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The Role of Smoothened-Dependent and -Independent Hedgehog Signaling Pathway in Tumorigenesis.

ABSTRACT: The Hedgehog (Hh)-glioma-associated oncogene homolog (GLI) signaling pathway is highly conserved among mammals, with crucial roles in regulating embryonic development as well as in cancer initiation and progression. The GLI transcription factors (GLI1, GLI2, and GLI3) are effectors of the Hh pathway and are regulated via Smoothened (SMO)-dependent and SMO-independent mechanisms. The SMO-dependent route involves the common Hh-PTCH-SMO axis, and mutations or transcriptional and epigenetic dysregulation at these levels lead to the constitutive activation of GLI transcription factors. Conversely, the SMO-independent route involves the SMO bypass regulation of GLI transcription factors by external signaling pathways and their interacting proteins or by epigenetic and transcriptional regulation of GLI transcription factors expression. Both routes of GLI activation, when dysregulated, have been heavily implicated in tumorigenesis of many known cancers, making them important targets for cancer treatment. Hence, this review describes the various SMO-dependent and SMO-independent routes of GLI regulation in the tumorigenesis of multiple cancers in order to provide a holistic view of the paradigms of hedgehog signaling networks involving GLI regulation. An in-depth understanding of the complex interplay between GLI and various signaling elements could help inspire new therapeutic breakthroughs for the treatment of Hh-GLI-dependent cancers in the future. Lastly, we have presented an up-to-date summary of the latest findings concerning the use of Hh inhibitors in clinical developmental studies and discussed the challenges, perspectives, and possible directions regarding the use of SMO/GLI inhibitors in clinical settings.

SUBMITTER: Chai JY

PROVIDER: S-EPMC8466551 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Hedgehog proteins are pivotal morphogens acting through a canonical pathway involving first activation of ligand binding to Patched followed by alleviation of Smoothened receptor inhibition, leading to activation of Gli transcription factors. Noncanonical Hedgehog signaling remains poorly characterized but is thought to be mainly dependent on Smoothened. However, Smoothened inhibitors have yielded only partial success in combating Hedgehog signal transduction-dependent cancer, suggesting that noncanonical Smoothened-independent pathways also are clinically relevant. Moreover, several Smoothened-dependent effects (e.g. neurite projection) do not require transcriptional activation, further suggesting biological importance of noncanonical Smoothened-dependent pathways. We comprehensively characterized the cellular kinome in Hedgehog-challenged murine WT and Smoothened-/- fibroblasts as well as Smoothened agonist-stimulated cells. A peptide assay-based kinome analysis (in which cell lysates are used to phosphorylate specific kinase substrates), along with endocytosis, Lucifer Yellow-based, and immunoblotting assays, identified an elaborate signaling network of both Smoothened-dependent and -independent pathways that mediates actin reorganization through Src-like kinases, activates various proinflammatory signaling cascades, and concomitantly stimulates Wnt and Notch signaling while suppressing bone morphogenetic protein (BMP) signaling. The contribution of noncanonical Smoothened-independent signaling to the overall effects of Hedgehog on cellular physiology appears to be much larger than previously envisioned and may explain the transcriptionally independent effects of Hedgehog signaling on cytoskeleton. The observation that Patched-dependent, Smoothened-independent, noncanonical Hedgehog signaling increases Wnt/Notch signaling provides a possible explanation for the failure of Smoothened antagonists in combating Hedgehog-dependent but Smoothened inhibitor-resistant cancer. Our findings suggest that inhibiting Hedgehog-Patched interaction could result in more effective therapies as compared with conventional Smoothened-directed therapies.

Project description:Sonic Hedgehog (Shh) signaling induces neovascularization and angiogenesis. It is not known whether the hedgehog signaling pathway in endothelial cells is essential to angiogenesis. Smoothened (Smo) transduces hedgehog signaling across the cell membrane. This study assessed whether endothelial Smoothened-dependent Shh signaling is required for Shh-mediated angiogenesis and ischemic tissue repair. Endothelial-specific smoothened knockout mice, eSmoNull were created using Cre-lox recombination system. eSmoNull mice had no observable phenotype at baseline and showed normal cardiac function. Smoothened in CD31+ cells isolated from eSmoNull hearts was significantly reduced compared to CD31+ cells from eSmoWT littermate control hearts. Fluorescence immunostaining of eSmoNull heart sections showed Smo expression in endothelial cells was abolished. The hind-limb ischemia (HLI) model was used to assess the response to ischemic injury. Perfusion ratio, limb motor function, and limb necrosis were not significantly different after HLI between eSmoNull mice and eSmoWT. Capillary densities in the ischemic limb in eSmoNull mice were also similar to eSmoWT at 4 weeks after HLI. Next, response to exogenous Shh was assessed in the corneal angiogenesis model. There was no significant difference in corneal angiogenesis induced by administration of Shh pellets between eSmoWT and eSmoNull mice. Furthermore, in vitro experiments demonstrated that direct Shh had limited effects on endothelial cell proliferation and migration. However, conditioned media from Shh-treated fibroblasts had a more potent effect on endothelial cell proliferation and migration than non-treated conditioned media. Furthermore, Shh treatment of fibroblasts dramatically stimulated angiogenic growth factor expression, including PDGF-B, VEGF-A, HGF and IGF. PDGF-B was the most upregulated and may contribute to the large neo-vessels associated with Shh-induced angiogenesis. Taken together, these data demonstrate that Shh signaling via Smoothened in endothelial cells is not required for angiogenesis and ischemic tissue repair. Shh signaling via stromal cells likely mediates its angiogenic effects.

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The Role of Smoothened-Dependent and -Independent Hedgehog Signaling Pathway in Tumorigenesis.

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