Wif1 Inhibits the Growth of Basal Cell Carcinoma

Wif1 Inhibits the Growth of Basal Cell Carcinoma

Becker, Marco

Dissertation

Angenommen am: 2015-09-01

Erschienen: 2015-12-22

Betreuer: Hahn, Heidi Prof. Dr.

Gutachter: Hahn, Heidi Prof. Dr.

Gutachter: Dobbelstein, Matthias Prof. Dr.

Zum Verlinken/Zitieren: http://hdl.handle.net/11858/00-1735-0000-0028-867F-F

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Name: Becker M 2015 Diss fertig jetzt auch mit seitenzahlen.pdf

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Zusammenfassung

Englisch

Basal cell carcinoma (BCC) belongs to the group of non-melanoma skin cancers and is the most commonly diagnosed cancer in fair-skinned individuals. In the majority of BCC the tumor suppressor gene patched1 (PTCH) is mutated resulting in aberrant hedgehog (HH) signaling. Analysis of human and murine BCC shows that the putative tumor suppressor Wnt inhibitory factor 1 (Wif1) is highly expressed by this tumor entity. However, malignant forms of skin cancer, i.e. squamous cell carcinomas and melanomas, also express Wif1. Thus, the objective of this thesis was to analyze the role of Wif1 in BCC by Wif1 overexpression in the BCC cell line ASZ001 and by Wif1 depletion in the BCC mouse model Ptch flox/flox CreERT2 T/-. Indeed, tumor-intrinsic Wif1 overexpression in ASZ001 significantly inhibits tumor growth in nude mice. The Wif1-mediated tumor suppression was not due to diminished vascularization or alterations in canonical Wnt, Hh or PI3K/Akt signaling activity. It also was not due to induction of differentiation or apoptosis. However, we found that Wif1-expressing tumors were characterized by a decrease in Ki67 positive cells which was accompanied by phosphorylation of PKC and Erk1 along with moderately increased deposition of collagens. Vice versa, BCC growth is enhanced in Ptch-knockout mice on a Wif1-deficient background due to an increase in proliferation. Together, the data suggest that Wif1 is both necessary and sufficient to restrict BCC growth and may be one of the factors that are responsible for the very low metastatic potential of this tumor entity.

Keywords: Wnt inhibitory factor 1; Basal Cell Carcinoma; Wif1; BCC; skin cancer; Wif-1