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Hedgehog signaling and the Gli code in stem cells, cancer, and metastases

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Published in Science Signaling. 2011, vol. 4, no. 200, p. pt9
Abstract The Hedgehog (Hh)-Gli signaling pathway is an essential pathway involved in development and cancer. It controls the Gli code-the sum of all activator and repressor functions of the Gli transcription factors. Through the Gli code, and Gli1 in particular, it modulates the fate and behavior of stem and cancer stem cells, as well as tumor growth and survival in many human cancer types. It also affects recurrence and metastasis and is enhanced in advanced tumors, where it promotes an embryonic stem (ES) cell-like gene expression signature. A central component of this signature, Nanog, is critical for glioblastoma and cancer stem cell survival and expansion. Gli1 activity is also enhanced by several oncogenic proteins, including Ras, Myc, and Akt, and by loss of tumor suppressors, such as p53 and PTEN. The oncogenic load boosts Gli1 levels, which supports tumor progression, and promotes a critical threshold of Gli1 activity that allows cells to enter the metastatic transition. In colon cancers, this transition is defined by enhanced Hh-Gli and, surprisingly, by repressed Wnt-Tcf signaling. Together our data support a model in which the Gli code, and Gli1 in particular, acts as a key sensor that responds to both Hh signals and the oncogenic load. We hypothesize that, in turn, the Gli-regulated ES-like factors induce a reprogramming event in cancer stem cells that promotes high invasion, growth and/or metastasis. Targeting the Gli code, the autoregulatory Gli1-Nanog module and interacting partners and pathways thus offers new therapeutic possibilities.
Keywords AnimalsColonic Neoplasms/genetics/metabolism/pathology/therapyEmbryonic Stem Cells/metabolism/pathologyGene Expression Regulation, NeoplasticHedgehog Proteins/genetics/metabolismHomeodomain Proteins/genetics/metabolismHumansNeoplasm InvasivenessNeoplasm MetastasisNeoplastic Stem Cells/metabolism/pathologyOncogene Protein p21(ras)/genetics/metabolismPTEN Phosphohydrolase/genetics/metabolismProto-Oncogene Proteins c-akt/genetics/metabolismProto-Oncogene Proteins c-myc/genetics/metabolismTranscription Factors/genetics/metabolismTumor Suppressor Protein p53/genetics/metabolismWnt Signaling Pathway
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PMID: 22114144
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Article (Published version) (273 Kb) - document accessible for UNIGE members only Limited access to UNIGE
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Research group Stemness dans le développement et les maladies: Signalisation, reprogrammation et mécanismes des métastases (776)
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RUIZ ALTABA, Ariel. Hedgehog signaling and the Gli code in stem cells, cancer, and metastases. In: Science Signaling, 2011, vol. 4, n° 200, p. pt9. https://archive-ouverte.unige.ch/unige:30426

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Deposited on : 2013-10-16

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