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p63 and potential p63 targets in squamous cell carcinoma of the head and neck
Umeå University, Faculty of Medicine, Medical Biosciences.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Squamous cell carcinoma of the head and neck (SCCHN), the 6th most common cancer worldwide, has a low 5-year survival. Disease as well as treatment often causes patients severe functional and aesthetic problems. In order to improve treatment and diagnosis at earlier stages of tumour development it is important to learn more about the molecular mechanisms behind the disease. p63, an important regulator of epithelial formation, has been suggested to play a role in the development of SCCHN. Six different isoforms of p63 have been found and shown to have various functions. The aim of the studies in this thesis was to learn more about the role of p63 and proteins connected to p63 in SCCHN.

Expression of p63, Cox-2, EGFR, beta-catenin, PP2A and p53 isoforms was mapped in tumours and normal tumour adjacent tissue from patients with SCCHN using western blot or RT-PCR. Results showed no significant difference between tumours and normal tumour adjacent tissue concerning expression of EGFR and beta-catenin. Cox-2 and PP2A showed significantly higher expression in tumours while p63 was more expressed in normal tumour adjacent tissue. However, expression of all these proteins in normal tumour adjacent tissue differed from tissue from disease-free non-smoking individuals. Smoking in itself did not affect expression of these proteins. The p53 isoforms p53, p53beta, p53gamma, ∆133p53, ∆133p53beta and ∆133p53gamma were expressed at RNA level in samples both from tumours and normal tumour adjacent tissue, though most of them at fairly low levels.

The functional properties of the different p63 isoforms have not been fully mapped. By establishing stable cell lines over-expressing the different p63 isoforms we investigated their specific effect on tumour cells from SCCHN. Only the ∆Np63 isoforms could be stably over-expressed, whereas no clones over-expressing TAp63 could be established. Using microarray technique, cell lines stably expressing the ∆Np63 isoforms were studied and CD44, Keratins 4, 6, 14, 19 and Cox-2 were found to be regulated by p63.

In conclusion, the present project adds new data to the field of p63 and SCCHN. For example, we have shown that clinically normal tumour adjacent tissue is altered compared to normal oral mucosa in non tumour patients, and that smoking does not change expression of p63, Cox-2, EGFR, beta-catenin or PP2A in oral mucosa. Novel p53 isoforms are expressed in SCCHN, and even though levels are very low they should not be overlooked. Furthermore, CD44, keratins 4, 6, 14, 19 and Cox-2 were identified as p63 targets in SCCHN.

Place, publisher, year, edition, pages
Umeå: Medicinsk biovetenskap , 2008. , 60 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1148
Keyword [en]
SCCHN, p63, Cox-2, EGFR, β-catenin, PP2A, p53
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-1522ISBN: 978-91-7264-473-1 (print)OAI: oai:DiVA.org:umu-1522DiVA: diva2:141299
Public defence
2008-02-22, Betula, 6M, Umeå Universitet, SE-90185, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2008-02-04 Created: 2008-02-04 Last updated: 2009-03-13Bibliographically approved
List of papers
1. Expression of p63, COX-2, EGFR and beta-catenin in smokers and patients with squamous cell carcinoma of the head and neck reveal variations in non-neoplastic tissue and no obvious changes in smokers.
Open this publication in new window or tab >>Expression of p63, COX-2, EGFR and beta-catenin in smokers and patients with squamous cell carcinoma of the head and neck reveal variations in non-neoplastic tissue and no obvious changes in smokers.
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2005 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 27, no 6, 1661-1667 p.Article in journal (Refereed) Published
Abstract [en]

