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Title
Synergistic crosstalk of hedgehog and interleukin6 signaling drives growth of basal cell carcinoma
AuthorSternberg, Christina ; Gruber, Wolfgang ; Eberl, Markus ; Tesanovic, Suzana ; Stadler, Manuela ; Elmer, Dominik P. ; Schlederer, Michaela ; Grund, Sandra ; Roos, Simone ; Wolff, Florian ; Kaur, Supreet ; Mangelberger, Doris ; Lehrach, Hans ; Hache, Hendrik ; Wierling, Christoph ; Laimer, Josef ; Lackner, Peter ; Wiederstein, Markus ; Kasper, Maria ; Risch, Angela ; Petzelbauer, Peter ; Moriggl, Richard ; Kenner, Lukas ; Aberger, Fritz
Published in
International Journal of Cancer, Hoboken, 2018, Vol. 143, page 2943-2954
PublishedHoboken : Wiley, 2018
LanguageEnglish
Document typeJournal Article
Keywords (EN)basal cell carcinoma / GLI transcription factors / hedgehog / GLI signaling / interleukin6 signaling / STAT transcription factors
ISSN1097-0215
URNurn:nbn:at:at-ubs:3-10276 Persistent Identifier (URN)
DOI10.1002/ijc.31724 
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 The work is publicly available
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Synergistic crosstalk of hedgehog and interleukin6 signaling drives growth of basal cell carcinoma [3.61 mb]
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Abstract (English)

Persistent activation of hedgehog (HH)/GLI signaling accounts for the development of basal cell carcinoma (BCC), a very frequent nonmelanoma skin cancer with rising incidence. Targeting HH/GLI signaling by approved pathway inhibitors can provide significant therapeutic benefit to BCC patients. However, limited response rates, development of drug resistance, and severe side effects of HH pathway inhibitors call for improved treatment strategies such as rational combination therapies simultaneously inhibiting HH/GLI and cooperative signals promoting the oncogenic activity of HH/GLI. In this study, we identified the interleukin6 (IL6) pathway as a novel synergistic signal promoting oncogenic HH/GLI via STAT3 activation. Mechanistically, we provide evidence that signal integration of IL6 and HH/GLI occurs at the level of cisregulatory sequences by cobinding of GLI and STAT3 to common HHIL6 target gene promoters. Genetic inactivation of Il6 signaling in a mouse model of BCC significantly reduced in vivo tumor growth by interfering with HH/GLIdriven BCC proliferation. Our genetic and pharmacologic data suggest that combinatorial HHIL6 pathway blockade is a promising approach to efficiently arrest cancer growth in BCC patients.

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CC-BY-License (4.0)Creative Commons Attribution 4.0 International License