Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 Sep 19;19(9):2835.
doi: 10.3390/ijms19092835.

Hedgehog Signaling in Lung Cancer: From Oncogenesis to Cancer Treatment Resistance

Etienne Giroux-Leprieur  1   2 , Adrien Costantini  3   4 , Vivianne W Ding  5 , Biao He  6
Affiliations
Review

Hedgehog Signaling in Lung Cancer: From Oncogenesis to Cancer Treatment Resistance

Etienne Giroux-Leprieur et al. Int J Mol Sci. .

Abstract

Hedgehog signaling pathway is physiologically activated during embryogenesis, especially in lung development. It is also reactivated in many solid tumors. In lung cancer, Hedgehog pathway is closely associated with cancer stem cells (CSCs). Recent works have shown that CSCs produced a full-length Sonic Hedgehog (Shh) protein, with paracrine activity and induction of tumor development. Hedgehog pathway is also involved in tumor drug resistance in lung cancer, as cytotoxic chemotherapy, radiotherapy, and targeted therapies. This review proposes to describe the activation mechanisms of Hedgehog pathway in lung cancer, the clinical implications for overcoming drug resistance, and the perspectives for further research.

Keywords: Epidermal Growth Factor Receptor (EGFR); Sonic Hedgehog; cancer stem cell; chemoresistance; immune checkpoint inhibitor; lung cancer; oncogenesis; radiotherapy; tyrosine kinase inhibitor.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Hedgehog (Hh) pathway activation. At basal state, Ptch inhibits Smo, and Gli proteins are kept in the cytosol par suppressor of fused homolog (SUFU) (A). In canonical Hh pathway activation, Sonic Hedgehog (Shh) binds to Ptch, Smo is activated, leading to translocation of Gli in the nucleus and transcription of target genes. Non-canonical Hh Pathway activation involves Epidermal Growth Factor receptor (EGFR), TGF-β, AKT-PI3K, and TNF-α pathways, with direct activation of Gli without Smo activation (B).
Figure 2
Figure 2
Shh activation in lung cancer and clinical implications. CSCs: cancer stem cells; TKIs: tyrosine kinase inhibitors; ICIs: immune checkpoint inhibitors. (?): not enough supporting evidence.
See this image and copyright information in PMC

References

    1. Ingham P.W., Nakano Y., Seger C. Mechanisms and functions of Hedgehog signalling across the metazoa. Nat. Rev. Genet. 2011;12:393–406. doi: 10.1038/nrg2984. - DOI - PubMed
    1. McMahon A.P., Ingham P.W., Tabin C.J. Developmental roles and clinical significance of hedgehog signaling. Curr. Top. Dev. Biol. 2003;53:1–114. - PubMed
    1. Motoyama J., Liu J., Mo R., Ding Q., Post M., Hui C.C. Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus. Nat. Genet. 1998;20:54–57. doi: 10.1038/1711. - DOI - PubMed
    1. Briscoe J., Thérond P.P. The mechanisms of Hedgehog signalling and its roles in development and disease. Nat. Rev. Mol. Cell Biol. 2013;14:416–429. doi: 10.1038/nrm3598. - DOI - PubMed
    1. Wu F., Zhang Y., Sun B., McMahon A.P., Wang Y. Hedgehog Signaling: From Basic Biology to Cancer Therapy. Cell Chem. Biol. 2017;24:252–280. doi: 10.1016/j.chembiol.2017.02.010. - DOI - PMC - PubMed

Substances