Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

Activation of sonic hedgehog signaling pathway is an independent potential prognosis predictor in human hepatocellular carcinoma patients

“…The HH gene family, which codes a much more sophisticated set of secreted proteins, was first identified (3,30,31). SHH is active only in stem cells and/or endodermal progenitor in adults (16,23).…”

“…SHH is active only in stem cells and/or endodermal progenitor in adults (16,23). Recent studies showed that aberrant signaling of this pathway is involved in a variety of human cancers (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). The HH pathway essentially consists of PTCH, the motive protein, SMOH, and the transcriptional factors GLI2 and GLI3.…”

Cilia have high cAMP levels that are inhibited by Sonic Hedgehog-regulated calcium dynamics

“…Remarkably, SHH regulation of ciliary cAMP and downstream signals is not dependent on inhibitory G protein (Gα i/o ) signaling but rather Ca 2+ entry through a Gd 3+ -sensitive channel. Therefore, PIP 3 sustains high basal cAMP that maintains PKA activity in cilia and Gli repression. SHH activates Gli by inhibiting cAMP through a G protein-independent mechanism that requires extracellular Ca 2+ entry.…”

“…Primary cilia are essential for Hedgehog (HH) signaling, which is important during development and is misregulated in some cancers (2,3). In HH signaling, there is a basal or Sonic Hedgehog (SHH)-off state during which cAMP-dependent protein kinase A (PKA) phosphorylates Gli proteins, which are then cleaved to the transcriptional repressor form (4).…”

“…cAMP | cilia | PKA | Hedgehog | PIP 3 P rimary cilia are immotile organelles composed of specialized structural and signaling proteins (1). Primary cilia are essential for Hedgehog (HH) signaling, which is important during development and is misregulated in some cancers (2,3).…”