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The last tenascin : insights on tenascin-W functions and regulation

Martina, Enrico. The last tenascin : insights on tenascin-W functions and regulation. 2012, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_10081

Abstract

Over the last decade, it became clear that the tumor stroma plays an active role in the process of tumor progression, by interacting with the transformed cells and providing a permissive microenvironment for malignant growth. The tumor microenvironment is a complex system comprised of extracellular matrix and the different cell populations within it. The extracellular matrix that surrounds solid tumors is very different from the healthy counterpart. Various proteins are upregulated in the tumor stroma, among them two members of the tenascin family, tenascin-C and tenascin-W. Similar to tenascin-C, tenascin-W is mainly expressed during development and in the adult its expression is restricted. Tenascin-W has previously been found in the stroma of breast cancer and colon carcinoma. We have extended the range of human solid tumors that express tenascin-W to brain tumor, melanoma, lung and kidney carcinoma, and we show that tenascin-W is not detectable in the corresponding normal tissues. Moreover, we demonstrate that tenascin-W is often localized in close proximity with tumor blood vessels. Our in vitro studies reveal that tenascin-W has an antiadhesive, pro-migratory effect on a variety of cultured cells, in particular endothelial cells. We therefore postulate a pro-angiogenic role for tenascin-W in tumors. Due to its specific expression in solid tumors, we propose tenascin-W as a tumor biomarker.
We also report that tenascin-W is upregulated during osteogenic differentiation of human bone marrow derived mesenchymal stem cells, fitting with its expression during bone development reported in chicken and mice.
In order to shed light on the mechanism of regulation, we studied the human tenascin-W promoter. We found a putative GATA binding site in this promoter that enhances reporter gene activity when deleted or mutated. We used a labeled DNA probe harboring the binding site in pulldown experiments, followed by mass spec identification of the binding proteins. We identified four members of the NuRD repressor complex among the proteins pulled down. The specific binding of the CHD4 core component of the complex to the human tenascin-W promoter was confirmed by chromatin immunoprecipitation. We therefore speculate that the human tenascin-W gene is silenced by NuRD-mediated chromatin remodeling.
Advisors:Chiquet-Ehrismann, Ruth
Committee Members:Christofori, Gerhard and Bentires-Alj, Mohamed
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Division of Biochemistry and Genetics > Tumor Biology (Christofori)
Item Type:Thesis
Thesis no:10081
Bibsysno:Link to catalogue
Number of Pages:101 S.
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:50
Deposited On:16 Oct 2012 13:20

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