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Oral lichen planus: studies of factors involved in differentiation, epithelial mesenchymal transition and inflammation
Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Medical Biosciences.
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 [en]
oral lichen planus, differentiation, inflammation, autoimmune, premalign
National Category
Dentistry
Research subject
Odontology; Pathology
Identifiers
URN: urn:nbn:se:umu:diva-55419ISBN: 978-91-7459-441-6 (print)OAI: oai:DiVA.org:umu-55419DiVA: diva2:526808
Public defence
2012-06-08, Betula, by 6M, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2012-05-16 Created: 2012-05-14 Last updated: 2012-05-16Bibliographically approved
List of papers
1. Increased expression of Smad proteins, and in particular Smad3, in oral lichen planus compared to normal oral mucosa
Open this publication in new window or tab >>Increased expression of Smad proteins, and in particular Smad3, in oral lichen planus compared to normal oral mucosa
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.

Keyword
epithelial mesenchymal transition, oral lichen planus, smad, transforming growth factor β
National Category
Dentistry
Research subject
Odontology; Pathology
Identifiers
urn:nbn:se:umu:diva-36087 (URN)10.1111/j.1600-0714.2010.00902.x (DOI)000281550200009 ()20618616 (PubMedID)
Available from: 2010-09-16 Created: 2010-09-16 Last updated: 2017-12-12Bibliographically approved
2. Altered expression of miR-21, miR-125b, and miR-203 indicates a role for these microRNAs in oral lichen planus
Open this publication in new window or tab >>Altered expression of miR-21, miR-125b, and miR-203 indicates a role for these microRNAs in oral lichen planus
Show others...
2012 (English)In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 41, no 1, 90-95 p.Article in journal (Refereed) Published
Abstract [en]

Background: Oral lichen planus (OLP), which is a chronic inflammatory disease of the oral mucosa with unknown etiology, affects about 2% of the population. MicroRNAs are small non-coding RNAs involved in normal processes such as development and differentiation as well as progression of human diseases. The aim of this study was to investigate the expression of miR-21, miR-125b, and miR-203 and to compare RNA levels of their potential targets, the tumor suppressor p53 and its relative p63, both known to be deregulated in OLP.

Methods: In biopsies from 20 patients with OLP and 20 age- and sex-matched healthy controls, epithelium was laser dissected and analyzed for the expression of miR-21, miR-125b, miR-203, p53, and p63 using qRT/PCR.

Results: Increased expression of miR-21 and miR-203, decreased expression of miR-125, and down-regulation of p53 and ΔNp63 RNA were seen in OLP compared to normal oral mucosa. When comparing microRNA expression to levels of p53 and p63 RNA, a significant negative correlation was seen between ΔNp63 and miR-203 and between miR-21 and p53, respectively.

Conclusion: Results indicate a role for the studied microRNAs in changes seen in OLP.

Keyword
miR-125b;miR-203;miR-21;oral lichen planus
National Category
Dentistry
Research subject
Odontology; Pathology
Identifiers
urn:nbn:se:umu:diva-49757 (URN)10.1111/j.1600-0714.2011.01084.x (DOI)21943223 (PubMedID)
Available from: 2011-11-17 Created: 2011-11-17 Last updated: 2017-12-08Bibliographically approved
3. Increased levels of COX-2 in oral lichen planus supports an autoimmune cause of the disease
Open this publication in new window or tab >>Increased levels of COX-2 in oral lichen planus supports an autoimmune cause of the disease
Show others...
2012 (English)In: Journal of the European Academy of Dermatology and Venereology, ISSN 0926-9959, E-ISSN 1468-3083, Vol. 26, no 11, 1415-1419 p.Article in journal (Refereed) Published
Abstract [en]

Background: Oral lichen planus (OLP) is a chronic inflammatory disease for which the pathogenesis is not fully understood. OLP has autoimmune features and auto immunity has been suggested as a potential cause, whereas WHO has classified OLP as a premalignant condition. Association between chronic inflammation and cancer is known and chronic inflammation is one of the characteristics of OLP. A protein connected to inflammation and suggested to be involved in cancer development is cyclooxygenase-2 (COX-2) which can be inhibited by microRNA-26b (miR-26b).

