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Abnormal expression of proteins in Notch and Wnt pathways in human squamous cell carcinoma of the skin
Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background Members of the Notch pathway are involved in various differentiation processes. Signalling via the Wnt/ß-catenin-pathway controls transcription of genes involved in proliferation events. These two pathways are interconnected through the cytoplasmic protein Dishevelled (Dvl-1).

Objectives To evaluate the expression patterns of Notch1, Dvl-1 and ß-catenin proteins in human squamous cell carcinomas of the skin.

Methods 40 formalin-fixed paraffin-embedded SCCs were included in this study. Expression was detected with immunohistochemistry using avidin-biotin and DAB visualization.

Results The majority of the normal epidermal cells lacked expression of Notch1, while the dysplastic and invasive tumour cells showed strong staining. Expression of Dvl-1 was observed in normal human epidermis, with a more intense staining indysplastic cells in 8 of 38 (21%) cases. Besides the expected cytoplasmic staining, 27 of 38 (71%) secs displayed nuclear staining and a potential nuclear localisation signal was identified. ß-catenin showed membranous and weak cytoplasmic staining in normal as well as tumour cells.

Conclusions We have found enhanced expression of Notch1 in the majority of SCCs, indicating a disturbed differentiation process. We have also for the first time showed over-expression of Dvl-1 in dysplastic epidermal cells as well as normal staining of the nucleus. A classical nuclear localization signal is also identified in the Dvl-1 isoform A, whereas two other isoforms lack this recognition sequence.

National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-85100OAI: oai:DiVA.org:liu-85100DiVA: diva2:564575
Available from: 2012-11-02 Created: 2012-11-02 Last updated: 2012-11-02
In thesis
1. Molecular alterations in squamous cell carcinomas of the skin: emphasis on genes on chromosome 9q
Open this publication in new window or tab >>Molecular alterations in squamous cell carcinomas of the skin: emphasis on genes on chromosome 9q
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Skin cancer is the most common type of cancer in the western world. The incidence of melanoma and non-melanoma skin cancer is continuously increasing and, in Sweden, 2300 new cases per year are diagnosed of squamous cell carcinoma (SCC) alone. In this thesis, we have investigated genes and proteins from signal transduction pathways important for tumor development. Special emphasis has been put on chromosomal region 9q22-q31 where frequent loss of heterozygosity has been observed in non-melanoma skin cancers.

Mutation analysis of the PTCH1 and XPA genes, connected to the familial cancer syndromes nevoid basal cell carcinoma syndrome and xeroderma pigmentosum, respectively, was performed. Based on lack of mutation or altered mRNA expression, we conclude that these two genes are not likely to be involved in development of sporadic SCCs. Next, we studied the correlation of the two phenotypes, anchorage independence and tumorigenicity, to the loss of chromosome 9 material in a panel of somatic cell hybrids. By microsatellite analysis, we show that the anchorage independence gene is located distal to the marker D9S155. The mapping of the gene for tumor suppression revealed three commonly deleted regions on chromosome regions 9p23-p22, 9p21-p12 and 9q31-q33. Another two candidates from the 9q22-q31 region, CORO2A and TßR-I, were investigated both at the gene and the protein level. We did not detect any alterations in the TßR-I gene or protein, but CORO2A protein was over-expressed in 4 of 40 (10%) tumors, indicating an involvement in sec carcinogenesis in a subset of tumors. In one healthy individual from the control population, we found a heterozygous germline mutation in CORO2A creating a stop codon, which results in a truncated protein. Thus, one functional allele might be sufficient to sustain a normal cellular function. When investigating occurrence of aberrant protein expression in the interconnected Wnt and Notch pathways, Notch1 was found to be expressed in only 5 of 40 (14%) of the normal epidermal cells, while strong staining was displayed in all the tumors. No altered expression of the most central protein of the Wnt pathway, ß-catenin, was observed, but the up-stream Dvl-1 protein was found to be up-regulated in 8 of 38 (21%) tumors. Dvl-1 was also detected in the nucleus in the majority of normal and tumor cases and a potential nuclear localization signal was identified in the Dvl-1 A isoform.

None of the genes from the chromosomal region 9q22-q31 displayed alterations consistent with those of a tumor suppressor gene. Most likely, this gene remains to be identified.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2004. 78 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 850
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-23974 (URN)3525 (Local ID)91-7373-823-9 (ISBN)3525 (Archive number)3525 (OAI)
Public defence
2004-05-19, Elsa Brändström-salen, Hälsouniversitetet, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-11-02Bibliographically approved

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Eklund, Lena K.Söderkvist, Peter

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