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Studies of p63 and p63 related proteins in patients diagnosed with oral lichen planus
Umeå University, Faculty of Medicine, Department of Odontology.
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Oral lichen planus (OLP) is a chronic inflammatory disease of the oral mucosa and also one of the more common mucosal conditions mostly affecting middle aged individuals. Even though OLP is well investigated the etiology of this disease is still unknown, even if autoimmunity as a possible etiologic factor has been suggested. WHO classifies OLP as a pre malignant condition but malignant transformation of OLP is a matter of great controversy. The p53 protein is a tumour suppressor with the potential to induce apoptosis or cell cycle arrest of DNA damaged cells. Another member of the p53 family, p63, comprises six different isoforms, and plays a crucial role in the formation of oral mucosa, salivary glands, teeth and skin. p63 has also been suggested to be involved in development of squamous cell carcinoma of the head and neck (SCCHN). β-catenin, E-cadherin and epidermal growth factor receptor (EGFR) are p63 related proteins and abnormalities in their expression are suggested to be involved in development of SCCHN.

Methods. Using immunohistochemistry and antibodies directed against p53 and those distinguishing between the p63 isoforms we analysed biopsies of OLP, SCCHN and normal oral tissue. We also mapped levels of p63 and p53 isoforms using RT-PCR technique. Furthermore expression of the p63 related proteins β-catenin, E-cadherin and EGFR was studied using immunoblot analysis. In an attempt to investigate autoimmunity as a causative factor of OLP we analysed sera from patients diagnosed with OLP and matched control individuals in order to see if there were autoantibodies directed against the p53 family.

Results. When mapping p53 and p63 protein status decreased expression of p63 and increased expression of p53 was seen in OLP compared to normal tissue. In accordance with these results, levels of p63 RNA were also lower in OLP lesions compared with normal tissue. Concerning p53 isoforms, the “original” p53 isoform was expressed in all OLP lesions and normal control tissue. Of the other isoforms, p53β and Δ133p53 were expressed in the majority of samples. Our results regarding p63 related proteins showed a generally lower expression of these proteins in OLP lesions compared to normal control tissue. When studying sera from patients with OLP we found circulating autoantibodies against all six p63 and four p73 isoforms in two patients.

Conclusions. The potential for malignant transformation of OLP is still a subject of discussion and rather controversial. While some of our results regarding status of p53 and p63 both at protein and RNA levels support this theory, other results concerning for example p63 related proteins point in the opposite direction. Based on our studies it is thus not possible to either support nor contradict the statement that OLP is a clear-cut premalignant condition. In our effort to understand the etiology of OLP we were the first to demonstrate autoantibodies against p63 and p73 in what could be a subgroup of OLP patients. OLP could thus be suggested to be not one distinct disease, but based on our data a disease comprising different subgroups.

Place, publisher, year, edition, pages
Umeå: Medicinsk biovetenskap , 2007. , 48 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1145
National Category
Pathobiology
Identifiers
URN: urn:nbn:se:umu:diva-1437ISBN: 978-91-7264-383-3 (print)OAI: oai:DiVA.org:umu-1437DiVA: diva2:141066
Public defence
2007-12-07, Betula, 6M, Umeå universitet, 901 85 umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2007-11-19 Created: 2007-11-19 Last updated: 2012-08-16Bibliographically approved
List of papers
1. Decreased expression of p63 in oral lichen planus and graft-vs.-host disease associated with oral inflammation.
Open this publication in new window or tab >>Decreased expression of p63 in oral lichen planus and graft-vs.-host disease associated with oral inflammation.
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2006 (English)In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 35, no 1, 46-50 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Oral lichen planus (OLP) and graft-vs.-host disease (GVHD) are conditions with increased risk of malignant transformation to squamous cell carcinoma of the head and neck (SCCHN). The p63 gene encodes six different proteins and is expressed at high levels in SCCHN. METHODS: Biopsies from patients diagnosed with OLP and GVHD were analysed for p63 protein expression using antibodies distinguishing between the major isoforms expressed in normal epithelia, in parallel with biopsies from normal buccal mucosa and SCCHN. RESULTS: In OLP and GVHD a decreased expression of all p63 isoforms was seen, while expression of p53 protein was upregulated, compared with normal mucosa. In SCCHN, p63 was abundantly expressed and some tumours showed strong p53 staining, suggestive of p53 mutation. CONCLUSIONS: Decreased p63 and increased p53 expression in OLP and GVHD indicates a coordinated action of these two related proteins to protect the oral mucosae from the damaging effects of underlying inflammation. In SCCHN disruption of the TP53 gene and overrepresentation of certain p63 isoforms

Keyword
Adult, Aged, Aged; 80 and over, Carcinoma; Squamous Cell/genetics/pathology, Cell Transformation; Neoplastic/genetics/pathology, DNA-Binding Proteins, Epithelium/pathology, Female, Gene Expression Regulation/genetics, Gene Expression Regulation; Neoplastic/genetics, Genes; Tumor Suppressor, Graft vs Host Disease/genetics/*pathology, Humans, Lichen Planus; Oral/genetics/*pathology, Male, Middle Aged, Mouth Mucosa/pathology, Mouth Neoplasms/genetics/pathology, Mutation/genetics, Phosphoproteins/*analysis/genetics, Precancerous Conditions/genetics/pathology, Stomatitis/genetics/*pathology, Trans-Activators/*analysis/genetics, Tumor Suppressor Protein p53/analysis/genetics, Tumor Suppressor Proteins, Up-Regulation
Identifiers
urn:nbn:se:umu:diva-15327 (URN)doi:10.1111/j.1600-0714.2005.00376.x (DOI)16393253 (PubMedID)
Available from: 2008-01-18 Created: 2008-01-18 Last updated: 2011-03-07
2. Expression of novel p53 isoforms in oral lichen planus.
Open this publication in new window or tab >>Expression of novel p53 isoforms in oral lichen planus.
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2007 (English)In: Oral Oncology, ISSN 1368-8375, Vol. 44, no 2, 156-161 p.Article in journal (Refereed) Published
Abstract [en]

