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Changes in the distribution pattern of Claudin tight junction proteins during the progression of mouse skin tumorigenesis
BACKGROUND: Despite the fact that morphological and physiological observations suggest that the tight junction (TJ)-based permeability barrier is modified/disrupted in tumorigenesis, the role of members of the Claudin (Cldn) family of TJ proteins is not well-understood. Using a well-established two-...
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Formato: | Texto |
Lenguaje: | English |
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BioMed Central
2007
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2217561/ https://www.ncbi.nlm.nih.gov/pubmed/17945025 http://dx.doi.org/10.1186/1471-2407-7-196 |
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author | Arabzadeh, Azadeh Troy, Tammy-Claire Turksen, Kursad |
author_facet | Arabzadeh, Azadeh Troy, Tammy-Claire Turksen, Kursad |
author_sort | Arabzadeh, Azadeh |
collection | PubMed |
description | BACKGROUND: Despite the fact that morphological and physiological observations suggest that the tight junction (TJ)-based permeability barrier is modified/disrupted in tumorigenesis, the role of members of the Claudin (Cldn) family of TJ proteins is not well-understood. Using a well-established two-stage chemical carcinogenesis model, we investigated the temporal and spatial changes in expression of those Cldns that we have previously demonstrated to be important in epidermal differentiation and the formation of the epidermal permeability barrier, i.e., Cldn1, Cldn6, Cldn11, Cldn12 and Cldn18. METHODS: The lower dorsal backskin of mice was treated topically with 7,12-dimethylbenz(a)anthracene (DMBA; 0.25 mg/ml in acetone) and following a 10-day incubation period, 12-O-tetradecanoyl-phorbol-13-acetate (TPA; 25 μg/ml in acetone) was applied three times a week to the same area. Backskin samples were dissected 2, 4, 6, 8 and 12 weeks after the initiation of the experimental protocol and immunohistochemistry was performed on sections using antibodies against the following: Cldn1, Cldn6, Cldn11, Cldn12, Cldn18, Ki67 and CD3. RESULTS: Our data indicate that along with the changes in epidermal cell morphology and differentiation that occur during tumor formation, there is a dramatic change in Cldn distribution consistent with cell polarity and barrier selectivity changes. Specifically, in the early stages of DMBA/TPA treatment, the suprabasal-specific Cldns occupy an expanded zone of expression corresponding to an increased number of suprabasal epidermal cell layers. As tumorigenesis progressed, the number of suprabasal epidermal layers positive for Cldn6, Cldn11, Cldn12 and Cldn18 was reduced, especially in the lower strata of the expanded suprabasal zone. In addition, a variably reduced cell membrane association of those differentiation-specific Cldns was observed, especially within the infiltrating epidermal structures. In contrast, Cldn1 (which is normally expressed in all the living layers of the epidermis) remained restricted to the cell membrane throughout the tumorigenesis protocol. However commencing 2 weeks after treatment there was a marked decrease in the number of Cldn1-positive basal cells, and the zone of Cldn1-null epidermal cells was expanded up into the lower stratified epidermis throughout the progression of DMBA/TPA treatment. In addition, there was no Cldn1 localization in the infiltrating epidermal structures of the tumorigenic epidermis. CONCLUSION: This is the first demonstration of the changes in Cldn expression in the progression of DMBA/TPA-induced skin tumors; however further investigation into the molecular mechanisms regulating the observed changes in barrier selectivity during tumorigenesis is required. |
format | Text |
id | pubmed-2217561 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2007 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-22175612008-01-30 Changes in the distribution pattern of Claudin tight junction proteins during the progression of mouse skin tumorigenesis Arabzadeh, Azadeh Troy, Tammy-Claire Turksen, Kursad BMC Cancer Research Article BACKGROUND: Despite the fact that morphological and physiological observations suggest that the tight junction (TJ)-based permeability barrier is modified/disrupted in tumorigenesis, the role of members of the Claudin (Cldn) family of TJ proteins is not well-understood. Using a well-established two-stage chemical carcinogenesis model, we investigated the temporal and spatial changes in expression of those Cldns that we have previously demonstrated to be important in epidermal differentiation and the formation of the epidermal permeability barrier, i.e., Cldn1, Cldn6, Cldn11, Cldn12 and Cldn18. METHODS: The lower dorsal backskin of mice was treated topically with 7,12-dimethylbenz(a)anthracene (DMBA; 0.25 mg/ml in acetone) and following a 10-day incubation period, 12-O-tetradecanoyl-phorbol-13-acetate (TPA; 25 μg/ml in acetone) was applied three times a week to the same area. Backskin samples were dissected 2, 4, 6, 8 and 12 weeks after the initiation of the experimental protocol and immunohistochemistry was performed on sections using antibodies against the following: Cldn1, Cldn6, Cldn11, Cldn12, Cldn18, Ki67 and CD3. RESULTS: Our data indicate that along with the changes in epidermal cell morphology and differentiation that occur during tumor formation, there is a dramatic change in Cldn distribution consistent with cell polarity and barrier selectivity changes. Specifically, in the early stages of DMBA/TPA treatment, the suprabasal-specific Cldns occupy an expanded zone of expression corresponding to an increased number of suprabasal epidermal cell layers. As tumorigenesis progressed, the number of suprabasal epidermal layers positive for Cldn6, Cldn11, Cldn12 and Cldn18 was reduced, especially in the lower strata of the expanded suprabasal zone. In addition, a variably reduced cell membrane association of those differentiation-specific Cldns was observed, especially within the infiltrating epidermal structures. In contrast, Cldn1 (which is normally expressed in all the living layers of the epidermis) remained restricted to the cell membrane throughout the tumorigenesis protocol. However commencing 2 weeks after treatment there was a marked decrease in the number of Cldn1-positive basal cells, and the zone of Cldn1-null epidermal cells was expanded up into the lower stratified epidermis throughout the progression of DMBA/TPA treatment. In addition, there was no Cldn1 localization in the infiltrating epidermal structures of the tumorigenic epidermis. CONCLUSION: This is the first demonstration of the changes in Cldn expression in the progression of DMBA/TPA-induced skin tumors; however further investigation into the molecular mechanisms regulating the observed changes in barrier selectivity during tumorigenesis is required. BioMed Central 2007-10-18 /pmc/articles/PMC2217561/ /pubmed/17945025 http://dx.doi.org/10.1186/1471-2407-7-196 Text en Copyright © 2007 Arabzadeh et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Arabzadeh, Azadeh Troy, Tammy-Claire Turksen, Kursad Changes in the distribution pattern of Claudin tight junction proteins during the progression of mouse skin tumorigenesis |
title | Changes in the distribution pattern of Claudin tight junction proteins during the progression of mouse skin tumorigenesis |
title_full | Changes in the distribution pattern of Claudin tight junction proteins during the progression of mouse skin tumorigenesis |
title_fullStr | Changes in the distribution pattern of Claudin tight junction proteins during the progression of mouse skin tumorigenesis |
title_full_unstemmed | Changes in the distribution pattern of Claudin tight junction proteins during the progression of mouse skin tumorigenesis |
title_short | Changes in the distribution pattern of Claudin tight junction proteins during the progression of mouse skin tumorigenesis |
title_sort | changes in the distribution pattern of claudin tight junction proteins during the progression of mouse skin tumorigenesis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2217561/ https://www.ncbi.nlm.nih.gov/pubmed/17945025 http://dx.doi.org/10.1186/1471-2407-7-196 |
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