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Increased expression of Smad proteins, and in particular Smad3, in oral lichen planus compared to normal oral mucosa
Umeå University, Faculty of Medicine, Department of Odontology.
Umeå University, Faculty of Medicine, Department of Odontology.
Division of Medical Sciences, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
Umeå University, Faculty of Medicine, Department of Medical Biosciences.
2010 (English)In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 39, no 9, 639-644 p.Article in journal (Refereed) Published
Abstract [en]

Backgound: Oral lichen planus (OLP) is a chronic inflammatory disease of the oral mucosa which the World Health Organisation (WHO) considers a premalignant condition. One step in malignant development is so called epithelial mesenchymal transition (EMT), a process whereby epithelial cells acquire mesenchymal characteristics. EMT occurs during embryogenesis and wound healing but also in some human diseases such as cancer and fibrosis. A factor known to induce EMT is transforming growth factor-beta (TGF-beta), which uses the Smad proteins as mediators for its signalling. TGF-beta is also often over-expressed in squamous cell carcinoma of the head and neck (SCCHN).

Methods: In the present study we mapped expression of Smad proteins in OLP lesions by immunohistochemistry, and compared to expression in normal and sensitive oral mucosa. The latter group of patients had developed SCCHN after shorter or longer periods of diffuse oral symptoms. The aim was to see if there were any signs of EMT related changes in the OLP lesions, as judged by changes in the TGF-beta pathway.

Conclusion: Changes in the TGF-beta pathway related to EMT are seen in the very earliest stages of oral malignancy and become more severe as lesions progress.

Place, publisher, year, edition, pages
2010. Vol. 39, no 9, 639-644 p.
Keyword [en]
epithelial mesenchymal transition, oral lichen planus, smad, transforming growth factor β
National Category
Dentistry
Research subject
Odontology; Pathology
Identifiers
URN: urn:nbn:se:umu:diva-36087DOI: 10.1111/j.1600-0714.2010.00902.xISI: 000281550200009PubMedID: 20618616OAI: oai:DiVA.org:umu-36087DiVA: diva2:351830
Available from: 2010-09-16 Created: 2010-09-16 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Oral lichen planus: studies of factors involved in differentiation, epithelial mesenchymal transition and inflammation
Open this publication in new window or tab >>Oral lichen planus: studies of factors involved in differentiation, epithelial mesenchymal transition and inflammation
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Lichen planus is a chronic inflammation of skin and mucosa with unknown cause. Oral Lichen Planus, OLP, affects around 2% of the population. Autoimmunity has been suggested as a possible cause as the disease has autoimmune features such as female predominance, cyclic nature and cytotoxic T-cell infiltrate. It has been suggested that the intense inflammatory response seen in OLP is caused by factors on the keratinocyte surface triggering the immune system. Chronic inflammation is one of the hallmarks of oral lichen planus and chronic inflammation is connected to increased risk of tumor development. WHO classifies OLP as a potentially malignant condition with increased risk of developing Squamous cell carcinoma of head and neck, SCCHN, but malignant transformation of OLP is a matter of controversy. The aim of these studies was to further elucidate the autoimmune and premalignant character of OLP. Factors involved in malignant transformation, autoimmunity and inflammation were analyzed in normal oral mucosa, OLP and SCCHN. Factors studied were the signal transducers of Transforming growth factor-β the Smad proteins, microRNAs, COX-2, the receptor CXCR-3 and its ligands CXCL-10 and -11 and ELF-3.

Material and methods: In the study on Smad protein expression formalin fixed and paraffin embedded biopsies from normal oral mucosa, OLP and SCCHN was used. For the remaining studies fresh frozen biopsies from OLP and normal controls was used. All of the fresh frozen OLP samples and their controls were micro dissected to be able to analyze the epithelial part only as well as sections of the whole biopsy. Methods used are immunohistochemistry, qRT-PCR and Western blot.

Results: Analyses of smad proteins expression showed a clear increase of smad3 and smad7 in OLP compared to normal oral mucosa. The expressions of smad proteins in the tumors were more heterogeneous. Some of the SCCHN samples showed a similar expression as OLP while others did not. Micro RNA analyzes showed that miR-21 and miR-203 was significantly increased in OLP epithelium compared to normal oral epithelium while the expression of miR-125b and their potential targets p53 and p63 was decreased in OLP. The presence of COX-2 was significantly higher in OLP than normal controls. At the same time the expression of miR-26b, a suggested repressor of COX-2 was decreased in OLP compared to normal mucosa. The receptor CXCR-3 and its ligands CXCL-10 and -11 were increased in OLP. Expressions of the differentiation involved factor ELF-3 mRNA as well as protein were decreased in OLP.

Conclusion: The factors studied are involved in differentiation, malignant transformation and inflammation. Some of the results in these studies indicate a similar expression pattern for OLP and SCCHN. Several of the factors studied are involved in differentiation and their deregulation suggests a disturbed differentiation pattern and this could indicate a premalignant character of OLP but malignant transformation of OLP lesions are relative rare. A lot of these factors are also involved in inflammatory processes and connected to autoimmune diseases and their deregulation in OLP could also support an autoimmune cause of the disease. Based on our studies a suggestion is that the disturbed differentiation pattern triggers the intense immune response directed against the epithelial cells seen in OLP.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2012. 60 p.
Series
Umeå University odontological dissertations, ISSN 0345-7532 ; 122
Keyword
oral lichen planus, differentiation, inflammation, autoimmune, premalign
National Category
Dentistry
Research subject
Odontology; Pathology
Identifiers
urn:nbn:se:umu:diva-55419 (URN)978-91-7459-441-6 (ISBN)
Public defence
2012-06-08, Betula, by 6M, Norrlands universitetssjukhus, Umeå, 09:00 (English)
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Available from: 2012-05-16 Created: 2012-05-14 Last updated: 2012-05-16Bibliographically approved

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