Objective: The aim was to map levels of COX-2 and miR-26b in OLP lesions to see if there was any correlation between expression of COX-2 and its regulator miR-26b in OLP.

Methods: In biopsies from 20 OLP patients and 20 age and gender-matched controls laser- micro dissection of epithelium was performed. Quantitative RT-PCR, immunohistochemistry and Western blot were used in the analysis.

Results: Levels of COX-2 mRNA were significantly higher while levels of miR-26b were significantly lower in OLP lesions compared to controls. Using immunohistochemistry normal oral mucosa samples did not show any expression of COX-2 while OLP samples expressed the protein. No COX-2 protein was detectable with Western blot.

Conclusion: Increased expression of COX-2 and decreased expression of miR-26b in OLP suggests both to play a role in OLP. COX-2 has been connected to both malignant development and autoimmunity but as malignant development of OLP is quite rare we suggest that the increased levels of COX-2 seen here support an autoimmune cause of the disease.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2012
Keyword
Oral lichen planus, MicroRNA, Cox-2
National Category
Dentistry Dermatology and Venereal Diseases
Research subject
Pathology; Odontology
Identifiers
urn:nbn:se:umu:diva-48570 (URN)10.1111/j.1468-3083.2011.04306.x (DOI)000310271000013 ()22017396 (PubMedID)
Available from: 2011-10-25 Created: 2011-10-25 Last updated: 2017-12-08Bibliographically approved
4. Autoantibodies and decreased expression of the transcription factor ELF-3 together with increased chemokine pathways support an autoimmune phenotype and altered differentiation in lichen planus located in oral mucosa
Open this publication in new window or tab >>Autoantibodies and decreased expression of the transcription factor ELF-3 together with increased chemokine pathways support an autoimmune phenotype and altered differentiation in lichen planus located in oral mucosa
Show others...
2013 (English)In: Journal of the European Academy of Dermatology and Venereology, ISSN 0926-9959, E-ISSN 1468-3083, Vol. 27, no 11, 1410-1416 p.Article in journal (Refereed) Published
Abstract [en]

Background  The pathogenesis of oral lichen planus (OLP), a chronic inflammatory disease, is not fully understood. It is known that OLP has autoimmune features, and it is suggested to be an autoimmune disease. ELF-3 is involved in differentiation of keratinocytes and deregulated in different tumours and inflammatory diseases. CXCR-3 and its ligands CXCL-10 and CXCL-11 are increased in autoimmune diseases and linked to Th-1 immune response. Objectives  To analyse and compare expression of ELF-3, CXCR-3, CXCL-10 and CXCL-11 in OLP lesions and controls in whole and microdissected epithelium. Methods  Tissue biopsies from 20 patients clinically and histologically diagnosed with OLP and 20 healthy controls were studied using whole tissues or microdissected epithelium. By the use of qRT-PCR, mRNA levels of ELF-3, CXCR-3, CXCL-10 and CXCL-11 were studied. Western blot was used for analysis of ELF-3 protein expression. Sera from 19 OLP patients and 20 controls were analysed with ELISA in search for autoantibodies. Results  The upregulation of CXCR-3, CXCL-10 and CXCL-11 found in OLP is similar to previous findings showing an autoimmune phenotype in lichen planus (LP) and lichen sclerosus. Decreased expression of the differentiation-related transcription factor ELF-3 was also seen in OLP lesions, and we further demonstrate presence of circulating autoantibodies against the ELF-3 protein in sera from 3 of 19 (16%) LP patients tested. Conclusions  On the basis of these findings, we confirm that OLP shows features of an autoimmune disease and suggest deregulated differentiation of keratinocytes to be one of the causes of the disease phenotype.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2013
National Category
Basic Medicine Dermatology and Venereal Diseases
Identifiers
urn:nbn:se:umu:diva-55418 (URN)10.1111/jdv.12027 (DOI)000325747200011 ()23134363 (PubMedID)
Available from: 2012-05-15 Created: 2012-05-14 Last updated: 2017-12-07Bibliographically approved

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