What is the role of the patched/hedgehog signaling pathways in the pathogenesis of basal cell carcinoma (BCC)?

Updated: Mar 02, 2020
  • Author: Robert S Bader, MD; Chief Editor: William D James, MD  more...
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Answer

The patched/hedgehog intracellular signaling pathway plays a role in both sporadic BCCs and nevoid BCC syndrome (Gorlin syndrome). This pathway influences differentiation of various tissues during fetal development. After embryogenesis, it continues to function in regulation of cell growth and differentiation. Loss of inhibition of this pathway is associated with human malignancy, including BCC.

The hedgehog gene encodes an extracellular protein that binds to a cell membrane receptor complex to start a cascade of cellular events leading to cell proliferation. Of the 3 known human homologues, sonic hedgehog (SHH) protein is the most relevant to BCC. Patched (PTCH) is a protein that is the ligand-binding component of the hedgehog receptor complex in the cell membrane. The other protein member of the receptor complex, smoothened (SMO), is responsible for transducing hedgehog signaling to downstream genes. [26, 27]

When SHH is present, it binds to PTCH, which then releases and activates SMO. SMO signaling is transduced to the nucleus via Gli. When SHH is absent, PTCH binds to and inhibits SMO. Mutations in the PTCH gene prevent it from binding to SMO, simulating the presence of SHH. The unbound SMO and downstream Gli are constitutively activated, thereby allowing hedgehog signaling to proceed unimpeded. The same pathway may also be activated via mutations in the SMO gene, which also allows unregulated signaling of tumor growth.

How these defects cause tumorigenesis is not fully understood, but most BCCs have abnormalities in either PTCH or SMO genes. Some even consider defects in the hedgehog pathway to be requirements for BCC development.

BCC most commonly develops on sun-exposed areas. Zhang et al reported that ultraviolet (UV)-specific nucleotide changes in PTCH, as well as the tumor suppressor gene TP53, are implicated in the development of early-onset BCC. [28]

UV-induced mutations in the TP53 tumor suppressor gene, which resides on band 17p13.1, have been found in some cases of BCC. [29] A germline single-nucleotide polymorphism (SNP) in the TP53 gene, rs78378222, has also been associated with susceptibility to BCC. [29] In addition, frameshift mutations of the BAX gene (BCL2–associated X protein) have been found in sporadic cases of BCC. A reduction of bcl-2 proteins is observed in the aggressive, infiltrative type of BCC.


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