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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Genet. | doi: 10.3389/fgene.2019.01185

Regulation and role of GLI1 in cSCC pathogenesis

 Heidi Hahn1*,  Joanna Pyczek1,  Natalia Khizanishvili1, Maria Kuzyakova1,  Sebastian Zabel1,  Julia Bauer1, Frauke Nitzki1, Steffen Emmert2,  Michael P. Schön3, Petra Boukamp4, Hans-Ulrich Schildhaus5 and Anja Uhmann1
  • 1Institute of Human Genetics, University Medical Center Göttingen, Germany
  • 2Department of Dermatology and Venerology, University Medical Center Rostock, Germany
  • 3Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, Germany
  • 4German Cancer Research Center (DKFZ), Germany
  • 5Institute of Pathology, University Medical Center Göttingen, Germany

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin tumor in humans. Although current therapies are sufficient to clear the tumor in many cases, the overall risk of cSCC metastasis is still 5 %. Alternative treatment options could help to overcome this situation. Here we focused on the role of the Hedgehog (HH) signaling pathway and its interplay with epidermal growth factor receptor (EGFR) signaling in cSCC. The analyses revealed that, despite lack of sonic HH (SHH) expression, a subset of human cSCC can express GLI1, a marker for active HH signaling, within distinct tumor areas. In contrast, all tumors strongly express EGFR and the hair follicle stem cell marker SOX9 at the highly proliferative tumor-stroma interface, whereas central tumor regions with a more differentiated stratum spinosum cell type lack both EGFR and SOX9 expression. In vitro experiments indicate that activation of EGFR signaling in the human cSCC cell lines SCL-1, MET-1 and MET-4 leads to GLI1 inhibition via the MEK/ERK axis without affecting cellular proliferation. Of note, EGFR activation also inhibits cellular migration of SCL-1 and MET-4 cells. Because proliferation and migration of the cells is also not altered by a GLI1 knockdown, GLI1 is apparently not involved in processes of aggressiveness in established cSCC tumors. In contrast, our data rather suggest a negative correlation between Gli1 expression level and cSCC formation because skin of Ptch+/- mice with slightly elevated Gli1 expression levels is significantly less susceptible to chemically-induced cSCC formation compared to murine wildtype skin. Although not yet formally validated, these data open the possibility that GLI1 (and thus HH signaling) may antagonize cSCC initiation and is not involved in cSCC aggressiveness, at least in a subset of cSCC.

Keywords: Hedgehog (Hh), Hedgehog, cutaneous squamous cell carcinoma, GLI1, EGFR, ERK

Received: 13 Mar 2019; Accepted: 25 Oct 2019.

Copyright: © 2019 Hahn, Pyczek, Khizanishvili, Kuzyakova, Zabel, Bauer, Nitzki, Emmert, Schön, Boukamp, Schildhaus and Uhmann. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Heidi Hahn, Institute of Human Genetics, University Medical Center Göttingen, Goettingen, Germany, hhahn@gwdg.de