                25 August 2018
                25 August 2018
                2018
                : 13
                : 59
                Affiliations
                [1 ]ISNI 0000 0004 0368 8293, GRID grid.16821.3c, Department of Dermatology, Renji Hospital, School of Medicine, , Shanghai Jiaotong University, ; Pujian Road 160, Shanghai, 200127 China
                [2 ]ISNI 0000000123704535, GRID grid.24516.34, Shanghai Skin Diseases Hospital, , Affiliated to Tongji University, ; Shanghai, China
                [3 ]ISNI 0000 0004 0639 0580, GRID grid.416271.7, Department of Dermatology, , Ningbo First Hospital, ; Ningbo, Zhejiang, China
                Article
                740
                10.1186/s13000-018-0740-x
                6109267
                30144817
                ce23cf05-e5db-4cb4-8198-bc76ff27e07a
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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.

                History
                : 3 May 2018
                : 16 August 2018
                Funding
                Funded by: National Science Foundation of China Research project
                Award ID: 81602772
                Funded by: Shanghai Municipal Commission of Health and Family Planning
                Award ID: 20134381
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2018

                Pathology
                aryl hydrocarbon receptor,nonmelanoma skin cancer,immunohistochemical study
                Pathology
                aryl hydrocarbon receptor, nonmelanoma skin cancer, immunohistochemical study

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