Oral lichen planus (OLP) is a chronic inflammatory disease of unknown origin, showing little spontaneous regression. WHO classifies OLP as a premalignant condition, however, the underlying mechanisms initiating development of cancer in OLP lesions are not understood. The p53 tumour suppressor plays an important role in many tumours, and an increased expression of p53 protein has been seen in OLP lesions. Recently it was shown that the human TP53 gene encodes at least nine different isoforms. Another member of the p53 family, p63, comprises six different isoforms and plays a crucial role in the formation of oral mucosa, salivary glands, teeth and skin. It has also been suggested that p63 is involved in development of squamous cell carcinoma of the head and neck (SCCHN). In contrast to p53, a decreased expression of p63 protein has been seen in OLP lesions. In this study, we mapped the expression of five novel p53 isoforms at RNA and protein levels in OLP and matched normal controls. In the same samples we also measured levels of p63 isoforms using quantitative RT-PCR. Results showed p53 to be expressed in all OLP lesions and normal tissues. The p53beta and Delta133p53 isoforms were expressed in the majority of samples whereas the remaining three novel isoforms analysed were expressed in only a few samples. Levels of p63 isoforms were lower in OLP lesions compared with normal tissue, however, changes were not statistically significant.

Identifiers
urn:nbn:se:umu:diva-16469 (URN)10.1016/j.oraloncology.2007.01.014 (DOI)17418619 (PubMedID)
Available from: 2008-01-17 Created: 2008-01-17 Last updated: 2011-09-02
3. Decreased expression of the p63 related proteins beta-catenin, E-cadherin and EGFR in oral lichen planus
Open this publication in new window or tab >>Decreased expression of the p63 related proteins beta-catenin, E-cadherin and EGFR in oral lichen planus
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2007 (English)In: Oral Oncology, ISSN 1368-8375, Vol. 44, no 7, 634-638 p.Article in journal (Refereed) Published
Abstract [en]

Oral lichen planus (OLP) is a chronic inflammatory disease and although classified by WHO as a premalignant condition, the risk for transformation into squamous cell carcinoma of the head and neck (SCCHN) is a matter of great controversy. The p63 gene encodes six different proteins which are required for development of ectodermally derived tissues such as oral mucosa, salivary glands, teeth and skin. p63 is highly expressed in SCCHN whereas decreased expression is seen in OLP. beta-catenin, E-cadherin and epidermal growth factor receptor (EGFR) are p63 related proteins, and abnormalities in their expression suggested they are involved in development of squamous cell carcinoma of the head and neck (SCCHN). In this study we mapped the expression of these p63 related proteins in OLP and matched normal healthy controls. Results showed decreased expression of beta-catenin, E-cadherin and EGFR in the vast majority of OLP samples compared with the normal controls. This is the first comprehensive study mapping expression of several p63- and SCCHN-related proteins in tissue from patients with OLP. Results showed a mixed expression pattern with OLP variably resembling normal as well as tumour tissue. Based on our present and previous data it cannot be judged whether OLP lesions are at an increased risk of malignant development.

Keyword
p53, oral lichen planus
National Category
Dentistry
Identifiers
urn:nbn:se:umu:diva-6886 (URN)doi:10.1016/j.oraloncology.2007.08.001 (DOI)17936670 (PubMedID)
Available from: 2008-01-17 Created: 2008-01-17 Last updated: 2011-09-02
4. Detection of antibodies against p63 and p73 isoforms in sera from patients diagnosed with oral lichen planus.
Open this publication in new window or tab >>Detection of antibodies against p63 and p73 isoforms in sera from patients diagnosed with oral lichen planus.
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2007 (English)In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 36, no 2, 93-98 p.Article in journal (Refereed) Published
Abstract [en]

Background: Oral lichen planus (OLP) is a chronic inflammatory disease of oral mucosa. Despite numerous publications and intense research, the etiology of OLP is still unknown, however, autoimmunity as a possible causative factor has been discussed. Methods: In the present study sera from 20 patients clinically and histologically diagnosed with OLP were analyzed for antibodies directed toward p53, p63, and p73 using Western blot. Results: Sera from two patients reacted with all six p63 isoforms, and one also with p73. The strongest reaction was noted against the TAp63beta protein, which is the most potent transactivator of all p63 proteins and is implicated in the differentiation of stratified epithelia. Conclusions: This is the first demonstration of antibodies directed against all p63 and some p73 isoforms in sera from patients diagnosed with OLP.

Keyword
Aged, Aged; 80 and over, Animals, Case-Control Studies, DNA-Binding Proteins/*immunology, Female, Humans, Lichen Planus; Oral/*blood/immunology, Male, Membrane Proteins/immunology, Mice, Middle Aged, Nuclear Proteins/*immunology, Rabbits, Tumor Suppressor Protein p53/*immunology, Tumor Suppressor Proteins/*immunology
Identifiers
urn:nbn:se:umu:diva-16466 (URN)doi:10.1111/j.1600-0714.2007.00504.x (DOI)17238971 (PubMedID)
Available from: 2008-01-17 Created: 2008-01-17 Last updated: 2011-01-25Bibliographically approved

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