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Scientific article
English

Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways

Publication date2007
Abstract

Melanoma is one of the most aggressive cancers, and its incidence is increasing. These tumors derive from the melanocyte lineage and remain incurable after metastasis. Here we report that SONIC HEDGEHOG (SHH)-GLI signaling is active in the matrix of human hair follicles, and that it is required for the normal proliferation of human melanocytes in culture. SHH-GLI signaling also regulates the proliferation and survival of human melanomas: the growth, recurrence, and metastasis of melanoma xenografts in mice are prevented by local or systemic interference of HH-GLI function. Moreover, we show that oncogenic RAS-induced melanomas in transgenic mice express Gli1 and require Hh-Gli signaling in vitro and in vivo. Finally, we provide evidence that endogenous RAS-MEK and AKT signaling regulate the nuclear localization and transcriptional activity of GLI1 in melanoma and other cancer cells. Our data uncover an unsuspected role of HH-GLI signaling in melanocytes and melanomas, demonstrate a role for this pathway in RAS-induced tumors, suggest a general integration of the RAS/AKT and HH-GLI pathways, and open a therapeutic approach for human melanomas.

Keywords
  • Animals
  • COS Cells
  • Cell Proliferation
  • Cells, Cultured
  • Cercopithecus aethiops
  • Fibroblasts/metabolism
  • Foreskin/cytology
  • Gene Expression Regulation, Neoplastic
  • Hedgehog Proteins/ physiology
  • Humans
  • Male
  • Melanocytes/metabolism/physiology
  • Melanoma/genetics/ metabolism/physiopathology
  • Melanoma, Experimental/genetics/metabolism/physiopathology
  • Mice
  • Mice, Nude
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase Kinases/ metabolism
  • Models, Biological
  • Neoplasm Transplantation
  • Proto-Oncogene Proteins c-akt/ metabolism
  • Signal Transduction
  • Transcription Factors/ physiology
  • Transplantation, Heterologous
Citation (ISO format)
STECCA, Barbara et al. Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways. In: Proceedings of the National Academy of Sciences of the United States of America, 2007, vol. 104, n° 14, p. 5895–5900. doi: 10.1073/pnas.0700776104
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ISSN of the journal0027-8424
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