How Bad Is the Hedgehog? GLI-Dependent, Hedgehog-Independent Cancers on the Importance of Biomarkers for Proper Patients Selection.
Hedgehog (HH) signaling plays an important role both during embryonic development and adult life. It is involved in the regulation of cell differentiation, cell proliferation and tissue polarity, as well as in the maintenance of stem cells, tissue repair, and regeneration (Briscoe and Therond, 2013; Jiang and Hui, 2008). Three ligands, Indian, Sonic, and Desert HH, can activate this pathway. Binding of HH ligands to their receptor, PTCH1 (Figure 1) lift its inhibition on SMO, resulting in activation and nuclear translocation of GLI transcription factors (Javelaud et al., 2012). The vertebrate GLI gene family is composed of three distinct genes GLI1, GLI2, and GLI3, encoding Krüppel-like transcription factors. GLI proteins exhibit distinct regulations, biochemical properties, and target genes. GLI3 acts as the main repressor of the pathway in the absence of HH ligands, whereas, in their presence, GLI2 is the main HH effector that drives the expression of GLI1 (Briscoe and Therond, 2013).