THE HEDGEHOG (HH)/GLIOMA-ASSOCIATED ONCOGENE (GLI) SIGNALING PATHWAY

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The Hedgehog (HH)/glioma-associated oncogene (GLI) cascade is a complex signaling pathway which plays a crucial role in vertebrate embryogenesis by controlling cell fate, proliferation, survival and differentiation (36-38). Three HH homologues have been identified in vertebrates: Sonic Hedgehog (SHH), Desert Hedgehog (DHH) and Indian Hedgehog (IHH). These three ligands initiate HH signaling through the binding to transmembrane protein receptors named Patched (PTCH 1/2) which are located at the base of a non-motile structure protruding from the cell surface called “primary cilium” (36-38). While in the absence of the HH ligand, PTCH1 receptor represses signal transduction by inhibiting the transmembrane protein Smoothened (SMO) to enter the cilium, upon ligand binding the inhibitory function of PTCH1 receptor on SMO is abolished, resulting in SMO activation. SMO enters the cilium and promotes the activation of cytoplasmic GLIs and their translocation to the nucleus, where they initiate transcription of HH target gene products (36,37). Three GLI proteins are involved in this signaling: GLI1 and GLI2 have activating effects, while GLI3 antagonizes the function of SHH–GLI1 (36-38). Among the negative modulators of HH signaling pathway, the suppressor of fused (SUFU) protein can bind and maintain GLI proteins in the cytoplasm in the absence of HH ligands thus preventing their nuclear translocation (37). The HH signaling has an important role along with other signaling pathways such as those mediated by ErbB receptors (8,9) and Wnt/β-catenin (39) in regulating embryonic development, differentiation and cell survival (36).

Aberrant HH signaling, which can be achieved by mutational inactivation of PTCH, aberrant expression of its ligand, constitutive activation of SMO or gene amplification of the GLI transcription factors, has been implicated in initiation and/or maintenance of different cancer types including basal cell carcinoma (BCC), gastrointestinal, lung, brain tumors and rhabdomyosarcoma (36-38). In addition, there is evidence that dysregulation of HH signaling can be involved in development and progression of breast cancer (38,40). Indeed, the expression of SHH was found to be upregulated in early stage breast carcinoma, indicating that the upregulation of SHH may be an early event in breast carcinogenesis (41). HH signaling can be blocked at many levels by a variety of small molecules that target different members of its pathway. To date, several antagonists of SMO have entered clinical trials (42). A schematic representation of the HH-GLI signaling pathway is illustrated in Figure 1, panel C.