title: Indian hedgehog controls proliferation and differentiation in skin tumorigenesis and protects against malignant progression.
abstract: Mutations in the hedgehog pathway drive the formation of tumors in many different organs, including the development of basal cell carcinoma in the skin. However, little is known about the role of epidermal Indian hedgehog (Ihh) in skin physiology. Using mouse genetics, we identified overlapping and distinct functions of Ihh in different models of epidermal tumorigenesis. Epidermal deletion of Ihh resulted in increased formation of benign squamous papilloma. Strikingly, Ihh-deficient mice showed an increase in malignant squamous cell carcinoma and developed lung and lymph node metastases. In a sebaceous gland tumor model, Ihh deficiency inhibited tumor cell differentiation. More mechanistically, IHH stimulated cell proliferation by activating the transcription factor GLI2 in human keratinocytes and human tumors. Thus, our results uncover important functions for Ihh signaling in controlling proliferation, differentiation, malignant progression, and metastasis of epithelial cancer, establishing Ihh as a gatekeeper for controlling the grade of tumor malignancy.
authors.affiliation: Center for Molecular Medicine Cologne CMMC, University of Cologne, 50931 Cologne, Germany.
authors.forename: Parisa
authors.initials: P
authors.lastname: Kakanj
authors.forename: Karen
authors.initials: K
authors.lastname: Reuter
authors.forename: Gilles
authors.initials: G
authors.lastname: Séquaris
authors.forename: Claudia
authors.initials: C
authors.lastname: Wodtke
authors.forename: Peter
authors.initials: P
authors.lastname: Schettina
authors.forename: Daniela
authors.initials: D
authors.lastname: Frances
authors.forename: Christos C
authors.initials: CC
authors.lastname: Zouboulis
authors.forename: Beate
authors.initials: B
authors.lastname: Lanske
authors.forename: Catherin
authors.initials: C
authors.lastname: Niemann
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism / Q000473:pathology*; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D014162:Transfection
chemical_list: D053823:Hedgehog Proteins