Hedgehog signaling in skin cancers

Abstract

An increasing progress on the role of Hedgehog (Hh) signaling for carcinogenesis has been achieved since the link of Hh pathway to human cancer was firstly established. In particular, the critical role of Hh signaling in the development of Basal cell carcinoma (BCC) has been convincingly demonstrated by genetic mutation analyses, mouse models of BCCs, and successful clinical trials of BCCs using Hh signaling inhibitors. In addition, the Hh pathway activity is also reported to be involved in the pathogenesis of Squamous Cell Carcinoma (SCC), melanoma and Merkel Cell Carcinoma. These findings have significant new paradigm on Hh signaling transduction, its mechanisms in skin cancer and even therapeutic approaches for BCC. In this review, we will summarize the major advances in the understanding of Hh signaling transduction, the roles of Hh signaling in skin cancer development, and the current implications of "mechanism-based" therapeutic strategies.

Figure 1. A simplified model for Hh signaling in mammalian cells

SMO is the key signal transducer of the Hh pathway. A, In the absence of Hh ligands, the PTCH receptor at the base of the primary cilium suppresses the function of SMO by preventing its entry into the cilium. Without SMO activation, Gli proteins are processed with Su(Fu), GSK3β, PKA, and CKI into a repressor form (Gli-R), which disable the Hh signaling pathway. B, In the presence of Hh, it binds to PTCH. The binding can be repressed by HIP and supported by Cdo, Gas1 and Boc. Upon binding, the Hh/PTCH complex becomes internalized in endosomes and later degraded. Without inhibition from PTCH, SMO becomes activated and facilitated Gli activation n (GliA), which stimulates Hh target gene expression.