Squamous cell carcinoma of the head and neck (SCCHN), the 6th most common malignancy in the world, is associated with smoking and has a low 5-year survival rate. Various changes have been described at different stages of SCCHN tumour development, including overexpression of p63, a protein important for development of normal epidermal structures. p63 has been suggested to activate beta-catenin, and nuclear accumulation of beta-catenin is an important event in many cancers. Elevated COX-2 activity and overexpression of EGFR protein has been shown in a variety of human cancers, including SCCHN. An important question for the pathogenesis of SCCHN is when the genetic changes take place during the natural course of the disease, and whether they appear in clinically normal oral mucosa to predispose tumour development. We mapped the expression of p63, COX-2, EGFR, beta-catenin, and PP2A in oral mucosa from smokers/non-smokers and from patients with SCCHN. We also considered if changes occurring in tumours are present in the clinically normal tissue adjacent to the tumour. No direct influence of heavy smoking on the levels of the proteins studied could be seen. Tumours and clinically normal non-neoplastic tissue from SCCHN patients showed increased expression of COX-2 and PP2A. Interestingly, non-neoplastic tissue adjacent to SCCHN also showed increased beta-catenin, although this was not seen in tumours. The data support the notion that pre-existing alterations in clinically normal epithelium exist in patients with SCCHN and could be important for the pathogenesis of the disease and for local recurrences.

Keyword
Adult, Aged, Aged; 80 and over, Blotting; Western, Carcinoma; Squamous Cell/genetics/metabolism/*pathology, Cyclooxygenase 2/genetics/metabolism, DNA-Binding Proteins, Female, Genes; Tumor Suppressor, Head and Neck Neoplasms/genetics/metabolism/*pathology, Humans, Male, Membrane Proteins/genetics/metabolism, Middle Aged, Mouth Mucosa/*metabolism, Phosphoprotein Phosphatase, Phosphoproteins/metabolism, RNA; Messenger/genetics/metabolism, Receptor; Epidermal Growth Factor/metabolism, Reverse Transcriptase Polymerase Chain Reaction, Smoking, Trans-Activators/metabolism, Tumor Markers; Biological/genetics/*metabolism, Tumor Suppressor Proteins, beta Catenin/metabolism
Identifiers
urn:nbn:se:umu:diva-15216 (URN)16273222 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2017-12-14Bibliographically approved
2. Expression of p53 isoforms in squamous cell carcinoma of the head and neck.
Open this publication in new window or tab >>Expression of p53 isoforms in squamous cell carcinoma of the head and neck.
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2007 (English)In: Eur J Cancer, ISSN 0959-8049, Vol. 43, no 3, 617-23 p.Article in journal (Refereed) Published
Keyword
Carcinoma; Squamous Cell/genetics/*metabolism, DNA; Complementary/metabolism, Genes; p53, Head and Neck Neoplasms/genetics/*metabolism, Humans, Immunoblotting/methods, Protein Isoforms, RNA; Messenger/metabolism, RNA; Neoplasm/metabolism, Reverse Transcriptase Polymerase Chain Reaction/methods, Transcription; Genetic, Tumor Suppressor Protein p53/*metabolism
Identifiers
urn:nbn:se:umu:diva-16467 (URN)10.1016/j.ejca.2006.10.019 (DOI)17215121 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2009-03-06Bibliographically approved
3. Elevated expression of p63 causes upregulation of Cox-2 in squamous cell carcinoma of the head and neck
Open this publication in new window or tab >>Elevated expression of p63 causes upregulation of Cox-2 in squamous cell carcinoma of the head and neck
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Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-2934 (URN)
Available from: 2008-02-04 Created: 2008-02-04 Last updated: 2010-01-13Bibliographically approved
4. DeltaNp63 isoforms regulate CD44 and keratins 4, 6, 14 and 19 in squamous cell carcinoma of head and neck.
Open this publication in new window or tab >>DeltaNp63 isoforms regulate CD44 and keratins 4, 6, 14 and 19 in squamous cell carcinoma of head and neck.
2007 (English)In: J Pathol, ISSN 0022-3417, Vol. 213, no 4, 384-91 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-6887 (URN)10.1002/path.2237 (DOI)17935121 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11Bibliographically approved

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