Hedgehog signaling in tissue homeostasis, cancers, and targeted therapies

Abstract

The past decade has seen significant advances in our understanding of Hedgehog (HH) signaling pathway in various biological events. HH signaling pathway exerts its biological effects through a complex signaling cascade involved with primary cilium. HH signaling pathway has important functions in embryonic development and tissue homeostasis. It plays a central role in the regulation of the proliferation and differentiation of adult stem cells. Importantly, it has become increasingly clear that HH signaling pathway is associated with increased cancer prevalence, malignant progression, poor prognosis and even increased mortality. Understanding the integrative nature of HH signaling pathway has opened up the potential for new therapeutic targets for cancer. A variety of drugs have been developed, including small molecule inhibitors, natural compounds, and long non-coding RNA (LncRNA), some of which are approved for clinical use. This review outlines recent discoveries of HH signaling in tissue homeostasis and cancer and discusses how these advances are paving the way for the development of new biologically based therapies for cancer. Furthermore, we address status quo and limitations of targeted therapies of HH signaling pathway. Insights from this review will help readers understand the function of HH signaling in homeostasis and cancer, as well as opportunities and challenges of therapeutic targets for cancer.

NF-κB in biology and targeted therapy: new insights and translational implications

“…Hedgehog signaling is a highly conserved pathway with important roles in the control of cell proliferation, tissue homeostasis, tumorigenesis, and embryonic development. 170 , 171 Members of the Hedgehog gene family include Sonic Hedgehog (SHh), Indian Hedgehog (IHh), and Desert Hedgehog (DHh), of which SHh has been the most widely and intensively studied. In the resting state, Smoothened (Smo) is inhibited by Hedgehog’s receptor PTCH.…”

“…When Hedgehog binds to PTCH, activated Smo transmits signals through Gli, Sufu, and Kif7, resulting in the generation of the Gli-activated form (GliA), which translocates to the nucleus and leads to transcriptional activation of Hh target genes. 170 , 171 NF-κB signaling plays a pivotal role in the generation of apical ectodermal ridges of limb buds during development, and inhibition of NF-κB in vertebrate limb mesenchyme downregulates the expression of SHh and Twist. 172 In chronically damaged fibrotic livers, Smo suppresses transcriptional expression of miR-378a-3p via p65 activation, which subsequently upregulates the expression level of Gli3.…”

Influence of intersignaling crosstalk on the intracellular localization of YAP/TAZ in lung cells

“…In cultured hepatic stellate cells, activation of the SHH pathway positively regulates YAP, which supports and controls myofibroblastic differentiation in the liver [ 80 ]. In non-small cell lung cancer (NSCLC), cell proliferation is mediated by GLI proteins [ 81 ], in particular, Gli1 knockdown reduces tumor cell proliferation and viability [ 82 ]. However, SHH ligand-independent pathway is activated in NSCLC [ 83 ], so crosstalk might occur between Hippo and non-canonical SHH pathways via GLI1 and YAP-TEAD interactions [ 84 ].…”

Can Plant Extracts Help Prevent Hair Loss or Promote Hair Growth? A Review Comparing Their Therapeutic Efficacies, Phytochemical Components, and Modulatory Targets

“…Hedgehog ligands, including sonic hedgehog (SHH), desert hedgehog (DHH), and Indian hedgehog (IHH), are paracrine signaling factors that mediate cell-to-cell communication [161]. The SHH signaling pathway is involved in regulating hair follicle morphogenesis [162].…”