The role of the Hedgehog signaling pathway in cancer: A comprehensive review

Abstract

The Hedgehog (Hh) signaling pathway was first identified in the common fruit fly. It is a highly conserved evolutionary pathway of signal transmission from the cell membrane to the nucleus. The Hh signaling pathway plays an important role in the embryonic development. It exerts its biological effects through a signaling cascade that culminates in a change of balance between activator and repressor forms of glioma-associated oncogene (Gli) transcription factors. The components of the Hh signaling pathway involved in the signaling transfer to the Gli transcription factors include Hedgehog ligands (Sonic Hh [SHh], Indian Hh [IHh], and Desert Hh [DHh]), Patched receptor (Ptch1, Ptch2), Smoothened receptor (Smo), Suppressor of fused homolog (Sufu), kinesin protein Kif7, protein kinase A (PKA), and cyclic adenosine monophosphate (cAMP). The activator form of Gli travels to the nucleus and stimulates the transcription of the target genes by binding to their promoters. The main target genes of the Hh signaling pathway are PTCH1, PTCH2, and GLI1. Deregulation of the Hh signaling pathway is associated with developmental anomalies and cancer, including Gorlin syndrome, and sporadic cancers, such as basal cell carcinoma, medulloblastoma, pancreatic, breast, colon, ovarian, and small-cell lung carcinomas. The aberrant activation of the Hh signaling pathway is caused by mutations in the related genes (ligand-independent signaling) or by the excessive expression of the Hh signaling molecules (ligand-dependent signaling - autocrine or paracrine). Several Hh signaling pathway inhibitors, such as vismodegib and sonidegib, have been developed for cancer treatment. These drugs are regarded as promising cancer therapies, especially for patients with refractory/advanced cancers.

An Unbalanced Chromosome Translocation Between 7p22 and 12q13 Leads to ACTB-GLI1 Fusion in Pericytoma

“…The members of the GLI family are main mediators of the highly conserved Hedgehog signaling pathway, which plays a critical role in embryonic development (17)(18)(19)(20). Aberrant Hedgehog signaling is associated with the development and progression of various types of cancer and is implicated in multiple aspects of tumorigenesis (21)(22)(23)(24)(25)(26)(27). Transcript variant 2 (NM_001160045) lacks the first two coding exons of transcript variant 1, transcription initiation occurs from an internal AUG site, and codes for Nterminally truncated protein isoform 2 (NP_001153517), also known as GLI1DeltaN (32).…”

A Higher Proportion of Craniosynostosis Genes Are Cancer Driver Genes

“…The WNT signaling pathway is associated with craniosynostosis (Timberlake et al, 2016), and is also associated with cancer (Clevers, 2006; Clevers and Nusse, 2012; Zhan et al, 2017). The Hedgehog signaling pathway is discussed in connection to craniosynostosis (Jenkins et al, 2007), and is also associated with cancer (Jiang and Hui, 2008; Skoda et al, 2018).…”

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

“…It targets SMO (smoothened), a transmembrane protein that transduces signals to the cytoplasm upon binding to cholesterol [471][472][473]. The hedgehog pathway facilitates embryonic development [474] but is also activated in cancer where it contributes to cellular proliferation and differentiation ( Figure 4A) [475][476][477]. Hedgehog pathway signaling activates the glioblastoma Gli1/2/3 genes (named so because they were initially identified in glioblastomas [478]) through a complex epistatic pathway of negative regulators [479].…”