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Title

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

Authors
Stecca, Barbara
Correa, Rafael
Beermann, Friedrich
Published in Proceedings of the National Academy of Sciences. 2007, vol. 104, no. 14, p. 5895-5900
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 AnimalsCOS CellsCell ProliferationCells, CulturedCercopithecus aethiopsFibroblasts/metabolismForeskin/cytologyGene Expression Regulation, NeoplasticHedgehog Proteins/ physiologyHumansMaleMelanocytes/metabolism/physiologyMelanoma/genetics/ metabolism/physiopathologyMelanoma, Experimental/genetics/metabolism/physiopathologyMiceMice, NudeMice, TransgenicMitogen-Activated Protein Kinase Kinases/ metabolismModels, BiologicalNeoplasm TransplantationProto-Oncogene Proteins c-akt/ metabolismSignal TransductionTranscription Factors/ physiologyTransplantation, Heterologous
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PMID: 17392427
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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, 2007, vol. 104, n° 14, p. 5895-5900. https://archive-ouverte.unige.ch/unige:9038

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Deposited on : 2010-07-12

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