Brennan-Crispi, DM, Overmiller, AM, Tamayo-Orrego, L et al. (11 more authors) (2019) Overexpression of Desmoglein 2 in a mouse model of Gorlin syndrome enhances spontaneous basal cell carcinoma formation through STAT3-mediated Gli1 expression. Journal of Investigative Dermatology, 139 (2). pp. 300-307. ISSN 0022-202X
Abstract
Activation of the Hedgehog (Hh) pathway is causative of virtually all sporadic and Gorlin syndrome-related basal cell carcinomas (BCC), with loss of function of Patched1 (Ptc1) being the most common genomic lesion. Sporadic BCCs also overexpress desmoglein-2 (Dsg2), a desmosomal cadherin normally found in the basal layer. Using a mouse model of Gorlin syndrome (Ptc1+/lacZ mice), we found that overexpressing Dsg2 in the basal layer (K14-Dsg2/Ptc1+/lacZ) or the superficial epidermis (Inv-Dsg2/Ptc1+/lacZ mice) resulted in increased spontaneous BCC formation at 3 and 6 months, respectively. The tumors did not show loss of heterozygosity of Ptc1, despite high levels of Gli1 and phosphorylated Stat3. A panel of sporadic human BCCs showed increased staining of both Dsg2 and P-Stat3 in 9/9 samples. Overexpression of Dsg2 in ASZ001 cells, a Ptc1-/- BCC cell line, induced Stat3 phosphorylation and further increased Gli1 levels, both in an autocrine and paracrine manner. Three different Stat3 inhibitors reduced viability and Gli1 expression in ASZ001 cells, but not in HaCaT cells. Conversely, stimulation of Stat3 in ASZ001 cells with IL-6 increased Gli1 expression. Our results indicate that Dsg2 enhances canonical Hh signaling downstream of Ptc1 to promote BCC development through the activation of P-Stat3 and regulation of Gli1 expression.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2018 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology. This is an author produced version of a paper published in Journal of Investigative Dermatology. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | basal cell carcinoma; hedgehog; stat3; desmoglein; signalling |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Experimental Oncology (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cancer and Pathology (LICAP) > Section of Experimental Oncology (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 19 Sep 2018 10:43 |
Last Modified: | 03 Oct 2019 00:38 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.jid.2018.09.009 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:135900 |